key: cord-266974-yrc5qnmr authors: akbulut, nurcan; limaro, naomi; wandschneider, lisa; dhonkal, rhanjeet; davidovitch, nadav; middleton, john; razum, oliver title: aspher statement on racism and health: racism and discrimination obstruct public health’s pursuit of health equity date: 2020-07-18 journal: int j public health doi: 10.1007/s00038-020-01442-y sha: doc_id: 266974 cord_uid: yrc5qnmr nan the covid-19 pandemic has unmasked structural racial inequalities. association of schools of public health in the european region (aspher) member schools need to act against racism now. the covid-19 public health crisis has elicited strong public health system responses. but the pandemic has also uncovered profound and neglected structural inequalities and injustices in our societies. these structural inequalities developed through enduring discrimination against ethnic, cultural and other minority groups. they became apparent in several ways over the last 6 months. • people of asian descent experienced discrimination in public spaces in reaction to the pandemic presumably having originated in china (devakumar et al. 2020a ). • ethnic/racial minority groups in europe are more adversely affected by the covid-19 pandemic compared to most white people. in the uk, black people are four times more likely to die from covid-19 than white people, even after controlling for socio-economic disadvantage (platt and warwick 2020) . • ethnic/racial minority groups in europe often live in crowded conditions, especially so when they are refugees. under such circumstances, physical distancing is a privilege that they cannot afford (bozorgmehr et al. 2020 ). • ethnic/racial minority groups in europe often live in poor social conditions with precarious forms of employment, so they suffer most from the adverse socio-economic consequences of the pandemic. at the same time, they lack equal access to health care as well as social protection, putting them at greater risk of adverse health outcomes. • ethnic/racial minority groups in europe are also often in occupations which have key functions in the pandemic. examples are health and social care, transport, delivery services, food supply and security roles. workers in these fields have been particularly vulnerable to infection (devakumar et al. 2020a ). in summary, the pandemic has not only caused a global public health crisis; it has also increased and accentuated longstanding structural social inequalities and ethnic/racial discrimination (devakumar et al. 2020b) . the amalgamation of different forms of inequalities resulting from racism and socio-economic disadvantages signals an urgent need to protect the health of vulnerable groups. on the one hand, social inequalities which the pandemic reinforces need to be tackled; on the other hand, inappropriate government policy responses to it must be addressed. a striking current instance of this fact is provided in the failure of the european union and its member states to evacuate migrants and refugees from the camps on greek islands to enable living circumstances that allow physical distancing and provide safe spaces (veizis 2020) . apart from the uk rapid review, there is as yet little work addressing the differential ethnic/racial impact of the pandemic or of social countermeasures taken, of diminished health and social care and of economic disruption. aspher, as europe's representative organization for schools of public health, accordingly has issued its first statement on covid-19 impact on health inequalities and vulnerable populations on 2 june 2020 (aspher 2020). in addition, aspher will pursue health equity by fighting systemic racism and discrimination. 1. we will continue to call upon all public health organizations and governments in all countries to strengthen the protection of the health of vulnerable groups. we also call for urgent and decisive action to minimize the social impact of the covid-19 pandemic on socially and economically marginalized minorities. 2. racism has a considerable impact on health inequalities. we therefore call on public health scientists to routinely include racism as a fundamental social determinant of health in all research and to strengthen cross-disciplinary collaboration on issues related to racism and health. 3. we need to rigorously name and scrutinize such systemic disadvantages for what they are, i.e. structural racism (hardeman et al. 2018 ). it is a task for society to put an end to systemic racism and structural inequalities through civic engagement, critical awareness, education, equal opportunities in life, political integrity and scientific evidence. in addition, we must hold politicians accountable for their actions, including their handling of information and media. 4. we advocate for communities and governments to embrace comprehensive public health strategies for addressing all causes of violence in our cities and places. preventive models addressing communities as a whole have to be implemented to address violence and inequalities. these must include significant partnership working and retraining of all statutory workers including those with regulatory powers and workforces, including police, prisons and places of detention. 5. aspher member schools of public health should be role models for eliminating all forms of racism, discrimination, inequality and disadvantage. 6. we reassert our commitment to health as a fundamental human right, to equality and fairness, to respect for all people worldwide, to solidarity with oppressed people and to protecting and improving the health of all the people we serve. member schools should review systematically their curricula and teaching with respect to racism, discrimination and inequalities in health and in public health interventions to reduce inequalities and improve health more fairly. 7. we also call on schools of public health to critically address their own policies with regard to racism and discrimination-as employers, and in their recruitment of staff and students; as landowners and procurers of goods and services, and in their policies towards acceptance of grants and donations. 8. we call on all our schools of public health to work within their academic institutions to audit, review and develop policies and programmes to address and eliminate racism. racism and discrimination are public health issues, globally and in europe. they are contributing factors to the covid-19 crisis. as public health researchers and practitioners, we must be aware of this. we need to take the necessary actions to address racism and discrimination in order to attain health equity. acknowledgements open access funding provided by projekt deal. conflict of interest the authors declare that they have no conflict of interest. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/. covid-19-how and why is the pandemic exacerbating and amplifying health inequalities and vulnerabilities in europe? aspher sars-cov-2 in aufnahmeeinrichtungen und gemeinschaftsunterkünften für geflüchtete: epidemiologische und normativ-rechtliche aspekte abubakar i (2020a) racism and discrimination in covid-19 responses racism, the public health crisis we can no longer ignore naming institutionalized racism in the public health literature: a systematic literature review are some ethnic groups more vulnerable to covid-19 than others? the institute for fiscal studies leave no one behind'' and access to protection in the greek islands in the covid-19 era key: cord-103337-a1yidr4y authors: aleta, a.; moreno, y. title: age differential analysis of covid-19 second wave in europe reveals highest incidence among young adults date: 2020-11-13 journal: nan doi: 10.1101/2020.11.11.20230177 sha: doc_id: 103337 cord_uid: a1yidr4y most of the western nations have been unable to suppress the covid-19 and are currently experiencing second or third surges of the pandemic. here, we analyze data of incidence by age groups in 25 european countries, revealing that the highest incidence of the current second wave is observed for the group comprising young adults (aged 18-29 years old) in all but 3 of the countries analyzed. we discuss the public health implications of our findings. europe is experiencing a second wave of the covid-19 pandemic, with incidence levels rising across all european countries. authorities have already begun to enforce non-pharmaceutical interventions (npis) to avoid the collapse of the healthcare system, which will likely induce further drops in the estimated 2020 gross domestic product due to additional slowdowns of the economy in many sectors. whether we are able to tailor our response to this second wave in such a way that npis minimize social impact and economical losses is key for the future of europe and its rapid recovery after the pandemic is brought under full control. this fundamentally depends on understanding better how the current surge of covid-19 is unfolding and affecting the different strata of the population, which will eventually make it possible to adapt public policy responses and implement targeted measures on the fly. to understand the evolution of the ongoing wave, one should trace it back to its origin in the summer, when the incidence started to grow again after the effects of the strict restrictions that were imposed in the spring faded out, which resulted in an increased number of local outbreaks and community transmission of covid-19 in most of europe. for instance, it has been reported that a variant of sars-cov-2 emerged in early summer 2020 in spain and spread to multiple european countries since then [1] . the source of the outbreak that spain experienced in the summer can be related to outbreaks that started among agricultural workers in the north-east of the country -particularly in aragon and catalonia. these outbreaks then moved to the local population and replicated through the rest of the country. an analysis of the incidence by age group in one of these regions -aragon, see figure 1 -shows that in early summer the disease spread mainly within the 15-24 and 25-34 age groups. however, coinciding with the end of the summer and the start of the academic year, the disease spread mostly in the 15-24 age group. to elucidate if this pattern is characteristic of this region or if it is more general, we have collected data on the covid19 incidence in 25 european countries aggregated by age groups during the period from 1 september to 27 october. figure 2 shows the fraction of new cases in a given age bracket relative to the population of that age group. the horizontal line represents the situation in which the disease propagates homogeneously through the different age strata. several features of the data are worth highlighting. first, in all countries but three (czechia, romania, and slovenia), the maximum ratio of accumulated incidence in the period analyzed corresponds to the age bracket of young adults -mainly between 18-29 years old. secondly, the incidence curves are not markedly peaked for the elderly as it happened in march-april during the first wave [2, 3] . third, the overall ratio of infected to population size of a given age group is below one for children in all countries. these very robust and regular patterns of the incidence of the current second wave are a remarkable observation given that countries in europe responded distinctly and at different times during the early stages of the pandemic. the fact that the age-differential incidence is common to most countries in europe points to common causes and similar transmission routes. noticeably, a similar pattern has also been observed in the united states [4] . a . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; figure 2 : total number of new cases since 1 september to 27 october in each age bracket, divided by the size of the group. in red, the age bracket with the largest deviation from 1. several hypotheses could be advanced as most likely explanations for the striking regularity in age differential patterns across european countries. the higher incidence in young adults could result from interventions such as reopening of universities and other educational centers across europe [5] . nonetheless, it could also be rooted in behavioral factors associated with this age group [6] , rather than from demographic or cultural causes specific to each european country or to differences in public interventions. these behavioral determinants could be the perception of low risk in this group and youngers' social mixing and lifestyle -this is arguably the age group with the largest mobility and contact heterogeneity. the latter hypothesis is also consistent with the observation that the high incidence in younger people does not propagate to other age groups. from a public health perspective, these data could prove fundamental to understand which factors impact the evolution of the current surge of covid-19 and to adapt our response to the present unfolding of the covid-19 pandemic. first, more efforts should be devoted to communicating with young adults to induce a change that reduces the incidence among them. reporting data of incidence by age group to the general public could help to raise scienceswitzerland . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; rooted awareness among the targeted age group. secondly and important for the current debate regarding the role of schools, children seem to be infected less often than what would be expected if the transmission of sars-cov-2 would be homogeneously distributed across age groups. this points to the success of policies aimed at protecting this group [7, 8] . we note that it is also possible that the observed pattern for the children is either because they could be less susceptible to be infected or that they might be less likely to be tested as they are mostly asymptomatic. data however seems to indicate that the main reason is the former rather than the latter. admittedly, if a large fraction of children were transmitting the disease, a surge in the age groups of their parents -those in close contact with them-should be expected, which is not a feature of the data in most countries. likewise, the results suggest that schools for under 16-18 years old could remain unsheltered given that the benefits of keeping them open seem to overcome the social cost of a closure [9, 10] . these results could help understand what are the main drivers of the second wave and to better design and adapt public health interventions during this stage of the pandemic. furthermore, the previous findings highlight the need for more research in relation to tracing and identification of transmission chains, which will disambiguate what are the sources of contagion by age-strata. we also urge authorities to make available as much epidemiological data by age, sex, and other traits as possible to enable analyses like the one discussed here. funding: aa and ym acknowledge partial support from intesa sanpaolo innovation center. ym acknowledges partial support from the government of aragon and feder funds, spain through grant e36-20r (fenol) and 17030/5423/440189/91019, and by mineco and feder funds (fis2017-87519-p). the funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; https://doi.org/10.1101/2020.11.11.20230177 doi: medrxiv preprint emergence and spread of a sars-cov-2 variant through europe in the summer of covid-19 cases and case fatality rate by age -knowledge for policy european commission the changing demographics of covid-19 recent increase in covid-19 cases reported among adults european commission/eacea/eurydice, 2020. the organisation of the academic year in europe -2020/21. eurydice facts and figures risk attitudes across the life course surveillance of covid-19 school outbreaks no evidence of secondary transmission of covid-19 from children attending school in ireland impact of school closures for covid-19 on the us healthcare workforce and net mortality: a modelling study covid-19, school closures, and child poverty: a social crisis in the making key: cord-277833-x81ni7m5 authors: stienen, martin n. title: covid-19 in europe: le roi est mort, vive le roi! date: 2020-05-18 journal: neurospine doi: 10.14245/ns.2040202.105 sha: doc_id: 277833 cord_uid: x81ni7m5 nan covid-19 in europe: le roi est mort, vive le roi! there's no doubt about it. we europeans were astonished to see how such a small (120 nm) corona virus could spread so quickly around the world, has since brought the global economy to its knees and dominates all areas of life. when the first reports from distant wuhan, china appeared on the evening news, many of us thought that the epidemic would likely remain local or at least regional, controlled by the chinese government's large-scale containment measures. despite a long history of bacterial & viral pandemics in europe (e.g., plague "black death" 1347-1351, influenza "flu pandemic" 1889-1890 & "spanish flu" 1918-1919, hiv/aids pandemic 1981-today), 1-3 the impact of the viral epidemics in the last decades on us has been moderate -avian flu h5n1, swine flu h1n1, ebola epidemic, to name but a few... in contrary, the "coronavirus disease 2019" (covid-19) was increasingly diagnosed -at a staggering rate -in europe, especially in spain, italy, germany, united kingdom, france among other countries. on 30 january 2020 the world health organization declared the outbreak to be a public health emergency of international concern, and recognized it as a pandemic on 11 march 2020. 4, 5 in the past couple of weeks, the covid-19 crisis with its near 2.5 million confirmed cases (170,000 casualties) has fundamentally impacted our practice as spine surgeons worldwide, as it has exerted a significant effect on us as human beings. i work as neurosurgeon at the university hospital zurich, switzerland. 6 fortunately, switzerland was not among the first european countries to be affected, which allowed protective measures to be implemented before the pandemic could strike the country too badly. as of now (21 april, 2020) the country has 27,673 confirmed cases of covid-19, of which 1,429 succumbed (5.2%). the situation in zurich is even more manageable: there are 3,728 confirmed cases of covid-19, of which 90 died (2.4%). intensive care and ventilation units have been expanded, but their capacities are still not fully utilized. with the exception of the canton of ticino and some regions of the romandy (e.g., geneva), swiss hospitals and public health care were not pushed to the limits. the situation in switzerland might be generalized to whole of europe, where most regions were able to control the situation fairly well and the regions that decompensated under a wave of high caseloads were -fortunately -but few. in my role as a spine surgeon, i reduced my professional activities in accordance with national and institutional guidelines -the reasons and necessity for this are described well in the editorial by jain and wang. 7 despite the recommendations of professional societies, 8 i have experienced difficulties to decide from case to case which patient should be postponed or declared an emergency and be operated on in times of limited resources -mostly with the intention to avoid unbearable suffering or permanent neurological damage (fig. 1 ). many patients are eagerly awaiting a surgical procedure, but in many countries, it is unclear yet when we will be allowed to resume elective surgery. fortunately, i have experienced a high level of understanding and acceptance of these regulations by patients and their relatives. most spine surgeons in the public sector in europe are employed by hospitals -on more or less fixed salary -without major economic pressure to operate and with the comfortable protection of high social security standards for a system-relevant profession. this makes it easier for us to accept novel "home office" concepts, shifting away from the manual act of surgery and instead focusing on academic activities and working off the long overdue "to do" list. moreover, we are privileged to be well-protected by the safety strategies of our institutions. at zurich university hospital, whenever i perform emergency procedures, i do this under special protective measures. until proven otherwise, all patients are initially treated like a "covid-19 case, " which has a certain impact. the conditions to operate are more difficult, as the mandatory class-ii facepiece mask (ffp-2) render breathing difficult and the sealed goggles regularly fog up during the procedure, complicating the visualization of critical structures. all of the problems that i personally faced in the covid-19 crisis so far appear negligible, however, when put into wider context. we are not only spine surgeons but compassionate human beings and the fact that individual fates are forgotten behind the sheer number of casualties -many of them dying alonehas touched me to the heart. moreover, i was shocked by the selfish and nationalist tendencies of some individuals and governments, competing for restricted health care goods on the global market. it is sad but very likely that the heavy blow of this crisis is yet to come: as the european economy continues to bleed out, unemployment and poverty are on the rise, which has a well-known and long-lasting (spanning over several generations) negative effect on bodily and mental health. 9, 10 the european union just like other international institutions seem paralyzed, while nationalist governments, extremists and criminal societies such as the mafia cleverly exploit the situation for their own purposes and benefit. the damage that those midand long-term effects will cause are less in focus right now but are going to exceed the direct damage resulting from covid-19 by far. in addition, there are only few reports of covid-19 and fig. 1 . case vignette of a 67-year-old patient with idiopathic parkinson disease (treated by deep brain stimulation), hypothyroidism, hypercholesterolemia and a history of 3 prior spinal fusion procedures presenting with nonunion at l3/4 and severe proximal junctional kyphosis at l1/2 to the extent that the screw heads and rods at the l2 level risk to violate the skin (with subsequent risk of infection) and neurological compromise at the junctional level could occur. (a) lateral standing whole spine xray. (b) anteroposterior standing whole spine x-ray. the patient reports extreme, barely manageable back pain from the l2 screw stabbing the l1/2 disc space and scratching the l1 vertebral endplate with every movement. the patient fulfills certain risk factors for unfavorable course in case of covid-19 infection and according to the nass (north american spine society) guidelines he would qualify for "elective" or potentially for "urgent" care. 8 how long can and should appropriate surgical treatment be postponed, weighting risk of treatment vs. risk of delaying treatment? its damage produced in less developed countries, which is still in the air as serious threat to humankind. on the contrary, i have also experienced and observed many positive aspects as a result of this crisis -ceasefire in some battle regions of yemen and syria, reduction of environmental pollution and return of nature to a surprising extent, spare time to be spent with family and with reflection on the essentials. moreover, there is solidarity with friends and surgeon colleagues from particularly affected regions, ultra-fast implementation of long overdue digital solutions for remote work, covid-19 information and webinars organized by the eans (european association of neurosurgical societies), ao spine, and other organizations on short notice to lend a voice to and sympathize with severely affected spine surgeons. it is believed that pandemics such as the current one will become more frequent, 11 and their severity may vary depending on infectivity and virulence, amongst other factors. viruses and other pathogens might even be used as weapons by bioterrorists or corrupt governments in the future. the patchwork carpet of european countries and federal states -many of which followed different strategies to contain the virus -offer great opportunities to compare strategies with regards to effectiveness in a highly mobile 21st century society. as we continue to fight back the further spread of the disease, the lessons learned by the current covid-19 pandemic should be used to prepare for what lies in front of us. this is true for all aspects of life, but it is our responsibility to define standards in such situations for the field of spine surgery including patient care, education of students/residents/fellows and research. initiatives such as the current neurospine emergency bulletin pave the way. recent insights into the hiv/aids pandemic world health organization. statement on the second meeting of the international health regulations world health organization world health organization. who director-general's opening remarks at the media briefing on covid-19 -13 world health organization universitätsspital zürich: 80 years of neurosurgical patient care in switzerland covid-19 and the role of spine surgeons. neurospine forthcoming burr ridge (il): nass the impact of poverty on the current and future health status of children poverty and health coronavirus isn't an outlier, it's part of our interconnected viral age world economic forum; c2020 epidemiology of the black death and successive waves of plague mortality burden of the 1918-1919 influenza pandemic in europe key: cord-272147-itdx3wqi authors: white, alexandre i r title: historical linkages: epidemic threat, economic risk, and xenophobia date: 2020-03-27 journal: lancet doi: 10.1016/s0140-6736(20)30737-6 sha: doc_id: 272147 cord_uid: itdx3wqi nan the art of medicine historical linkages: epidemic threat, economic risk, and xenophobia as a historian and medical sociologist, i have been studying the histories of international responses to epidemic events and what they can tell us about the nature of power, economics, and geopolitics. a historical understanding of the international regulations for containing the spread of infectious diseases reveals a particular focus on controls that have protected north american and european interests. in the past months, there have been xenophobic attacks on people of asian descent connected to coronavirus disease 2019 and precipitous losses in global stock exchanges and risk of recession. most reports have treated these as separate phenomena: considering one to be a cultural consequence of epidemic fears run rampant and the other to be the impact of the pandemic on global trade. yet if one pauses to consider the history of the global management of pandemic disease threats, epidemics and global commerce have been inextricably related. part of this history is the role of xenophobic responses to infectious disease threats. the xenophobia that has occurred in relation to the covid-19 pandemic can be situated in a longer history that dates back to 19th-century epidemics and the first international conventions on controlling the spread of infectious diseases. while quarantine, cordon sanitaire, and other social distancing practices date back to 14th-century europe and earlier, by the 19th century the spread of epidemic diseases emerged as a problem that required an international, coordinated response. european colonial expansion brought smallpox and other diseases to the americas and africa from the time of columbus to the 1800s. these epidemics wrought widespread devastation for indigenous peoples. simultaneously, europeans encountered new diseases in the tropics. colonisation brought a particular encounter with diseases capable of harming europeans. the napoleonic wars were global in nature and also revealed the vulnerability of european powers to diseases emerging from their colonial domains, and the capacity of these diseases to emerge in europe. by the end of the 18th century, however, the preexisting forms of ad-hoc and uncoordinated quarantine of ships at port by european powers was being tested, especially in the mediterranean. epidemics of plague and cholera that would claim hundreds of thousands of lives in europe-while claiming far more in india and elsewhere-became a concern. but quarantines were costly, and were also an effective tactic for imposing trade tariffs and enacting trade wars under the guise of public health. a new system was needed to better manage the spread of infectious disease. from 1851 to 1938, 14 conferences were held to standardise international regulations for the establishment of quarantine and the sanitary management of plague, cholera, and yellow fever. in 1892, the first international sanitary conventions were adopted, codifying the first agreements for the prevention of the international spread of infectious diseases. these conventions aimed to maximise protection from disease with minimum effects on trade and travel. plague, cholera, and yellow fever, became the focus of massive international concern due to their threat to continental europe and the economic threats the diseases posed to global trade. the early international sanitary conventions did not police the spread of these three diseases from europe to other countries or focus on any diseases endemic to europe. the threat of diseases emerging from colonial sites that could disturb systems of trade and travel led to aggressive control of these diseases in sites of epidemic outbreak and aggressive scrutiny of those people deemed to be responsible for disease spread. the importance of colonial trade from asia led to the rise of a particular scrutiny and bias against people of asian descent-especially chinese migrants and indian muslims travelling around the world. in the eyes of colonial health officials and the drafters of the first international sanitary conventions, the spread of cholera and plague was an economic, epidemic, and political risk to the long-term stability of the global economy. the particular anxieties over the threat of plague being spread by the free travel of colonised populations drove the colonial administrators in ceylon (now sri lanka) to prophesise the potential collapse of the tea industry-and by extension their entire colony. because trade with europe was so crucial to the colony, in the late 19th century the colonial administrators endeavoured to sacrifice all trade with india rather than risk the threat of plague arriving with migrant workers from the subcontinent. in one letter between colonial administrators, it was suggested, in a derogatory way, that if even a single person from india or east asia entered ceylon without being exposed to sanitary surveillance "there would have been great peril to the colony for these coolies being free immediately on landing (in ceylon) to spread over the island would scatter the seeds of disease as they went". such xenophobic sentiments were shared elsewhere. the heightened scrutiny and bias against non-europeans who were blamed for spreading disease have historically resulted in aggressive racist and xenophobic responses carried out in the name of health controls. in 1901 in cape town, south africa, an epidemic of bubonic plague resulted in the quarantine and forced removal of most of the city's black african population to a racially segregated quarantine camp. this camp and practice of eviction can be viewed as part of the blueprint for future forced removals and a precursor to racially segregated south african townships before and during apartheid. similar scrutiny was a feature of the policing of the hajj. under the international sanitary conventions from 1892 to 1938, muslim pilgrims travelling from india were perceived in europe as a threat because of their potential to meet and spread disease to european muslims during the hajj, who would then return to europe by passage through the suez canal. quarantines and controls were enacted for muslims pilgrims who travelled both from india to mecca and back to europe after the pilgrimage. the disease surveillance and sanitary system that governed the hajj has historically been one of the largest of its kind in the world. concerns about the economic risks of disease spread were not limited to european empires, and neither were the xenophobic practices associated with those concerns. the usa has a history of anti-chinese sentiment in response to epidemics. historian james mohr has described how in honolulu, doctors, colonial administrators, and the general us colonial population lamented the outbreak of bubonic plague in 1900 because it prompted fears that the city would become associated with asia, where plague was then present. as plague spread in honolulu and countries around the world closed their borders or quarantined all vessels arriving from its port, the honolulu city administrators embarked on a full quarantine of the city's chinatown, allowing no one to leave. these quarantines imposed considerable hardships on those within, limiting employment, movement, and access to supplies. the area of quarantine encompassed chinese and non-us properties immediately near the harbour, but avoided buildings and businesses that were owned by white americans and immediately connected to sites of quarantine. ultimately, the public health authorities burned contaminated buildings, but fires spread beyond their control and consumed most of chinatown in flames. similar anti-chinese responses occurred in san francisco during the plague epidemic of 1900-04, when chinese-specific quarantines were enacted. my own research suggests that the concern for the trading relationships central to us economic growth were pivotal to us congress endorsing the creation of who. in a 1945 report accompanying the resolution that ultimately heralded us support for who, it stated that: "particularly in our shrinking world, the spread of disease via airplane or other swift transport across national boundaries gives rise to ever present danger. thus to protect ourselves that we must help wipe out disease everywhere…the records of our export trade show that countries with relatively high living standards buy most of our goods. if the rest of the world continues in illhealth and abject poverty our own economy will suffer." in 1948, the un and world health assembly transferred responsibility for the international sanitary conventions to who in its charter. the international sanitary conventions were reformed and ultimately renamed under who to the international health regulations in 1969, which were revised to their current form in 2005. more recently, nations have aligned infectious disease control policy alongside concerns for national security. in the current pandemic of covid-19, we also see the links between epidemic risk, xenophobic responses, and the global economy. verbal and physical attacks on people of asian descent and descriptions of the disease as "the chinese virus" are all connected in this long legacy of associating epidemic disease threat and trade with the movement of asian peoples. we have seen huge sell-offs on asian stock markets and distinct drops in share prices in european and us financial markets. what was once an initial economic concern for global trade as it related to china has now had effects on all scales of the economy from small businesses to the fortune 500 and potentially on a scale we have not seen since the worst financial crises of the 20th century. when we think about the framing of disease threats, we must recognise that the history of international infectious disease control has largely been shaped by a distinctly european perspective, prioritising epidemic threats that arose from colonial (or now post-colonial) sites that threatened to spread disease and affect trade. covid-19 is a serious and dangerous pandemic, but we must ask ourselves who our responses are designed to protect and who are they meant to vilify? in a pandemic, the best responses are those that protect all members of the population. a eurocentric or us-centric view that excludes or stereotypes others will do much more harm than good. as the epicentre of the epidemic shifts for now to europe and the usa and as global responses intensify, we should be prepared for more economic risk and confront racist or xenophobic responses for what they are-bigoted opinions with no basis in public health or facts. center for medical humanities and social medicine, johns hopkins university and johns hopkins school of medicine, baltimore, md 21205-2113, usa alexandrewhite@jhu.edu plague and fire: battling black death and the 1900 burning of honolulu's chinatown contagion: how commerce has spread disease global risks, divergent pandemics: contrasting responses to bubonic plague and smallpox in 1901 cape town security, disease, commerce: ideologies of postcolonial global health the evolution, etiology and eventualities of the global health security regime two regimes of global health the politics of securing borders and the identities of disease campbell l. chinese in uk report "shocking" levels of racism after coronavirus outbreak. the guardian, feb 9, 2020 tavernise s, oppel jr ra. spit on, yelled at, attacked: chinese-americans fear for their safety.the key: cord-300792-hpyywul0 authors: thaler, m.; khosravi, ismail; hirschmann, m. t.; kort, n. p.; zagra, l.; epinette, j. a.; liebensteiner, m. c. title: disruption of joint arthroplasty services in europe during the covid-19 pandemic: an online survey within the european hip society (ehs) and the european knee associates (eka) date: 2020-05-02 journal: knee surg sports traumatol arthrosc doi: 10.1007/s00167-020-06033-1 sha: doc_id: 300792 cord_uid: hpyywul0 purpose: the aim of the present study was to evaluate the impact of the coronavirus (covid-19) pandemic on joint arthroplasty service in europe by conducting an online survey of arthroplasty surgeons. methods: the survey was conducted in the european hip society (ehs) and the european knee associates (eka). the survey consisted of 20 questions (single, multiple choice, ranked). four topics were addressed: (1) origin and surgical experience of the participant (four questions); (2) potential disruption of arthroplasty surgeries (12 questions); (3) influence of the covid-19 pandemic on the particular arthroplasty surgeon (four questions); (4) a matrix provided 14 different arthroplasty surgeries and the participant was asked to state whether dedicated surgery was stopped, delayed or cancelled. results: two-hundred and seventy-two surgeons (217 ehs, 55 eka) from 40 different countries participated. of the respondents, 25.7% stated that all surgeries were cancelled in their departments, while 68.4% responded that elective inpatient procedures were no longer being performed. with regard to the specific surgical procedures, nearly all primary tja were cancelled (92.6%) as well as aseptic revisions (94.7%). in most hospitals, periprosthetic fractures (87.2%), hip arthroplasty for femoral neck fractures and septic revisions for acute infections (75.8%) were still being performed. conclusion: during the current 2020 covid-19 pandemic, we are experiencing a near-total shutdown of tja. a massive cutback was observed for primary tja and revision tja, even in massively failed tja with collapse, dislocation, component failure or imminent dislocation. only life-threatening pathologies like periprosthetic fractures and acute septic tja are currently undergoing surgical treatment. level of evidence: v. electronic supplementary material: the online version of this article (10.1007/s00167-020-06033-1) contains supplementary material, which is available to authorized users. the public health disruption in europe caused by the coronavirus disease 2019 (covid19) pandemic has resulted in a significant reallocation of health care resources with the focus on the management of covid 19 patients [16] . has rapidly become a global public health threat, endangering the health and well-being of all people, but especially vulnerable older populations [13] . the pandemic is also causing social disruption, exceptional healthcare utilization, and economic instability worldwide. the organisation for economic co-operation and development (oecd) recently reported that for each month of containment, there is a loss of 2 percentage points in annual gdp (growth domestic product) growth. oecd further stated that the tourism sector alone is facing a decrease up to 70% [6] . controlling the spread of covid-19 has become the singular focus of most countries in europe, with unprecedented international collaboration and rapid dissemination of emerging scientific evidence. until now, most publications have described demographic characteristics, clinical symptoms, biological behaviour, and radiological or pathological findings associated with covid-19 [17] . pandemics like the covid-19 disease or the spanish flu have wrought massive changes in patient care [19] . most healthcare resources as well as medical staff are needed to take care of covid-19 infections. hence, it can be presumed that joint arthroplasty service has substantially declined over recent weeks throughout europe [5] . asian orthopaedic surgeons based on the lessons learned from sars in 2003 postponed or cancelled all elective surgeries requiring > 23 h of hospitalization which predominantly affected joint arthroplasty [3] . it is well known from other medical disciplines that a reduction in major organ transplantation (> 25%) as well as a significant reduction in colorectal surgery, and concerns about urology patients, especially in those with a malignant tumour, have already been reported during the covid-19 pandemic [2, 4, 10] . over the last decades, total joint arthroplasty (tja) has grown rapidly and proved its added value for the benefit of nationwide healthcare and patients [14] . the outbreak of covid-19 in europe has potentially influenced the frequency of elective surgeries, like primary and revision arthroplasty. the members of the european hip society (ehs) and the european knee associates (eka) are predominantly arthroplasty surgeons and a cohort with great expertise in arthroplasty. consequently, we surveyed the members of the ehs and the eka regarding the covid-19 pandemic and its influence on their work. the aim of the present study was to evaluate the impact of the covid-19 pandemic on joint arthroplasty service in europe by means of an online survey of arthroplasty surgeons in the ehs and the eka. a prospective online survey of the members of two european orthopaedic societies was performed: ehs and eka. the ehs, consisting of 510 members (328 of them are european full members), was founded in 1992, and its aim is "to provide a forum for the discussion of research, advances in clinical practice and the results of predominantly surgical procedures of all types relating to the hip joint" (art. 2a ehs constitution) and a special focus is on hip replacement. the european knee associates (eka) is a section of the european society of sports traumatology, knee surgery and arthroscopy (esska). within esska, the eka is an association particularly dealing with the management of degenerative diseases of the knee joint. consequently, its members focus on knee arthroplasty and osteotomy around the knee. the eka currently has 208 members. no approval was obtained from an institutional review board, because the survey was anonymous and no patient data were included. data were collected using survey-monkey (https ://www.surve ymonk ey.com): an online data collection program. the survey consisted of 20 questions (single/multiple choice and ranked questions) and was conducted from march 30, 2020, to april 10, 2020 (see online appendix 1 for survey details). four main topics were addressed: (1) origin and surgical experience of the participant (four questions); (2) potential disruption of arthroplasty surgeries (12 questions); (3) influence of the pandemic on the particular arthroplasty surgeon (four questions); (4) a matrix provided 14 different arthroplasty surgeries and the participant was asked to state whether the dedicated surgery was stopped, delayed or cancelled at her or his department. a link to the above-mentioned survey was sent to the members of both societies via email and society's newsletter. all data gathered from the online database were calculated as frequencies and percentages. a total of 272 surgeons (217 ehs, 55 eka) participated in the present survey. the participating surgeons were on average 20 years (min: 1 year, max: 47 years) in practice. the majority worked at an academic centre (44.6%) and a private hospital (44.5%), while 37.1% worked in a public hospital. arthroplasty surgeons from 40 different countries responded. the majority lived in italy (13.9%), germany (9.6%) and france (8.1%). 64.6% had received a specific covid-19 training. of the respondents 25.7% stated that all surgeries were cancelled in their departments, while 68.4% responded that elective inpatient procedures were no longer being performed, and 68% reported that all outpatient procedures were cancelled. elective inpatient and outpatient surgery was also restricted, namely to 20.6% and 15.4%, respectively. only 0.7% of the respondents reported no changes at their department. on a four-level scale of escalation, 52.6% stated that they are at the last stage, treating only life-threatening diseases (fig. 1 ). only 5.9% of the participants stated that they were still doing primary tja (table 1 ; fig. 2 ). regarding routine aseptic revisions, only 3.8% of the participants reported that they were still performing such procedures. in most hospitals, periprosthetic fractures (87.2%), total hip arthroplasty/ hemiarthroplasty for femoral neck fractures and septic revisions for acute infections (75.8%) were still being performed. second-stage revisions with re-implantation of the implants were being performed by 18.8% of the respondents. 50.9% of the participants reported that massively failed tja (collapse, the vast majority (82.6%) of arthroplasty surgeons stated that their personal surgical volume was drastically reduced, a delay in surgeries was reported by 50.7%, training or teaching of students, residents and fellows was stopped for 52.2% of the surgeons and more conservative clinical care was being performed by 20.4% of the respondents. of the arthroplasty surgeons, 46.7% were performing more administrative work than usual, 39.3% were even allocated to nonorthopaedic duties and 53% stated that they were effectively not working due to institutional or self-imposed deferral of elective surgery. regarding post-operative follow-up, 45.7% stated that they were following only high-risk patients after tja. of the surgeons, 31.6% and 25.7% reported that they were still doing normal clinical and radiologic follow-ups, respectively (fig. 3) . rehabilitation and physical therapy after tja were available for selected cases (40.8%), for inpatient patients (16.5%), for outpatient patients (28.7%), and no physical therapy or rehabilitation after tja was reported in 30.1% of cases. of the surgeons, 21.3% stated that they tried to keep a distance to their families, 22.6% reported that they avoided physical contact with their families and 21.7% performed surface disinfection at home. likewise, 5.5% lived in separate rooms at home, 2.9% stated that they do not even go home anymore, and 15.8% were on vacancy during the pandemic. the majority of respondents knew either patients and/or hospital staff with a positive covid-19 test. findings of the survey in more detail are provided in tables 2, 3 the most important finding of the present study was the massive cutback in primary as well as revision tja service in europe during the covid-19 pandemic. primary tja was reported by only 5.9% of survey participants as still being carried out. 3.8% of the participants stated that they were still performing aseptic tja revisions and 18.8% communicated that they were doing tja reimplantation after previous removal of septic implants (2nd stage). in addition, postoperative follow-up visits and rehabilitation were also reported to be drastically impaired (fig. 2) . these type of approach both by the health and hospital authorities and the orthopaedic surgeons has several undoubtable reasons: save resources for covid-19 patients (medical and nurse staff, hospital beds, intensive care units, economical resources), to reduce the risks of contamination (of the staff, of the patients of the whole community) in an "open environment" such as the hospitals which are difficult to be controlled, to avoid contamination of fragile patients that are the majority of tja patients especially in the post-operative time, to guarantee a safe and effective rehabilitation time. when comparing our findings with those of other studies, it appears that the literature on that subject is scarce. liebensteiner et al. questioned surgeons from germany, switzerland and austria on a broad range of orthopaedic procedures [9] . only 10% and 30% of their participants stated that they were still able to offer arthroscopic procedures, depending on the joint and procedure. liebensteiner et al. found that 25% of the participating surgeons were still able to offer anterior cruciate ligament reconstructions, and 50% of the participants reported that rotator cuff repair was no longer being performed. hardly any participants (< 1%) reported that even femoral fractures or sarcoma patients were postponed. in addition, similar to our findings, those authors reported drastic disruptions in postoperative follow-ups and rehabilitation facilities. in summary, the findings of that study are in good agreement with those of the current study. some publications reported similar scenarios in other surgical disciplines. angelico et al. showed that major organ transplantation was reduced by 25% in recent weeks due to the lack of intensive care beds [2] . our results also show that intensive care units as well as intermediate care units are the bottleneck during the covid-19 pandemic (table 5) . hence, one can assume that this consequently leads to a 3 to 6 months 6 to 9 months 9 months to 12 months more than 12 months reduction in revision arthroplasty procedures, even when a patient has a massively failed tja. reduction of surgical volume was also reported for urology and colorectal surgeries [4, 10] . our results show a massive reduction in outpatient activities. a similar scenario was shown for urology patients [4] . during the study period, the coronavirus disease (covid-19) pandemic was evolving rapidly in europe, widely disrupting the personal, social, economic and professional life of healthcare workers. the overall goal of most governments in europe was to "flatten the curve" of new covid cases and to avoid a collapse of the national healthcare systems [1] . at the close of the survey, there were 840,246 confirmed covid-19 cases in europe with 70,583 fatalities [18] . affected by the catastrophic consequences of the pandemic, orthopaedic healthcare was substantially cut back on the whole continent. this drastic disruption has had a massive impact on tja, which is currently the international standard of care for surgical treatment of degenerative and rheumatologic joint diseases, as well as for certain fractures adjacent to the joint, like femoral neck fractures [7] . postponing tja in patients with high-stage osteoarthritis leads to more opioid use and poorer overall outcome regarding revision rate and readmission rate after tja [12] . however, at least life-threatening pathologies such as periprosthetic fractures and first-stage revisions of acute infected tja can still be treated appropriately even in the present difficult scenario. more than 3.1 million total hip arthroplasties and 2.5 million total knee arthroplasties are performed every year in europe [7, 11] to increase quality of life and improve the mobility of patients to enhance their life expectancy. hence, the described cutback in arthroplasty services also has severe economic consequences for implant companies and their employees, as well as the families of the employees. tja outcome is outstanding, and total hip arthroplasty has been named by several reports as "the operation of the century" [8] . in europe, more than 24 national joint registries with over 40 years of experience are monitoring the life expectancy of implants and are responsible for quality assessment and management in tja [11] . the beneficial impact of tja regarding mobility, social life, work capability, prevention of cardiovascular diseases, general health, patient satisfaction, decreasing pain and increasing joint function, especially in elderly persons, but nowadays in young active people as well, is undisputed. hence, if access to tja is restricted, the direct and indirect costs to a nation's society are enormous, because of early retirement, inability to work, direct costs to the healthcare systems caused by the immobility of people and indirect costs to the healthcare system, like employment status, earnings, time missed from work (or absenteeism), and disability payments [14] . there is no doubt that the covid-19 outbreak in europe influences our daily behaviour and prevention strategies [15] . as mentioned in our results, also most arthroplasty surgeons have contact with infected patients or infected hospital staff. consequently, they change their attitude towards their families to prevent them from becoming infected with the disease. these lifestyle modifications range from affordable changes like washing and disinfecting the hands more often (87.1%) to significant changes like avoiding close physical contact with their families (22.1%), staying away from home (2.9%) or staying in a separate room at home (5.5%). the study has some limitations. first, the expert opinion of the members of two societies was evaluated jointly in one study. however, both societies consist of predominantly arthroplasty experts and opinion leaders. second, the respondents came from various countries that maintain different strategies toward the pandemic and that were at different levels of severity of the pandemic at the moment of the survey. the 2020 covid-19 pandemic has currently triggered a neartotal shutdown of arthroplasty surgeries in europe. a massive cutback was observed for primary tja and revision tja, even in massively failed tja with collapse, dislocation, component failure or imminent dislocation. out of trauma cases and malignancy, only life-threatening pathologies like periprosthetic fractures and acute septic tja are currently being treated surgically. author contributions mt was responsible for data collection and manuscript writing. ik wrote the survey, helped during writing of the manuscript by providing results, figures and table. mth performed a revision of the manuscript. mcl, npk, jae and lz were responsible for the data collection and also reviewing the manuscript. mt provided the concept of the study and developed the survey. all authors read and approved the final manuscript. funding none. conflict of interest the authors declare that they have no competing interest. informed consent not applicable. flattening the curve for incarcerated populations-covid-19 in jails and prisons the covid-19 outbreak in italy: initial implications for organ transplantation programs novel coronavirus and orthopaedic surgery: early experiences from singapore covid-19 pandemic-is virtual urology clinic the answer to keeping the cancer pathway moving? disruption of arthroplasty practice in an orthopaedic center in northern italy during covid-19 pandemic secretary general angel gurrã­a's statement for the g20 videoconference summit on covid-19 international survey of primary and revision total knee replacement the operation of the century: total hip replacement massive cutback in orthopaedic healthcare services due to the covid-19 pandemic: an online survey of almost 1400 orthopaedic surgeons in austria the possible impact of covid-19 on colorectal surgery in italy mapping existing hip and knee replacement registries in europe what are the costs of hip osteoarthritis in the year prior to a total hip arthroplasty? implications of covid-19 for patients with pre-existing digestive diseases the direct and indirect costs to society of treatment for end-stage knee osteoarthritis the outbreak of covid-19 coronavirus and its impact on global mental health covid-19: a potential public health problem for homeless populations novel coronavirus covid-19: current evidence and evolving strategies who (2020) who coronavirus 2019 situation report-82 dynamic modelling of costs and health consequences of school closure during an influenza pandemic key: cord-146091-kpvxdhcu authors: sanchez-lorenzo, arturo; vaquero-mart'inez, javier; calb'o, josep; wild, martin; santurt'un, ana; lopez-bustins, joan-a.; vaquero, jose-m.; folini, doris; ant'on, manuel title: anomalous atmospheric circulation favored the spread of covid-19 in europe date: 2020-04-26 journal: nan doi: nan sha: doc_id: 146091 cord_uid: kpvxdhcu the current pandemic caused by the coronavirus sars-cov-2 is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march 2020. it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february 2020 (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is a new coronavirus first noticed in late 2019 in the hubei province, china 1,2 . the virus has a probable bat 3, 4 origin, and causes the ongoing coronavirus disease 2019 . although it is crucial to find a proper vaccine and medical treatment for this pandemic, it is also relevant to know the main factors controlling the transmission of the virus and disease, including the role of meteorological conditions in the spread of the virus. the world health organization (who) states that robust studies are needed to refine forecasting models and inform public health measures 5 . respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (>5 μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (<5 μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin 6 . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs 7 , where cell receptors for some infectious respiratory viruses are located, including the angiotensin converting enzyme ii (ace2) used by sars-cov-2 to infect the individual 3 . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [8] [9] [10] . a recent study has described that the sars-cov-2 virus can remain viable at least up to 3 hours in airborne conditions 11 . respiratory droplets and aerosols loaded with pathogens can reach distances up to 7-8 meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person 12 . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov-2 virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people 13 . another study has also shown evidence of potential airborne transmission in a health care institution 14 . recent studies have pointed out a main role of temperature and humidity in the spread of covid-19. warm conditions and wet atmospheres tend to reduce the transmission of the disease [15] [16] [17] [18] [19] [20] [21] [22] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around 5-11ºc, never falling below 0ºc, and specific humidity of 3-6 g/kg aproximately 18 . the first major outbreak in europe was reported in northern italy in late february 2020. following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present (28 th march 2020) italy and spain are still the two main contributors of cases and deaths in the continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february 2020 has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february 2020 was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure 1 , figure s1 ). this spatial configuration represents the well-known north atlantic oscillation (nao) 23, 24 in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe 25 . figure 2 and figure s2 show maps for february 2020 for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis 18 , the sars-cov-2 virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around 5ºc and 11ºc, which are the conditions shown in figure 2 for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao 26 . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, showed in february 2020 the strongest positive value during 1950-2010 ( figure s3 ). the ao reflects the northern polar vortex variability at surface level 27 , and it consists of a lowpressure centre located over the norwegian sea and the arctic ocean and a high-pressure belt between 40 and 50ºn, forming an annular-like structure. positive values of the ao index mean a strong polar vortex, and the anomalous positive phase experienced during early 2020 has been linked with the recent ozone loss just registered over the arctic region 28 . we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid-19 outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries 29 . thus, the sars-cov-2 virus was already in europe in early 2020, but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid-19 spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries ( figure s4 ) with the highest number of covid-19 cases reported so far (see data and methods). figure 3 (top) shows that there is a statistically significant (r 2 =0.481, p<0.05) second order polynomial fit between the anomalies of the 500 hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than 1,000 cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of 500 hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r 2 =0.50, p<0.05), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid-19 in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid-19 and meteorological data within spain (see data and methods, figure s5 ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure 4 ). they indicate that lower mean temperatures (i.e., average of around 8-11ºc) and lower specific humidity (e.g., <6 g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r 2 =0.838, p<0.05) and are not independent of each other. the temperatures as low as 8-10ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas of higher potential for the spread of the virus, as reported so far in the literature [15] [16] [17] [18] [19] [20] [21] [22] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than 13ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid-19 mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure 3 ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid-19 described above has some intriguing resemblances with the 1918 influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the 1918 flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors 30 . in spain, a south-north gradient is also reported in the 1918 flu after controlling for demographic factors 31 . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions 31 . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november 1918) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s6 ). in other words, the nao was also in its positive phase just before the major outbreak of the 1918 influenza pandemic. this resembles the spatial patterns described above for the current covid-19 outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid-19 in europe (i.e., italy and spain) may be favored by an anomalous atmospheric circulation pattern in february, characterized by a positive phase of the nao and ao. taking into consideration current evidences in the literature, it seems that suitable conditions of air temperature and humidity were reached in northern italy and inland spain. indeed, meteorological conditions can affect the susceptibility of an infected host by altering the mucosal antiviral defense 32 and the stability and transmission of the virus 33 , as well as social contact patterns 34 . we also hypothesize that the anomalous meteorological conditions experienced in italy and spain promoted the airborne contagion both indoors and outdoors, in addition to the direct and indirect contact and short-range droplets, which helped to speed up the rates of effective reproductive number (r) of the virus ( figure s7 ). equally, the anticyclonic conditions, amplified in some areas by temperature inversions, may have reduced the dispersion of the virus outdoors. this stability and lack of precipitation can also produce more processes of suspension and resuspension of the infected aerosols indoors and, especially, outdoors, in a similar way as resuspension of anthropogenic pollutants in cities 35, 36 . equally, it is also suggested that high atmospheric pollutant concentrations can be positively related to increase fatalities related to respiratory virus infections 37, 38 and even covid-19 39 . this is a relevant issue as the main hotspot of covid-19 in italy is located in the po valley, one of the most polluted regions of europe, as well as the madrid region (the most affected region so far in spain) 40 . although the outbreak of a pandemic is controlled by a high number of biological, health, ncep/ncar 1 , era5 2 and era20c 3 atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. figure s4 . location of the 15 countries used in this study that provided cases and deaths of covid-19. figure s5 . location of the autonomous communities of spain, as well as the two autonomous cities of ceuta and melilla. the canary islands has not been included in this study due to its geographical location in tropical latitudes. figure s7 . schematic representation of particles emitted by a cough, with the large droplets settled down nearby (e.g., 1 m distance) and the smaller airborne particles spreading in suspension for longer time, and reaching longer distances, especially in dry and stable conditions as compared to wet environments. it is also possible that a resuspension of aerosol particles can eventually happen due to human activities (e.g., walking, cleaning, etc.) or air flows, which is enhanced under dry conditions due to the lack of precipitation. only statistically significant fields (p<0.05) are plotted as estimated by a student's t-test. map composed with the data and tools provided by the knmi climate explorer website (https://climexp.knmi.nl/start.cgi). the maps show a consistent picture of an intensification of the positive nao phase, which implies that in the future winter conditions as experienced over europe past february 2020 could become more common. clinical features of patients infected with 2019 novel coronavirus in wuhan , 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time of covid-19 cases. under rev high temperature and high humidity reduce the transmission of covid-19 humidity and latitude analysis to predict potential spread and seasonality for covid-19 analysis of meteorological conditions and prediction of epidemic trend of 2019-ncov infection in 2020. medrxiv roles of meteorological conditions in covid-19 transmission on a worldwide scale spread of sars-cov-2 coronavirus likely to be constrained by climate. medrxiv temperature dependence of covid-19 transmission extension to the north atlantic oscillation using early instrumental pressure observations from gibraltar and south-west iceland decadal trends in the north atlantic oscillation: regional temperatures and precipitation. science (80-. ) cloudiness climatology in the iberian peninsula from three global gridded datasets (isccp, cru ts 2.1, era-40) an overview of the north atlantic oscillation. in the north atlantic oscillation: climatic significance and environmental impact 1-35 stratospheric memory and skill of extended-range weather forecasts rare ozone hole opens over arctic -and it's big first cases of coronavirus disease 2019 (covid-19) in the who european region mortality burden of the 1918-1919 influenza pandemic in europe spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in spain low ambient humidity impairs barrier function and innate resistance against influenza infection seasonality of respiratory viral infections a nice day for an infection? weather conditions and social contact patterns relevant to influenza transmission estimation of the contribution of road traffic emissions to particulate matter concentrations from field measurements: a review speciation and origin of pm10 and pm2.5 in spain environmental health : a global air pollution and case fatality of sars in the people ' s republic of china : an ecologic study the impact of ambient fi ne particles on in fl uenza transmission and the modi fi cation effects of temperature in china : a multi-city study exposure to air pollution and covid-19 mortality in the united states eea. air quality in europe -2019 report climate change 2013: the physical science basis. contribution of working group i to the fifth assess-ment report of the intergovernmental panel on climate change the ncep / ncar 40-year reanalysis project era5: fifth generation of ecmwf atmospheric reanalyses of the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know spread of sars-cov-2 coronavirus likely to be constrained by climate. medrxiv sanchez-lorenzo was supported by a fellowship ryc-2016-20784 funded by the ministry of science and innovation. javier vaquero-martinez was supported by a predoctoral fellowship (pd18029) from junta de extremadura and sgr 1362, catalan government) and the clices project this research was supported by the economy and infrastructure counselling of the junta of extremadura through grant gr18097 (co-financed by the european regional development fund) b conducted the analyses competing financial interests: the authors declare no competing financial interests corresponding author: arturo sanchez lorenzo key: cord-269389-x8i5x62v authors: gensini, gian franco; yacoub, magdi h.; conti, andrea a. title: the concept of quarantine in history: from plague to sars date: 2004-04-12 journal: j infect doi: 10.1016/j.jinf.2004.03.002 sha: doc_id: 269389 cord_uid: x8i5x62v the concept of ‘quarantine’ is embedded in health practices, attracting heightened interest during episodes of epidemics. the term is strictly related to plague and dates back to 1377, when the rector of the seaport of ragusa (then belonging to the venetian republic) officially issued a 30-day isolation period for ships, that became 40 days for land travellers. during the next 100 years similar laws were introduced in italian and in french ports, and they gradually acquired other connotations with respect to their original implementation. measures analogous to those employed against the plague have been adopted to fight against the disease termed the great white plague, i.e. tuberculosis, and in recent times various countries have set up official entities for the identification and control of infections. even more recently (2003) the proposal of the constitution of a new european monitoring, regulatory and research institution has been made, since the already available system of surveillance has found an enormous challenge in the global emergency of the severe acute respiratory syndrome (sars). in the absence of a targeted vaccine, general preventive interventions have to be relied upon, including high healthcare surveillance and public information. quarantine has, therefore, had a rebound of celebrity and updated evidence strongly suggests that its basic concept is still fully valid. the concept of 'quarantine' is radically embedded in local and global health practices and culture, attracting heightened interest during episodes of perceived or actual epidemics. the term, however, evokes a variety of emotions, such as fear, resentment, acceptance, curiosity and perplexity, reactions often to be associated with a lack of knowledge about the origins, meaning, and relevance of quarantine itself. historically quarantine has been defined as the detention and segregation of subjects suspected to carry a contagious disease. more recently, the term quarantine has come to indicate a period of isolation imposed on persons, animals or things that might spread a contagious pathology. 1 nowadays the word quarantine should be used to refer to compulsory physical separation (including restriction of movement) of groups of healthy individuals who have been potentially exposed to a contagious disease. 2 the term 'isolation' must be kept separate from the term quarantine, since the former denotes the separation and confinement of subjects already known to be infected with a contagious disease to prevent them from transmitting disease to other people; the latter, essentially the same procedures but with suspected transmitters of disease. from ancient times different populations have adopted varying strategies to prevent and contain disease. one of these is exactly what we would now call isolation. the old testament evidences how individuals affected by diseases were separated from others, and people with leprosy, as leviticus informs, had to live isolated all their lives. in the new testament, too, leprosy continues to be considered a reason for social discrimination, and is represented as curable only through the phenomenon of a divine intervention. the isolation, temporary or otherwise, of sick people has thus always been extensively used as one of the approaches to limit the spread of disease. 3 another strategy was the establishment of a time limit to the manifestation of diseases. in the v century b.c. hippocratic teaching had established that an acute illness only manifested itself within forty days. the case of plague was representative with respect to this; since a disease manifesting itself after 40 days could not be acute, but chronic, it could not be plague. in the ancient past the term pestis (plague) was used in a broad way to indicate every epidemic characterised by high mortality, and magical practices were implemented to fight different diseases since the idea of preventive instruments (such as quarantine) was still not present. 4 with regard to the real plague (the disease caused by yersinia pestis), one may remember the first great pandemic wave of the greek -roman period, and the recurrent epidemics throughout europe in the vi and vii centuries a.d. against acute, fatal diseases such as bubonic plague attempts were made by healthy communities to prevent entry of goods and people from infected communities. in the vii century a.d. armed guards were stationed between plague-stricken provence and the diocese of cahors. 5 particularly virulent was the impact of the disease on the whole of europe in the middle of the xiv century, when the plague spread from southern europe to germany and russia, causing the death of more than 30% of the european population. 6 medieval laws, renaissance health achievements and xvi -xviii centuries overview the concept of (modern) preventive quarantine is strictly related to plague and dates back to 1377, when the rector of the seaport of ragusa, today called dubrovnik (croatia), officially issued the socalled 'trentina' (an italian word derived from 'trenta', that is, the number 30), a 30-day isolation period. ships coming from infected or suspected to be infected sites were to stay at anchor for thirty days before docking. this same period of time became 40 days for land travellers, probably because the shorter period was not considered sufficient to prevent the spread of disease, and precisely from the italian number forty ('quaranta') comes the term quarantine. 7 furthermore, the chief physician of ragusa, jacob of padua, also advised establishing a place outside the city walls for the treatment of sick (or suspected to be infected) citizens. 8 the imposition to remain 30 -40 days in an isolated site was determined not only by health reasons, but also by economic necessity, since the quality and safety of the trade network needed to be protected from the black death. the attention dedicated by the ragusan rulers to the plague was, therefore, responsible for the creation of the first 'official' quarantining as a legal system aimed at defending both health and commercial aspects. 9 the following were the main tenets of the 1377 law of ragusa: visitors from areas where plague was endemic would not be admitted into ragusa until they had remained in isolation for a month; whoever did not observe this law would be fined and subjected to a month of isolation; no one from ragusa was allowed to go to the isolation area; people not assigned by the great council to care for quarantined persons were not allowed to bring food to isolated people. in 1423 venice set up one of the first known 'lazaretto' (quarantine station) on an island near the city, and the venetian system became a model for other european countries. 3 during the next 100 years similar laws were introduced in italian ports (pisa) and in french ones (marseilles), and they gradually acquired other connotations with respect to their original implementation in the context of the middle ages. 10 one such connotation was the institution of a social body to provide the necessary isolation structures (dispositions, facilities, implementation of the laws themselves); another, of more intellectual and medical content, was the gradual acquisition of the essential mechanisms of contagion. in effect, even during the early renaissance, physicians did not have a clear idea of infectiousness, though many waves of epidemics had succeeded one another in the course of the previous centuries. 11 it was only during the xvi century that girolamo fracastoro defined and empowered the concept itself, through the hypothesis that small particles were able to transmit disease. 4 this led the medical profession to integrate previously adopted remedies, simple and insufficient, with more precise quarantine interventions (even if not at an international level) that, however, became the remote bases for modern epidemiology and health sciences. 12 in the xvi century the quarantine system was expanded through the introduction of bills of health, a type of certification that the last port visited by travellers was free from disease. a clean bill, with the visa of the consul of the country of arrival, entitled the ship to the use of the port without quarantine. 5 in the course of the xviii century the practice of quarantine had become, on the one hand a notable nuisance, and on the other, a source of abuse. with regard to the former point, the periods of quarantine were variable across different countries, so that there was no certainty concerning the time needed to implement the quarantine itself. as consequence, not only delay, but perplexity was caused to travellers. with regard to the latter question, instances of bureaucratic and restrictive implementation of quarantine regulations were rife, and the disinfection of correspondence was used as an excuse for political espionage. 5 the upshot of this diffused dissatisfaction with quarantine measures was the emergence of the awareness of the need for a shared standardisation, which, in turn, led to the call for xix century international conferences. from a scientific-epidemiological point of view the concept of quarantine had come to be defined quite precisely in the course of the xix century, but the contemporaneous health organisation was not systematic and capillary enough to confront bursts of epidemics across europe in an organic way. the mid-xix century cholera epidemics, for example, evidenced the scantiness of international uniformity in quarantine practices. even if france had proposed, already in 1834, a meeting for the discussion of the international standardisation of quarantine, 13 it was only in 1851 that the first international sanitary conference took place in paris. collaboration at the international level was hard to achieve since quarantine policies mirrored not only health organisation views, but also national trade protection issues that varied from state to state. 14 open negotiation on quarantine was strongly limited by economic and political agendas, as documented by the 1885 rome conference, where a proposal regarding the inspection of quarantine of ships from india, using the suez canal, produced a violent discussion between britain and france based not on health questions, as much as on the extent of british dominance over the canal. with regard to the united states of america, protection against imported pathologies had always been retained a local issue, and so handled by the single states. only sporadic attempts had been performed to impose quarantine requirements until repeated and serious yellow fever epidemics led to the passing of federal quarantine legislation by congress in 1878, a set of laws that paved the way for federal involvement in quarantine activities. in 1892 the arrival of cholera from abroad prompted a reinterpretation of these laws so as to endow the federal government with more authority in the imposition of quarantine requirements. 13 it was only in 1893 that, after a number of conferences held in the second half of the xix century, an agreement was achieved both in europe and in the united states, concerning the notification of disease and other issues. after this achievement conventions and regulations began to be ratified regarding, in particular, relevant principles for the standardisation of quarantine measures. in the united states, as local authorities realised the benefits of federal involvement, local quarantine stations were gradually turned over to the government; in europe established periods of detention were fixed with special reference to cholera, yellow fever and plague. 14 it is interesting to observe how measures analogous to those employed against the plague have been adopted to fight against the disease that, not by chance, has been termed the great white plague: we refer to tuberculosis (tb). 15 before the tubercle bacillus was recognised as the causative agent of the disease, sanatoria had been set up as the only remedy for sufferers from tuberculosis; this may be considered as an application of the broad concept of 'preventive-therapeutic' quarantine. sanatoria constituted a simple and inexpensive tool to break the chain of transmission of the disease, since they guaranteed isolation. they, therefore, had a precise role in controlling tuberculosis, and it is for this reason that, between 1880 and 1930, sanatoria spread across the whole of europe and north america. even during the 1950s, although streptomycin was already on the market (1947), tb hospitals were considered important for tuberculosis therapy as sites dedicated to the isolation of tb patients, as recommended by quarantine practice. 16 in the scenario of contagious diseases of the past, the so-called 'health officers' deriving partly from medieval and renaissance predecessors and partly from figures created by the schools of hygiene, acquired fundamental importance. among their various functions were those of furnishing the single national health systems with appropriate corporate entities and legislative organisms, as well as obviously caring for the health of the whole population. in many european countries, including italy, these 'officers' represented, even in the second half of the xx century, the basis of all public health organisation devoted to the monitoring and control of infectious diseases. in the first 30 years of the xx century, a deep medicalization of quarantine measures occured. in 1903 the term 'lazaretto' (used especially for plague) was substituted by that of 'health station', since in europe, particularly in france and in italy, the distinction among sick, suspectedly sick, and healthy people, began to acquire a real medical value. four years later an international office of public health was established, and more than twenty nations adhered to it in less than 2 years. variola and typhus were added to the three (plague, cholera and yellow fever) historical quarantining diseases in 1926, and 2 years later this same international office imposed a set of quarantine rules targeted to all kinds of travellers (by land, sea and air). when the world health organisation replaced the international office of public health the expression 'quarantining diseases' disappeared, and pathologies controlled by international health laws (such as plague, cholera and yellow fever) or pathologies under surveillance (such as poliomyelitis, recurrent fever and typhus) appeared. 17 in the face of this resurgence of attention towards infectious diseases, tuberculosis was again made the object of specific measures, which, however, served to monitor and control other diseases. consequent to the high transmission and seriousness of tuberculosis in the europe of the nineteenth century, various countries set up official entities for the identification and control of infections. in the united kingdom a government-funded agency, the medical research council (mrc), was created in 1913 in the hope of finding scientific solutions to the illness. its activity was specifically directed to research. with reference to the other side of the atlantic, in the twentieth century (1967) quarantine measures became the task of the national communicable disease centre, at present called the centre for disease control (cdc) and prevention, an organisation, already equipped, in the sixties, with more than 50 quarantine stations located at every port and international airport, and, in the seventies, shifting its field of action from routine inspection to problem management, intervention and regulation. 10 more recently (2003) the proposal of the constitution of a new european monitoring, regulatory and research institution was made, since the already available system of surveillance, set up in europe to control the onset of epidemics, came up against an enormous challenge in the global emergency of the severe acute respiratory syndrome (sars). 18 in the absence of a targeted vaccine, general preventive interventions had to be relied upon, including high healthcare surveillance and public information. quarantine has, therefore, had a rebound of celebrity, as witnessed by the 'fact sheets' prepared and published by the cdc, in which one may read that 'quarantine is medically very effective in protecting the public from disease'. 19 the 'modern' quarantine for sars is a 10-day period (the incubation period of sars is in fact 2 -9 days) and, like the quarantines of the past, has been applied to persons who have been exposed to the disease and who may be infected, while, once again, isolation has been implemented to separate healthy people from sick ones. as mentioned above, the health emergency of sars has constituted a real challenge for health systems. however, it has also put into discussion the real effectiveness of quarantine measures, for, precisely as for every other health intervention, quarantine has limits of application of which the medical and social community should be perfectly aware. 20 a recent paper proposing a compartmental model for the geographical spread of infectious diseases shows how this scheme may be adopted to address the effectiveness of human quarantine. the model itself was applied to data deriving from a canadian historical record regarding the time period of the so-called spanish influenza pandemic (1918 -19) . information on the daily mobility patterns of subjects engaged in the fur trade throughout central canada before, during and after the epidemic were used to establish whether rates of travel were affected by informal quarantine policies, and then the same methodology was adopted to analyse the impact of observed differences in travel on the diffusion of the epidemic. this same model has suggested that quarantine effectiveness varies depending on when the limitation on travel between communities is applied, and on how long it lasts. 20 an operative template of such a type appears particularly interesting from our historical-scientific point of view since it links historical features to current scientific epidemiological evidence. similar to other effective health measures, quarantine is not a panacea, and has its limits. this is highlighted by the recent risk of bioterrorism, where a potentially large and diverse number of agents may be implicated. 21 in addition, other recent epidemics, such as the acquired immuno deficiency syndrome (aids), cannot be considered quarantine-able not only because of medical but also because of ethical and legal issues. 22 however, good quality evidence overall suggests that the basic concept of quarantine is still fully valid, and that the implementation of correct quarantine procedures must be tailored according to single health, social and geographical conditions. 20, 23, 24 large-scale quarantine following biological terrorism in the united states the origin of quarantine quarantine and isolation. 15th ed. the new encyclopaedia britannica the black death past and present. 2. some historical problems a state of deference: ragusa/dubrovnik in the medieval centuries storia della medicina dall'antichità a oggi trade and health policies in ragusa-dubrovnik until the age of george armmenius-baglivi history of the concept of quarantine plague, policy, saints and terrorists: a historical survey a short history of quarantine (victor c. vaughan) politics of quarantine in the 19th century international law and infectious diseases the evolution of the concept of 'fever' in the history of medicine: from pathological picture per se to clinical epiphenomenon (and vice versa) compliance, coercion, and compassion: moral dimensions of the return of tuberculosis international sanitary regulations. 3rd annotated ed. world health organization guideline on management of severe acute respiratory syndrome (sars) severe acute respiratory syndrome. fact sheet: isolation and quarantine simulating the effect of quarantine on the spread of the 1918-19 flu in central canada plague as a biological weapon: medical and public health management. working group on civilian biodefense quarantine and the problem of aids some historical comments on quarantine: part one some historical comments on quarantine: part two the authors would like to thank professor luisa camaiora, b.a., m.phil., for her correction of the english. key: cord-266467-qv6oxjwd authors: more, alexander f.; loveluck, christopher p.; clifford, heather; handley, michael j.; korotkikh, elena v.; kurbatov, andrei v.; mccormick, michael; mayewski, paul a. title: the impact of a six‐year climate anomaly on the “spanish flu” pandemic and wwi date: 2020-09-01 journal: geohealth doi: 10.1029/2020gh000277 sha: doc_id: 266467 cord_uid: qv6oxjwd the h1n1 “spanish influenza” pandemic of 1918–1919 caused the highest known number of deaths recorded for a single pandemic in human history. several theories have been offered to explain the virulence and spread of the disease, but the environmental context remains underexamined. in this study, we present a new environmental record from a european, alpine ice core, showing a significant climate anomaly that affected the continent from 1914 to 1919. incessant torrential rain and declining temperatures increased casualties in the battlefields of world war i (wwi), setting the stage for the spread of the pandemic at the end of the conflict. multiple independent records of temperature, precipitation, and mortality corroborate these findings. a century ago, in the autumn of 1918, the deadliest wave of the h1n1 influenza pandemic, known as the "spanish flu", claimed tens of millions of victims (krammer et al., 2018; taubenberger & morens, 2006) . it marked the beginning of the end of several years of unprecedented mortality throughout europe, due to the horrors of world war i (wwi), and an unusually extreme, multiyear climate anomaly that brought torrential rains to battlefields as well as urban areas. the inescapable muddy landscapes of the war remain a common theme of surviving wwi eyewitness accounts and photographs. despite recent work on the impact of climate change on the spread of viral infections and overall mortality, the role of environmental changes in the wwi-spanish flu period remains underexamined (grant & giovannucci, 2009; mamelund, 2011) . here we present a new, high-resolution climate proxy record from the high alpine monte rosa (4,450 m a.m.s.l.) colle gnifetti (cg) glacier in the heart of europe, indicating abnormally high influxes of north atlantic marine air in the years 1914-1919. we evaluate the glaciochemical data from this ice core with a detailed monthly record of overall mortality in europe for the same period and monthly precipitation and temperature measurements (ansart et al., 2009; bohleber et al., 2018; bunle, 1954; clifford et al., 2019; more et al., 2017 more et al., , 2018 schneider et al., 2014; sneed et al., 2015; willmott & matsuura, 2001) . the multiyear, extreme anomaly described here, in several independent but consilient records, had a significant impact in setting the stage for the onset, spread, and mutation of the h1n1 pandemic, while also increasing all-cause deaths due to widespread harvest failures and worsening battlefield conditions. the influenza pandemic of 1917-1919 claimed between 50 and 100 million lives (krammer et al., 2018; taubenberger & morens, 2006) . in europe, the estimated death toll was 2.64 million (ansart et al., 2009 ). various theories have been proposed to document its spread from asia to europe. historical research has recently focused on the recruitment of allied troops by the british in asia in spring 1917 and their transport to europe via canada and the atlantic crossing, as the most likely route of transmission (humphries, 2014) . ©2020 . the authors. this is an open access article under the terms of the creative commons attribution-noncommercial-noderivs license, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. studies have also suggested that the use of chlorine gas on the battlefields of wwi may have caused the virus to mutate into its most virulent form (erkoreka, 2009; oxford et al., 2005; taubenberger et al., 1997; worobey et al., 2014) . the environmental and especially climatic conditions in which the pandemic developed have received less attention in the scientific literature, even though historical accounts universally describe abnormally high precipitation and cold temperatures in the years preceding the onset of the pandemic, in 1917, and during its deadliest wave in 1918. in contrast, detailed research has shown how extreme weather conditions impacted the outcome of major battles on the western front, most notably during the battles of verdun (1916) (1917) , the somme (1916), the chemin-desdames (1917) , and the third battle of ypres-passchendaele (1917) (barbante et al., 2004; hussey, 1997) . extreme weather anomalies in these years disrupted governmental efforts in collecting meteorological records (savouret et al., 2011) . in this study, we combine a high-resolution glaciochemical record reconstructed from cg marine air proxies (na, cl − ) evaluated together with detailed monthly records of overall mortality from 13 european countries (figures 1 and 2 ) and instrumental measurements of precipitation and temperature for the same period ( figure 3 ). previous research on this cg record exposed in great detail variations detected in climate proxies and in the concentration of pollutants for this area due to its geographic proximity to events and its location under the influence of the iceland low and azores high pressure systems ( figure 4 ) (barbante et al., 2004; bohleber et al., 2018; döscher et al., 1995; more et al., 2018) . the glaciochemical records have been developed via discrete, inductively coupled plasma mass spectrometry (icp-ms, 465 data points for the period 1880-1980) and ion chromatography (ic, 581 data points for the period 1880-1980) analyses (more et al., 2017 (more et al., , 2018 sneed et al., 2015) . total european mortality peaked three times, concurrently or following cooling temperatures, increasing precipitation, and an extreme influx of cold marine air in winter 1915 , 1916 , and 1918 ). the glaciochemical and instrumental records corroborate historical accounts of torrential precipitation on the battlefields of wwi-resulting in increased casualties due to drowning, exposure, pneumonia, and other infections-and its severity may have significantly altered the migration patterns of birds such as the mallard duck, the primary reservoir for the h1n1 avian influenza virus (tucker et al., 2018) . , marine air proxies in the cg glacier and total mortality for 13 european countries 1914-1920 (ansart et al., 2009; bunle, 1954) . in 1915 in , 1916 in , and 1918 , overall mortality peaked during or immediately after periods of high marine air influx over europe. major battles of wwi where precipitation was a significant factor are labeled in black, along with the period of the three major waves of the spanish flu pandemic, the deadliest of which occurred in the autumn of 1918. , 1914-1920 . mean values of instrumental measurements of temperature and precipitation with overall deaths for 13 european countries (ansart et al., 2009; bunle, 1954; schneider et al., 2014; willmott & matsuura, 2001) . in the autumn and winter of 1918, mortality peaked together with high precipitation, with a peak in both records in the month of october, a slight decrease in november, and another peak in december of that year. the deadliest wave of the spanish influenza pandemic claimed most of its victims in the same months, where the arrow points to a double peak in both deaths and precipitation. precipitation on british, french, and german military operations, where newly dug trenches and tunnels filled with rainwater, as bitter cold temperatures caused thousands to endure frostbite at night, while mud slowed down the movement of troops and artillery during the day (barthas, 2014; churchill et al., 1916; de lécluse, 1998) . the highest increase in marine air proxies (figures 1 and 2 figure s4 ). starting in january 1916, precipitation in europe increased steadily throughout the year, with a peak in december 1916 ( figure s5 ), coinciding with the battles of the somme and verdun, where the mud and water-filled trenches and bomb craters swallowed everything, from tanks, to horses and troops, becoming what eyewitnesses described as the "liquid grave" of the armies (borden, 1917) . extended winter conditions delayed the start of the chemin-des-dames offensive until april 1917 (attal & rolland, 1993; savouret et al., 2011) . they also caused widespread harvest failures, resulting in the "turnip winter" of 1916-1917, whereby the german population resorted to root vegetables for their diet, due to failed potato and cereal harvests and the allied blockade (chickering, 2004) . after a brief respite, rain and cold returned again in the summer and autumn of 1917 ( figure s6) , with widespread flooding of the trenches in the third battle of ypres (passchendaele) in july-november, often bringing military operations to a standstill and substantially increasing casualties (barton et al., 2007; lloyd, 2017; reid et al., 1999) . the first wave of h1n1 influenza in europe emerged in the spring of 1918, most likely originating in the fall and winter of 1917, among allied troops that had arrived from asia and had established their base camp near boulogne (humphries, 2014) . the combination of extremely high precipitation, the concentration of millions of troops on the battlefields, unsanitary conditions, and the use of chlorine gas as a 10.1029/2020gh000277 chemical weapon have been cited as contributing factors to the mutation and emergence of the most lethal wave of the spanish influenza pandemic in the fall and winter of 1918-1919 (erkoreka, 2009; oxford et al., 2005; figure s7 ). later peaks in marine air proxies in 1921-1922 and 1926 are connected to documented residual activity from north atlantic hurricanes, particularly severe in those years, but not approximating the extremes of 1914 -1918 (landsea et al., 2012 . the deadliest wave of the flu in europe began in the autumn of 1918, closely following a period of extremely high precipitation and cold temperatures (figure 3 ). the coincidence between increased precipitation and mortality in this pandemic wave in late 1918 (figure 3 ) highlights the role of environmental conditions in a pandemic's morbidity and mortality, as already suggested in studies of recent h1n1 and other respiratory tract infections such as covid-19 in human populations (kissler et al., 2020; liu et al., 2020; viboud et al., 2004) especially in regions with extensive, long-term air pollution such as europe (clay et al., 2018; morales et al., 2017; more et al., 2017 ). an additional exacerbating factor may have been the influence of the weather anomalies on established patterns of avian migration, similar to those documented for other species in response to modern, anthropogenic climate change (tucker et al., 2018) . specifically, the migration of the mallard duck-one of the primary reservoirs of h1n1 avian influenza virus-may have been disrupted by the anomaly described here, resulting in increased presence of this species throughout europe in the autumn of 1917 and 1918, in close proximity to both military and civilian populations, as well as domesticated animals (oxford et al., 2005; saunders-hastings & krewski, 2016; taubenberger et al., 1997; worobey et al., 2014) . studies of disruptions in mallard migration have shown that changes in the environment-at start point and throughout the journey-can affect overall movement and direction (van toor et al., 2013) interrupting their normal migratory route (kleyheeg et al., 2019; tolf et al., 2012) . the transfer of h1n1 influenza virus from animals (avian and mammals) to humans (zoonosis) occurs primarily via water sources contaminated with fecal droppings from infected birds (breban et al., 2009; carter & sanford, 2012; pawar et al., 2018; vandegrift et al., 2010; vittecoq et al., 2017; worobey et al., 2014) . in autumn, the rate of influenza a viral infection can be as high as 60% in mallard populations, due to the exposure of immunologically naïve juveniles to the virus (bengtsson et al., 2016; tolf et al., 2012) . juveniles are especially prone to remain in the same area if their migration route is disrupted (van toor et al., 2013) . exposure of mammalian hosts to the same infected bodies of water where mallard ducks may have remained may explain connections to the current seasonal recurrence of h1n1 in human populations as shown in recent studies (belser & terrence, 2019; reid et al., 2004; smith et al., 2009; tang, 2009; weingartl et al., 2009) , suggesting that severe weather anomalies in 1917-1919 may have contributed to both the diffusion and mutation of the spanish flu virus, as previous studies have suggested. the influx of torrential rain accompanied by decreasing temperatures in the autumns of 1917 and 1918 provided ideal conditions for the survival and replication of the virus (brown et al., 2009; lowen & steel, 2014; reid et al., 2004; tang, 2009; weingartl et al., 2009) . prolonged exposure to decreasing temperatures may also have been a factor in increasing pneumococcal co-infections, which recent studies have found to be more common in the wwi years than previously thought (foxman et al., 2015 (foxman et al., , 2016 iwasaki et al., 2017; klugman & chien, 2009; meissner, 2016; morens et al., 2008; taubenberger et al., 1997; worobey et al., 2014) . retrospective epidemiological studies have now shown that a significant contribution to high mortality during the spanish flu pandemic came from pneumococcal co-infections, amounting to as much as one fifth of influenza victims, with a 34% mortality. the data presented here show that extreme weather anomalies captured in glaciochemistry and reanalysis records brought unusually strong influxes of cold marine air from the north atlantic, primarily between 1915 and 1919, resulting in unusually strong precipitation events, and that they exacerbated total mortality across europe, due to the interplay of environmental, ecological, epidemiological, and human factors. as we experience increasingly severe weather anomalies brought about by global climate change, and with the persistent seasonal recurrence of h1n1, the contribution of environmental change and human action to pandemic morbidity, mortality, and diffusion cannot be underestimated. indeed, the pandemic development history of the spanish influenza from 1917 to 1919 sends a warning into our own time, a century later, of the ongoing risks of war zones (including the use of chemical weapons), wildlife trade, unsanitary conditions, and humanitarian crises as incubators of disease, assisted by climate-change triggers. our past and 10.1029/2020gh000277 current crisis highlights our continuing and growing need for robust local and global public health and environmental agencies, such as the cdc, who and unep, dedicated to reducing the risk that climate change will aggravate epidemic outbreaks. the role of climate anomalies such as the one described in this study must be assessed in relation to more recent pandemics such as covid-19. mortality burden of the 1918-1919 influenza pandemic in europe ambleny, le temps d'une guerre historical record of european emissions of heavy metals to the atmosphere since the 1650s from alpine snow/ice cores drilled near monte rosa poilu: the world war i notebooks of corporal louis barthas beneath flanders fields: the tunnellers' war the 1918 flu, 100 years later does influenza a virus infection affect movement behaviour during stopover in its wild reservoir host temperature and mineral dust variability recorded in two low-accumulation alpine ice cores over the last millennium at the somme: the song of the mud. current opinion the role of environmental transmission in recurrent avian influenza epidemics avian influenza virus in water: infectivity is dependent on ph, salinity and temperature le mouvement naturel de la population dans le monde de 1906 à 1936 a new look at an old virus: patterns of mutation accumulation in the human h1n1 influenza virus since 1918 imperial germany and the great war the story of the great war pollution, infectious disease, and mortality: evidence from the 1918 spanish influenza pandemic a 2000 year saharan dust event proxy record from an ice core in the european alps comrades-in-arms: the world war i memoir of captain henri de lécluse a 130 years deposition record of sulfate, nitrate and chloride from a high-alpine glacier origins of the spanish influenza pandemic (1918-1920) and its relation to the first world war temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells two interferon-independent double-stranded rna-induced host defense strategies suppress the common cold virus at warm temperature the possible roles of solar ultraviolet-b radiation and vitamin d in reducing case-fatality rates from the 1918-1919 influenza pandemic in the united states paths of infection: the first world war and the origins of the 1918 influenza pandemic the flanders battleground and the weather in 1917 early local immune defenses in the respiratory tract projecting the transmission dynamics of sars-cov-2 through the post-pandemic period a comprehensive model for the quantitative estimation of seed dispersal by migratory mallards pneumococcal pneumonia and influenza: a deadly combination a reanalysis of the 1921-30 atlantic hurricane database changing rapid weather variability increases influenza epidemic risk in a warming climate passchendaele: the lost victory of world war i roles of humidity and temperature in shaping influenza seasonality geography may explain adult mortality from the 1918-20 influenza pandemic viral bronchiolitis in children possible explanations for why some countries were harder hit by the pandemic influenza virus in 2009-a global mortality impact modeling study next-generation ice core technology reveals true minimum natural levels of lead (pb) in the atmosphere: insights from the black death the role of historical context in understanding past climate, pollution and health data in trans-disciplinary studies: reply to comments on more predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness a hypothesis: the conjunction of soldiers, gas, pigs, ducks, geese and horses in northern france during the great war provided the conditions for the emergence of the "spanish" influenza pandemic of 1918-1919 morphological and biochemical characteristics of avian faecal droppings and their impact on survival of avian influenza virus gallipoli: the end of the myth origin and evolution of the 1918 "spanish" influenza virus hemagglutinin gene evidence of an absence: the genetic origins of the 1918 pandemic influenza virus reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. pathogens approche séquentielle des périodes contraignantes dans les tranchées sur le front de la marne et de la meuse gpcc's new land surface precipitation climatology based on quality-controlled in situ data and its role in quantifying the global water cycle dating the emergence of pandemic influenza viruses new la-icp-ms cryocell and calibration technique for sub-millimeter analysis of ice cores the effect of environmental parameters on the survival of airborne infectious agents 1918 influenza: the mother of all pandemics initial genetic characterization of the 1918 "spanish" influenza virus birds and viruses at a crossroad-surveillance of influenza a virus in portuguese waterfowl moving in the anthropocene: global reductions in terrestrial mammalian movements ecology of avian influenza viruses in a changing world association of influenza epidemics with global climate variability modeling the spread of avian influenza viruses in aquatic reservoirs: a novel hydrodynamic approach applied to the rhône delta (southern france) experimental infection of pigs with the human 1918 pandemic influenza virus terrestrial air temperature and precipitation: monthly and annual time series genesis and pathogenesis of the 1918 pandemic h1n1 influenza a virus the authors declare no conflicts of interest relevant to this study. all data pertaining to this article and for the entire project are available in open access (https://dataverse. harvard.edu/dataverse/historicalicecore). additional information may be obtained from a. f. m. (afmore@fas.harvard.edu). key: cord-340791-jcsfbxgu authors: vogel, hans-arthur title: the nature of airports date: 2019-03-22 journal: foundations of airport economics and finance doi: 10.1016/b978-0-12-810528-3.00001-9 sha: doc_id: 340791 cord_uid: jcsfbxgu this chapter presents the historic development of global air transportation. as it is the main function to accommodate this traffic growth, airports have advanced in response to it. first, their role within the air transport system will be described. a picture of their social, environmental, economic and political impact will be given next. this chapter’s feature is on airport products and services. the nature of airports chapter outline 1.1 introduction 3 1.2 the role of airports within the air transport system 4 airports are complex systems, providing infrastructure and services for the operations of aircraft and handling of passengers and cargo. this requires an adequate airfield, including a runway, aircraft parking apron, and terminal facilities for passengers, cargo, general aviation, and aircraft maintenance as well as supporting fixtures for access circulation/car parking, utilities, and other nonaeronautical use facilities. all of them are multifaceted in nature, while the commonality is that they have long lead times to plan and develop and are costly to build and maintain. this very nature of the airport business is a major determinant of the financial performance. another equally important factor is the demand side. airports have developed in response to the overall traffic growth, providing infrastructure and services to their airline customers. the success of aviation and the significant growth rates associated with that is causing an equally significant problem in terms of lacking infrastructure on the ground and in the air. various countries strongly support the industry on the whole, in order to participate in its benefits, for example, economic development and generation of employment. the population in other countries, however, is more critical regarding the environmental effects-especially when living in the vicinity of an airport. these notable differences are partially driven by their individual historical development in parallel to traffic growth and are, to a certain extent, addressing the challenges arising from these, in turn. as evidenced by the partial statistics on commercial aviation's long-term development in table 1 .1, it is a continuing success story and has been resilient vis-à-vis oil and/or gulf crises, other acts of war and terrorist attacks, severe acute respiratory syndrome (sars) and the like as well as economic recessions. during the second decade of this century, air transportation is performed by approximately 1,000 scheduled airlines with 25,000 aircraft in use, 170 air navigation services, and more than 4,000 airports (fonseca de almeida, 2014). according to icao (2017), 3.8 billion passengers and 52.6m tons of cargo were handled in 2016. in general, commercial airports have developed in response to the fast growth of the world's airline industry, which in turn is significantly correlated with the annual growth of the gross domestic product (gdp). it is essential to bear this in mind for the rest of the book, since the airport business is fundamentally driven by the numbers or traffic volume. airport operations and management are an important part of the air transport value chain. many other industries would be pleased to cope with the problems associated with the lasting growth (and, in a few regions, maturity) of aviation. some of the ensuing issues, however, are far from being solved and may pose a severe threat. lacking infrastructure on the ground and in the air results in capacity constraints in general and congested hub airports in particular. traffic growth, however, has actually developed significantly differently across the regions. fig. 1 .1 displays the regional passenger structure based on icao data. a clear trend of airport passengers in relative terms with regard to asia becomes visible, while north america falls behind and europe remains relatively stable. the underlying traffic shift is also reflected by the long-term volumes in passengers, aircraft movements and cargo handled. in spite of worldwide economic uncertainty and political instability in many countries, airports accommodated almost 7.7 billion passengers in 2016. as the passengers are being counted at both the departing and arriving airport, the numbers are about double those of icao and the international air transport association (iata). while the total passenger number has almost tripled since 1996, the regional distribution during this period is rather different-with direct implications for the affected airports. the demand for transportation in general, and for air transportation in particular, is primarily dependent on the status and growth of the economy, growth of the population, disposable income per capita and the resulting propensity to travel. the effects of different market maturity and the shift of the center of economic growth from north america (nam) and europe (eur) toward asia-pacific (asp) is illustrated by fig. 1.2 . although the middle east (mea) exhibits the highest overall growth rate for the period under scrutiny, it needs to be noted that this is due to the rather low traffic volume in base year 1996. latin america-caribbean (lac) and africa (afr) have grown at par with and slightly higher than global average, respectively. in addition to the long-term development of the passenger segment, fig. 1 .3 illustrates the development of the freight market during the last decade. after significant growth, volumes appear to stagnate after the effects of the most recent global financial crisis had been made up for in 2010. roughly two-thirds of air cargo are accommodated by the belly hold of passenger aircraft. after inspecting historical data and identifying an overall trend, the future outlook needs to be analyzed in order to fully comprehend the fundamentals driving the airport business. table 1 .2 displays the expected compound annual growth rate (cagr) or mean annual growth rate of the passenger sector over the specified period. based on rounded 4 billion travelers expected to have flown in 2017, iata projected this figure almost to double to 7.8 billion in 2036. this is equivalent to a cagr of 3.6% on average. other traffic projections, for example, airbus (2017) or boeing (2017) foresee healthy growth rates in a corridor between 4% and 5%, more toward the higher end regarding the short to medium range and toward the lower end for the longer term. airports council international (aci, 2016) is forecasting an even higher rate of 4.9% for passengers (and 2.3% for air cargo as well as 2.5% for aircraft movements) in the long term up to 2040. based on the regional trend described above, this scenario results in a tremendous change in passenger market shares, as displayed in fig. 1.4 . the uneven regional growth rates (cf. fig. 1 .2) are set to continue, primarily due to market maturity and gdp growth. while this will provide superior growth perspectives to airports in the asia-pacific region, the overall outlook is very positive across the board. regardless of the slightly different projections, volumes will more or less double during the next 20 years. against this background, iata is expecting that almost all of the world's top 100 airports require major infrastructure expansion during this period. moreover, there could be 100 more slot coordinated airports within 10 years' time already. that is in addition to the 189 level 3 and 122 level 2 airports (with some peak congestion) as of november 2017. all regions are concerned by this challenge, although europe is in the limelight of this infrastructure shortage (garcia, 2018; gittens, 2018; clark et al., 2018) . in order to accommodate for this growth scenario, adequate infrastructure is required both in the air and on the ground-substantially beyond current plans to expand capacity. otherwise, eurocontrol (2018) is afraid that according to their most likely scenario, there will be around 1.5 million flights more in demand than can be accommodated by 2040, and 166 million passengers will be unable to fly. it also means that the number of airports operating near capacity during most of the day, as it is the case at london heathrow (lhr), for example, will rise from six in summer 2016 to then sixteen. 1.3 the social, environmental, economic, and political impact of airports although airports are difficult neighbors due to their environmental impact which will be analyzed in section 1.3.2, they are an important economic factor for the cities and regions they serve. in addition to providing access to the global air transport system thus supporting connectivity, they also generate direct, indirect, and induced economic activities and employment (mcgraw, 2017) . the direct effects may be measured in employment and income resulting from the local airport operations, including the operator itself, other service providers, agencies, and the airlines. while indirect impacts refer to employment and economic activities linked to supplying the air transport industry, induced effects comprise employment and activity supported by the spending of air transport employees, for example, suppliers of goods and services purchased by employees. usually, their combined effect is being measured by the economic multiplier. the multiplier concept incorporates the spendings of direct employees as well as employees of supplying companies. finally, airports also support attracting and sustaining business development outside of air transport. these spin-off effects primarily materializing in the tourism and travel and trade industries are termed to be the catalytic impact (aci europe, 2015; air transport action group, atag, 2018). in their most recent study on the benefits of aviation, the atag (2018) reports the overall economic impact of aviation to have been around usd 2.7tn in 2016, supporting 3.6% of the global gdp, with 65.5 million jobs dependent on aviation and 10.2 million thereof directly in aviation on a global scale. furthermore, they estimated direct employment to have been 525,000 with airport operators and another 5.6 million with a retail and car rental company or government agencies such as customs on-airport. according to aci (2017), the 2015 data concerning its airports revealed a ratio of 12 for total employees on the airport site versus employees of the airport operator and a rule-of-thumb industry benchmark of eight airport employees per 10,000 passengers on average. significant regional variations need to be noted though for both, since the employment structure is affected by different operational, managerial and ownership models. these differences also apply to the total income of usd 151.8bn generated by aci airports globally. for europe alone, intervistas (2015) has quantified the overall economic impact of airports in terms of 12,343,900 total jobs and gdp of eur 674.5bn or 4.1% of the regional gdp, including catalytic effects. another local example is the impressive overall total economic impact of aviation on the dubai economy in 2013, which is estimated to be usd 26.7bn, comprising a "core" impact of usd 16.5bn and "tourism" benefits of usd 10.2bn. this is equivalent to 26.7% of dubai's total gdp and was sufficient to support 416,500 jobs or 21% of the dubai's total employment (oxford economics, 2014) . it needs to be noted, however, that other industries certainly do generate employment, attract additional businesses (including air traffic/airports) and prompt multiplier effects as well. also, impact studies are descriptive in nature and less qualified as a basis for decision-making than costàbenefit analyses. the latter address the question whether or not a project or sector is beneficial and also account for environmental implications-revealing favorable results for air transport in general (jorge-calderón, 2014). still, airports are now integrated into their region's socioeconomic engine with considerable economic and social benefits. these have frequently been capitalized on by politics, specifically where airports are in government ownership. quite often, however, the positive effects are overshadowed by the undisputed negative environmental impact, especially on residential areas in the vicinity of airportsàwhile the value of commercial property in aviation dependent use is enhanced (cohen and brown, 2017). in recent years, airport planning and development increasingly tend to be a controversial issue. airports have to deal with numerous local issues regarding noise, air quality, waste management, and other environmental concerns, as well as the policies resulting from these matters. eurocontrol (2017) explains the various environmental topics connected to aviation. with air transportation serving the growing needs for the traveling public, aviation, at the same time, encumbers costs or detriments onto society and nature. these main adversities, harming the environment, are identified as aircraft noise, air pollution, climate change, third party risks, and aviation emissions. aircraft noise is a fundamental harm to people living close to the airport, complaining about noise disturbances, especially during nighttime periods. the "balanced approach" presents a means to undertake noise management procedures at airports and implicates the reduction of noise at the source, land-use planning and management measures, noise mitigation procedures, and operational restrictions. the most remarkable aviation emissions responsible for local air pollution are oxides of nitrogen and carbon monoxide. the encroachment of the environment often induces environmentalists and public campaigners to protest against airports, because of possible airport expansion projects or because of the two basic aviation disturbances of noise and gas emissions. these groups have the ability and power to bring about very damaging repercussions to airports, which can lead to night curfews being enforced at airports. one example of the growing public campaigns and citizens' initiatives is the monday demonstrations inside the terminal of the frankfurt airport in 2014 against the airport and its generation of noise. being a good neighbor, however, is vital to get planning approval for potential expansion projects. noise insulation of neighboring houses, technological advances such as new aircraft engine technology as well as renewable energies are further mitigations-usually implying financial burdens for the industry. new aircraft engine technology enables the airports' surrounding area to be less harmed by aircraft noise, invoking fewer noise complaints. renewable energies are further technological advances airports can make use of, in order to be part of the move of "going green." due to the large area that airport infrastructure demands, regenerative energy sources, like solar energy devices, can be mounted either to the spacious rooftops or onto the airport's open land masses. additionally, airports can possibly opt for installing wind turbines and use them as regenerative energy sources. such endeavors also would favor the social and environmental influences of airports, as sustainability on the one hand fabricates a positive image of the airport for the public, and simultaneously is welcomed by environmentalists (federal aviation authority, faa, 2018a,b; pagliarello, 2018) . two initiatives support the efforts of "going green": aci's "carbon accreditation programme" and eurocontrol's "collaborative environmental management specification" (cem). the former was successfully implemented in europe a number of years ago and went global in november 2014. the program certifies airports at four different levels of accreditation covering all stages of carbon management: mapping, reduction, optimization, and neutrality. as of spring 2018, more than 200 airports in more than 60 countries across all regions have actually reached the fourth stage of carbon neutrality. the cem, on the other hand, was only launched in 2014 and is limited to europe, but includes aircraft operators, air navigation service providers, and trade associations in addition to airport operators. its objective is to facilitate the already existing activities of these core operational stakeholders by increasing their awareness of the various interdependencies. this, in turn, is to support sustainable airport development as an essential element for improving air transport movements capacity and flight efficiency (bates, 2017; eurocontrol, 2014 ). due to their significant importance for the economic development of a region and/ or an entire country, airports have frequently been subject to political activities. a prime example for the instrumental character of airport development-actually aviation on the whole-is the new dubai world central al maktoum airport, but also the expansion projects of neighboring abu dhabi (and to a certain extent also doha), where these investments are perceived to be a token of preparing the economies for the postàoil future. similarly, the bric countries have an overriding interest in developing their airports' system, as ground infrastructure may not be comparable to north america or europe. but governments of the developed nations also follow a similar agenda in supporting the competitiveness of their economies. in europe, the european commission (ec)-in its capacity as an economic regulator and competition authority-has come up with several directives and regulations to create a level playing field for airlines and a more efficient use of scarce capacities to the benefit of the traveling public. additional comprehensive measures were adopted to address the capacity shortage at europe's airports and improve the quality of services offered to passengers under the umbrella of the "better airports package" (ec, 2011) . more recently, the ec (2015) introduced their "new aviation strategy for europe," which is supposed to foster innovation and generate growth for european business, while letting passengers benefit from increasing connectivity and safer, cleaner as well as cheaper flights. (additional aspects of aviation/airport policy will be considered in feature 5.1.) from a commercial perspective, the two main groups of airport users are the airlines, representing the primary customers (b2b) and the travelers or consumers using the dedicated facilities (b2c). for the airlines, airports are instrumental for offering their product by providing the required infrastructure to operate aircraft and service their customers being passengers and cargo shippers. these genuine airline customers are airport users or consumers at the (continued) same time. this also holds true for meters and greeters as well as employees. the airline business requires adequate airport access as well as facilities and services at competitive fees and charges, plus a growth perspective for future development. in order to address the airlines' demand for adequate capacity and facilities to operate their business, airports provide the required infrastructure and offer a range of services. these represent the main sources of their revenue. at most airports aeronautical charges include the categories summarized by table 1 .3. furthermore, a number of airports impose peak charges and/or noise surcharges (or discounts, as applicable), as a constituent of the landing charges. more rarely, additional charges fall due for aircraft emissions and the usage of centralized infrastructure, such as baggage sorters and underground fueling system. ground handling services are not necessarily provided by the airport operator but frequently by third parties. the latter case will then generate commercial income based on a concession fee paid by the handling agent. also fuel charges are usually not collected by the airport but levied by the fuel companies. government taxes bypass the airport operator in general. while chapter 3, measuring the financial position, will give an example of a table of charges and chapter 10, regulatory regime, will add pricing aspects, it is worthwhile stating two relevant principles stipulated by icao's (2012) "policies on charges for airports and air navigation services": first, the "user pays principle," which means to say that users should bear the full and fair cost for the provision of required infrastructure; second, airport charges are essentially cost based (leighfisher, 2017) . the airlines' customers-the passengers consuming at the airport-have a different perspective. today's savvy travelers increasingly expect both air carriers and airports to understand their preferences and provide personalized offers, advice, and guidance for their door-to-door journeys. empowered consumers will be loyal to those addressing their needs for information, control, and individual service. this, for sure, includes easy access to and processing at the airport for boarding their flight (ascend, 2014) . in order to address this demand, airports provide the required infrastructure and offer a wide range of services and amenities. the latter are frequently provided by third parties instead of the airport operators themselves. for running their businesses on the airport premises, these concessionaires have to pay a percentage fee on their turnover on top of a fixed rental fee. the major services are summarized by table 1 .4, representing sources of commercial income for the airport operator generated on the landside, primarily driven by passenger volumes. it needs to be noted that airport employees also make use of several services and contribute to the generation of commercial revenue. the same applies to (continued) airlines (primarily on the airside) generate aeronautical revenue, commercial or nonaeronautical revenue results from activities on the landside of the airport where passengers consume. global market forecast airports council international (aci) the impact of an airport smoothing the airport experience 38à40. boeing, 2017. current market outlook 2017à2036. boeing commercial airplanes the fight for slots the effect of international airports on commercial property values: case studies of the airport business. routledge specification for collaborative environmental management (cem) environmental issues for aviation challenges of growth-european aviation in 2040. eurocontrol, brussels. european commission (ec), 2011. airport package. com (2011) 823 final. ec, brussels. european commission (ec), 2015. an aviation strategy for europe. com (2015) 598 final. ec environment and energy research & development federal aviation authority (faa) a future perfect? trends and challenges for the aviation industry. 14th airline marketing workshop forecast reveals air passengers will nearly double to 7.8 billion. iata, montreal, press release 55. international civil aviation organization (icao), 2010. icao database-air transport statistics. icao, montreal. international civil aviation organization (icao), 2012. icao's policies on charges for airports and air navigation services economic impact of european airports-a critical catalyst to economic growth aviation investment-economic appraisal for airports, air traffic management airlines and aeronautics airport design and operation, second ed review of airport charges the heterogeneous impact of airports on population and employment growth in cities the continuing development of airport competition in europe quantifying the economic impact of aviation in dubai the evolving challenge of noise authorities and airlines renting floor space for operations and back offices, parking facilities, as well as associated utilities. major characteristics of concession contracts will be introduced in chapter 3, measuring the financial position.as with any other business, meeting customer needs and expectations is key to operating an airport successfully. this appears to be mandatory, as copenhagen economics (ce, 2012) confirmed by oxera (2017) found that: these findings apply primarily to small ,10 million passengers per annum (mppa) and medium sized airports, while larger ones .40 mppa are affected more by competition for transfer passengers. in general, airports are competing for any additional traffic in terms of passengers and cargo, particularly for: g passengers in a shared local market, g connecting passengers, and g airline services on new and existing routes (oxera, 2017) .although the focus of this research was on europe, it can be concluded from the wide-spread granting of commercial incentives to airlines across regions that airport competition has become a worldwide phenomenon in the meantime. various enticements have actually developed into a major tool of airport marketing, in addition to putting their products to the shop-window at the different "routes conferences." feature 10.1 will discuss the competitive situation in the sector in more detail. this chapter presented the historic development of global air transportation. as it is their main function to accommodate traffic, airports have advanced in response to it. traffic volume and structure, however, are not under full control of airport management but subject to overall economic, political and regional developments. an overview of airports' social, environmental, economic, and political impact was given. environmental concerns as well as changing customer demands and consumer behavior pose new problems in the digital age. addressing these is an ongoing and costly endeavor.this chapter's feature introduced to airport products and services. basically, two main types can be differentiated. while products and services delivered directly to key: cord-283979-1dn7at6k authors: portillo, aránzazu; ruiz-arrondo, ignacio; oteo, josé a. title: arthropods as vectors of transmissible diseases in spain() date: 2018-12-14 journal: med clin (engl ed) doi: 10.1016/j.medcle.2018.10.008 sha: doc_id: 283979 cord_uid: 1dn7at6k different aspects related to globalization together with the great capacity of the arthropod vectors to adapt to a changing world favour the emergence and reemergence of numerous infectious diseases transmitted by them. diptera (mosquitoes and sandflies), ticks, fleas and lice, among others, cause a wide spectrum of diseases with relevance in public health. herein, arthropod-borne disease are reviewed, with special emphasis on the existing risk to contract them in spain according to different parameters, such as the presence of arthropod and the circulation or the possible circulation of the causative agents. infectious agents. most avs belong to insecta and arachnida classes (table 1) . to review the broad subject of arthropod vector-borne diseases (avbd) in spain is a complex task. just listing the arthropods that transmit diseases in our environment, such as dipterans (culicids and phlebotominae sand flies), fleas, lice, bed bugs and ticks, among others, and the diseases they transmit, or that they can transmit at any given time, would be a reason for one or several treatises. in any case, before discussing the subject, it should be remembered that the infections that they transmit are usually included in the socalled zoonoses. in this regard, the world organization for animal health estimates that at least 60% of infections that affect humans have a zoonotic origin 2 and, according to the pandemic emerging threats program of the american agency for international development, almost 75% of current threats also have this origin. 3 one of the many known routes for the acquisition of zoonoses, apart from direct contact with animals or their products, faecal-oral or respiratory routes, bites or scratches, the consumption of undercooked 2387-0206/© 2018 elsevier españa, s.l.u. all rights reserved. products or the intake of milk, is av transmission. 4 it is difficult to limit this issue to our country, since the setting is global and very dynamic, and diseases do not understand political borders. only a few months ago new threats appeared, such as the re-emergence of yellow fever in brazil or the epidemic of plague in madagascar. 5 however, in this review we will put the focus on avbd with greater risk to humans in our environment, without losing the "one health" perspective. avbd are subject to complex interactions (demographic, social and cultural changes, climate change, wars and famine or evolution of microorganisms) among which, undoubtedly, global transport systems and the consequent invasion of exotic species 6 stand out. generally speaking, travel, migration and globalization contribute to the emergence of infectious diseases. its importance has been debated for many years and, possibly, dates back to ancient times. 7 humans carry their usual microbiota, pathogens, ectoparasites and other possible vectors, the immunological history of past infections and vaccines, the genetic load (greater or lesser susceptibility), cultural preferences, behaviours, habits and customs, as well as luggage (pets, goods and others). 7 in the case of avbd, the equation for the appearance of a certain disease would be the following: the presence of competent vector arthropods plus susceptible population, together with the presence of reservoirs and/or intermediate hosts (sick people), could give result an epidemic. the introduction of the tiger mosquito (aedes albopictus) and the threat of its expansion could be a good example. it is thought that a. albopictus was introduced in europe in 1979 through albania, by the trade of used tyres, although the first publication on its introduction in the european continent dates back to 1990 in italy. 8 since then, a. albopictus has expanded throughout the mediterranean area. in spain, this aggressive mosquito is well established in catalonia, levante, in the coastal area of murcia and andalusia. it has also been detected in guipúzcoa, 9 and little by little it is introduced in other non-coastal areas such as aragon, extending through travel routes (for example, motorways). 10 the last detection was carried out in the community of madrid 11 (fig. 1) . a few months ago, the first specimens of this species were also identified in the north of portugal. this mosquito has been incriminated as a vector of numerous arboviruses in different parts of the world, including europe. a. albopictus, is the chikungunya virus vector. in this regard, most of the cases in europe are imported, although in the last two decades there have been different epidemic outbreaks in italy 12 and, recently, in france. 13 in spain, only imported cases have been reported. 14 this mosquito (next to aedes aegypti which, as will be detailed later, has been detected in a timely manner in europe) can act as a vector of the dengue virus and with less effectiveness of the zika virus. 15 in france, a. albopictus was responsible for the first autochthonous cases of dengue 16 and of those reported in the same country during the following years, one of them with a history of travel to madeira, where a large outbreak had been reported (more than a thousand cases) between 2012 and 2013. 17 in 2011, the occurrence of autochthonous cases of dengue in croatia were also attributed to a. albopictus, establishing the transmission by this mosquito in europe. 18 in spain we are only suffering from their annoying bites, for now. 19 table 2 shows arbovirus infection and table 3 shows other infections transmitted by dipterans worldwide, with the risk of transmission in spain. we have evaluated the risk of emergence and/or re-emergence of these diseases in spain according to the existing studies for each pathogen, the experience according to other diseases, previous immunity and other criteria, some of them subjective, that do not appear in the text. a. aegypti is the main zika vector and also a transmitter of yellow fever, dengue and chikungunya. in principle, this species is not a problem because it is not settled in europe, although it has been detected in some areas, such as in an airport in the netherlands and, more recently, in fuerteventura 20 (canary islands) (fig. 1) . in view of the zika epidemic in the americas, the ministry of health, social services and equality, in collaboration with the carlos iii health institute and the autonomous regions, has established a zika virus disease surveillance in spain. to date (last update in july 2017), 325 confirmed cases have been reported, all imported, except 4 congenital cases whose mothers were infected in the risk zone and 2 autochthonous cases of sexual transmission. 21 it should be noted that it is not necessary to resort to invasive or exotic species to refer to avbd. thus, anopheles atroparvus is present in spain, a good malaria vector. the official map of the distribution of this mosquito is not updated; however, although the risk of a malarial outbreak is low in our country, 22 recent events have involved this species in the two cases of autochthonous malaria registered in the north of the peninsula. 23 spain was an endemic country of malaria until 1964, when who declared it a the risk of emergence/re-emergence is calculated based on three factors: (a) presence of cases of the disease in humans in the last 5 years in europe, mediterranean, central and south american countries with a significant relationship with spain; (b) presence of the vector in spain; (c) pathogenicity of the virus for humans. each factor is scored with one point (presence in the first two factors and low pathogenicity in the third factor) or with zero points (absence in the first two factors and high pathogenicity in the third factor). the first two factors are added and the third is subtracted. the total score can range between 0 and 2, with 0 being: low risk; 1: moderate risk; 2: high risk. free zone. in europe, after the eradication of malaria, most cases are imported, although sporadic cases have recently been reported in many mediterranean countries such as france, italy, greece. 24 the emergence of autochthonous cases in greece between 2009 and 2017 has raised doubts about the real situation in europe as a malaria-free zone. 25 other diptera present in spain which we cannot ignore are phlebotominae sand flies. the species phlebotomus perniciosus and phlebotomus ariasi, are the competent vectors of the leishmaniasis agent (leishmania infantum). there are also other potential vectors of l. infantum in spain, as they are phlebotomus papatasi and phlebotomus sergenti. leishmaniasis is endemic throughout the mediterranean basin in europe and its geographic scope is spreading. usually, the epidemiology of leishmaniasis was linked to the rural habitat with the presence of dogs. the great epidemic outbreak of fuenlabrada with a high number of cases in an urban area, in which leishmaniasis was not common, showed the dangers of changing the urban model in spain. many houses were built in rural agricultural areas with gardens and peri-urban green spaces where wildlife was present. in these places the concentration of phlebotominae sand flies was high, and, in their environment, there were not only dogs but also other l. infantum reservoirs, such as hares and rabbits. this fact together with mild temperatures in recent years, decreasing the mortality of the vector, seems to be what caused the great outbreak. [26] [27] [28] undoubtedly, the presence of phlebotominae sand flies throughout the iberian peninsula is a great threat, since not only do they transmit leishmania, but they are also toscana virus vectors, which is causing numerous cases of meningoencephalitis in some areas of spain 29 and other phleboviruses such as the granada virus (without proven pathogenic power), the naples virus or the sicily virus. 30 another species of mosquito to which special attention is to be paid is culex pipiens. this species, which is distributed and well represented throughout the iberian peninsula, is capable of transmitting the west nile virus (wnv). west nile fever is becoming a serious problem in some areas of europe, as in greece, where there has been an outbreak with numerous neuroinvasive forms, 31 and in 2017 cases have been reported in france, italy, romania, hungary, croatia, serbia and austria. 32 in spain, according to the data from the situation report and wnv risk assessment, published in 2013, there are several species of mosquitoes capable of virus transmission. for example, culex modestus, culex perexiguus and culex theileri show a high vector competence, while c. pipiens and a. albopictus have a moderate vector competence. 33 the first human case of neuroinvasive disease due to wnv in our country was identified, retrospectively, in a patient diagnosed with meningitis in september 2004 who, in the days before the onset of symptoms, visited a village in badajoz, extremadura (spain). 34 in 2010, the ministry of the environment reported the detection of wnv in 36 equine farms in the provinces of cádiz, sevilla and málaga. 35 through this active surveillance, 15 suspected cases were investigated and two human cases of wnv meningoencephalitis were confirmed. 35 between 2011 and 2016, virus activity was detected in equines, suggesting that the virus is endemic in our country. 36 in addition, there was previous evidence about its circulation in birds that were considered for the development of a predictive virus circulation model in our country. 37 another factor that clearly influences infections transmitted by arthropod vectors is climate change. in 2017 the international conference on climate change and health was held in atlanta, which revolved around the idea that: "health is the human face of climate change". following this meeting, a special article was published in the new england journal of medicine which stated that the distribution of infectious diseases such as lyme borreliosis, rickettsiosis or west nile fever are expanding at the same rate as their avs. 38 we know that climate variations and extreme weather events have a profound impact on avbd. 39 mosquitoes and ticks are devoid of temperature regulation mechanisms and, for this reason, fluctuations in temperature greatly affect their reproduction and survival. 40 in our country, it is more than possible that the great increase in the number of ticks in recent years is due to the fact that winters, in general, are much milder than years ago. just to mention an example, ixodes ricinus, the tick that most frequently bites people in the north of spain, is very sensitive to climate warming. this, among other factors, is increasing its survival. 41 this species of tick transmits very prevalent diseases in europe, such as lyme disease or tickborne encephalitis, or others such as rickettsia monacensis infection, human anaplasmosis, and babesiosis. 42, 43 in spain, human cases of all of them have been described, except for tick-borne encephalitis. although there is a high suspicion of the circulation of the virus in spain, the molecular screening of hundreds of ticks has been carried out in our laboratory, with negative results. 43 in addition, other pathogens have been detected in i. ricinus specimens collected in spain, such as rickettsia helvetica, candidatus neoehrlichia mikurensis or borrelia miyamotoi, which leads us to be alert to the possible occurrence of human cases. [44] [45] [46] as a consequence of climate change, the hypothesis about the probable changes in the distribution of another species of tick, hyalomma marginatum, which is the crimean-congo hemorrhagic fever (cchf) vector in europe, has also been established. under warmer climate conditions, according to prediction models, it is expected that the distribution of this tick species will extend to new areas which were previously free of the vector. in relation to this issue, the epidemiology of mediterranean spotted fever seems clearly associated with climate change, especially with low rainfall values 47 and it has been shown that warming causes greater aggressiveness in its avs. table 4 shows the tick-borne diseases throughout the world, with the prediction of risk for spain (subjective assessments). to be able to show a perspective on the avbd, it is essential to monitor and identify microorganisms in vertebrates and arthropods, designing strategies before their transmission to humans. early detection and implementation of control strategies allow minimizing the impact on the population. between 1990 and 2010, 91% of emerging infections spread from a wild-type focal point. 2 occasionally, the infection is spread directly from reservoirs such as bats, rats or chimpanzees to domestic animals, which amplify the infection, or to people; other times, infection dissemination (spill-over) occurs through av such as ticks, fleas or mosquitoes. in any case, it is essential to carry out a surveillance and to know the microorganisms carried by av. a recent example in spain is the detection of cchfv in ticks of the species hyalomma lusitanicum collected in deer a few years ago 48 in the province of caceres and the explanation of one of the possible ways of the arrival of the virus to our country. 49 detection of the disease that appeared in 2016 as, to some extent, it was predictable. on september 1, 2016, the ministry of health issued a press release reporting the death of a man by cchf and the contagion of the nurse who had taken care of him in the icu of the vallecas hospital where he had been treated. the first two autochthonous cases of cchf in spain were confirmed 50 (fig. 2) . in the last cchfv situation report and transmission risk assessment in spain, 51 52 the diagnosis of tick-borne diseases is not always easy. we must bear in mind that a tick bite history is usually absent in at least half of the cases and that incubation periods can be very long. depending on the size of the tick, they can be very difficult to see (they can simulate a small mole), and their bite is painless. unless there is awareness or a high index of suspicion when faced with certain signs and/or clinical symptoms, who is going to think of a tickborne disease? it is clear, "what is not sought, is not found". 52 in 2018, who revised the list of emerging pathogens that could cause serious epidemics in the future and those that need to be investigated, including cchfv, ebola/marburg virus, zika virus, middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov), lassa virus, nipah virus and rift valley fever virus. in addition, this year the list is completed with disease x, referring to an international epidemic that could be caused by a pathogen whose pathogenic potential and route of transmission is unknown at the moment. this list takes into account the transmissibility between humans, the severity of cases and the percentage of mortality, the difficulty of control and diagnosis and the context of public health and global expansion. in addition, there are other diseases that need more attention as soon as possible: hemorrhagic fevers by other arenaviruses, chikungunya virus, diseases by other highly pathogenic coronaviruses or by emerging enteroviruses and febrile syndrome with severe thrombocytopenia. 53 many of these diseases are avborne. high high debonel/tibola: dermacentor-borne necrosis, erythema and lymphadenopathy/tick-borne lymphadenopathy; lar: rickettsiosis associated with lymphangitis. a in spain, borrelia hispanica relapsing fever. the risk of emergence/re-emergence is calculated based on two factors: (a) presence of cases of the disease in humans in the last 5 years in europe, mediterranean countries and central and south american countries with a significant relationship with spain; (b) presence of the vector in spain. each factor is scored with one point (presence in the two factors) or zero points (absence in the two factors) and both are added. the total score can range between 0 and 2, with 0 being: low risk, 1: moderate risk and 2: high risk. another av that is said to have killed more people than all wars together is the body louse (human pediculus), transmitting exanthematic or epidemic typhus (rickettsia prowazekii), endemic recurrent fever (borrelia recurrentis) and the trench fever (bartonella quintana). body lice have been a serious public health problem until recently. they live in the seams of clothes and multiply in cold weather, lack of hygiene and war conditions. a person can be infested with thousands of lice, and each specimen is capable of biting an average of five times a day. it is said that body lice were one of the main problems during the russian revolution, where three million people affected by exanthematic typhus died. thus, vladimir ilyich lenin (1870-1924) stated: either socialism defeats the louse, or the louse will defeat socialism". here in spain, it was also a problem during the post-war period and was used as propaganda by franco's regime. we can ask ourselves: is there a risk of an epidemic or an epidemic outbreak of exanthematic typhus? it could happen, as it occurred in burundi in 1996, when a large epidemic affected more than one hundred thousand patients. 54 all the alarms went off when a red cross nurse was diagnosed after returning from work in the affected country. body lice are not seen on the body surface but live in the seams of clothing, in 20 ± 2 • c temperatures. parasitism by body lice should be suspected in persons with signs of scratching and lack of hygiene, more frequently in cold times of the year. at present, body lice have reappeared in refugee camps in europe, as in the second world war. in november 2015, the european center for disease prevention and control reported the emergence of 27 cases of recurrent fever due to body lice at different points along the route followed by refugees arriving in italy from the syrian war. 55 in western europe, although we have not experienced any epidemic since the post-war period, and the fact that the condition had been eradicated, occasionally, there are r. prowazekii and b. quintana infection reports in homeless people parasitized by lice 56 and cases of brill-zinsser disease have been described in people who have suffered from exanthematic typhus which could lead to an epidemic outbreak in certain conditions. 57 fleas are other bloodsucking insects of worldwide distribution with an impact in public health. rickettsia can be transmitted to humans by at least two species: the rat flea (xenopsilla cheopis), which is the endemic or murine typhus vector (caused by rickettsia typhi), and the cat flea (ctenocephalides felis), which is the key vector of rickettsia felis and, occasionally, of r. typhi. as far as we know, rickettsias are not transmitted by the human flea (pulex irritans). in europe, murine typhus is a common avbd in mediterranean countries such as greece, cyprus, croatia and spain, including the canary islands. 58 it develops as a non-specific febrile disease, with or without rash, which is often underdiagnosed. in clinical practice, murine typhus should be included in the differential diagnosis of any patient with fever of intermediate duration, that is, in a patient with fever (more than 38 • c) of more than 7 and less than 28 days of progression, without focality to guide the diagnosis, which remains without a diagnosis after an initial evaluation that includes a complete clinical history, physical examination, complete blood count, chest x-ray and biochemical blood and urine tests. 59 r. felis infection is another rickettsiosis with characteristics similar to murine typhus, of which cases have also been published in spain 60 and that should be considered in patients with fever and/or rash, with a history of contact with cats or flea bites. despite the fact that there have been no reports of autochthonous yersinia pestis infection transmitted by the rat flea (x. cheopis) in spain, there is an alert for travellers at the time of writing this manuscript due to an epidemic outbreak in madagascar that has affected several thousand people. 5 finally, we should remember the phrase written by hans zinsser in 1934 in his book entitled: rats, lice and history: "nothing in the world of living creatures remains constant. infectious diseases are constantly changing, new ones are in the process of development and the oldest ones are changing or disappearing". currently, ticks are considered the most dangerous avs in the world, because of their ease in moving from animals to people, because of their ubiquitous nature (they are present on all continents, including antarctica) and because of their capacity to agglutinate inside them a host of pathogenic microorganisms potentially transmissible through their hematophagous habits. the human tampering of ecosystems (deforestation, erosion of geographical limits to facilitate travel, etc.) or climate change are some of the factors that are favouring a greater contact between wild animals (with their ticks and the diseases they transmit) and people, facilitating the expansion of ticks to new previously unoccupied areas. diptera, ticks or other av may play the leading role in the next pandemic. therefore, anticipating the next public health crisis is in our hands. the authors declare no conflict of interest. biology of disease 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situación y evaluación del riesgo para españa de virus del nilo occidental. centro de coordinación de alertas y emergencias sanitarias (ccaes), ministerio de sanidad west nile virus in spain: report of the first diagnosed case (in spain) in a human with aseptic meningitis west nile fever outbreak in horses and humans epidemiology and spatio-temporal analysis of west nile virus in horses in spain between risk mapping of west nile virus circulation in spain preventive medicine for the planet and its peoples vector-borne diseases and climate change: a european perspective impact of regional climate change on human health driving forces for changes in geographical distribution of ixodes ricinus ticks in tick-borne rickettsioses in europe the risk of introducing tick-borne encephalitis and crimean-congo hemorrhagic fever into southwestern europe (iberian peninsula). in: virology ii -advanced issues role of birds in dispersal of etiologic agents of tick-borne zoonoses detection of tickborne 'candidatus neoehrlichia mikurensis' and anaplasma phagocytophilum in spain in 2013 borrelia miyamotoi: should this pathogen be considered for the diagnosis of tickborne infectious diseases in spain? boutonneuse fever and climate variability crimean-congo hemorrhagic fever virus in ticks, southwestern europe crimean-congo hemorrhagic fever virus in ticks from migratory birds autochthonous crimean-congo hemorrhagic fever in spain informe de situación y evaluación del riesgo de transmisión de fiebre hemorrágica de crimea-congo (fhcc) en españa. ministerio de sanidad fiebre hemorrágica de crimea-congo: «lo que no se busca no se encuentra list of blueprint priority diseases outbreak of epidemic typhus associated with trench fever in burundi rapid risk assessment: communicable disease risks associated with the movement of refugees in europe during the winter season ectoparasitism and vector-borne diseases in 930 homeless people from marseilles zinsser disease in moroccan man fever of intermediate duration: new times, new tools and change of spectrum cluster of cases of human rickettsia felis infection from southern europe (spain) diagnosed by pcr we wish to thank jorge garcía labeaga, of urbe ingeniería, for his collaboration in the preparation of fig. 1 . key: cord-029402-5gun91ep authors: celi, giuseppe; guarascio, dario; simonazzi, annamaria title: a fragile and divided european union meets covid-19: further disintegration or ‘hamiltonian moment’? date: 2020-07-17 journal: j doi: 10.1007/s40812-020-00165-8 sha: doc_id: 29402 cord_uid: 5gun91ep despite being symmetric in its very nature, the covid-19 shock is affecting european economies in a very asymmetric way, threatening to deepen the divide between core and peripheral countries even more. it is not covid-19 itself, however, but the contradictions within the eu’s growth model and institutional architecture that would be to blame for such an outcome. the dramatic impact of the economic crisis brought on by the pandemic and the threat that it poses to eurozone survival seem to have forced a reluctant germany into action: a minor step, but an important signal. this note analyses the crossroads currently facing europe—the risk of disintegration vis-a-vis the opportunity for a ‘hamiltonian moment’—discussing possible future scenarios in the light of past developments. like viruses, crises too can rapidly change their dna: the financial crisis of 2008 changed from international to regional, from financial to real, eventually turning into an existential threat to the whole european integration project. in the institutional context of the eurozone (ez), the financial crisis soon developed into a sovereign debt crisis, dragging the banks along with it. in the austerity environment that followed, the southern periphery (sp) never completely recovered the losses in output, employment, and fiscal sustainability. thus, the "symmetric" coronavirus shock hit countries that were in highly asymmetric conditions. in fact, not all the countries of the union have the resources needed to intervene in support of their economy, prompting concern that countries with the deepest pockets might be getting an unfair advantage in the eu's single market. far from triggering mutual protection, the covid-19 crisis seems to be paving the way for the same mistakes that followed the 2008 financial crisis. the centrifugal forces threatening disintegration of the european monetary union (emu) seem to have been defused, albeit only in part and only in extremis, at least for the time being. however, the survival of the union depends not only on responding to the severe financial problems caused by the epidemic, but also means addressing the long-term, structural problems that led to the increasing divergences among her members. as chancellor merkel herself acknowledged, "it is in nobody's interest for germany alone to be strong after the crisis". 1 convergence is essential to put the union on a more solid basis so as to guarantee its long-term sustainability. what policies and what reforms should be implemented to pursue this objective? and are they economically and politically feasible? trying to answer these questions, we shall briefly review the institutional and structural causes of the increasing divergence between core and sp, shedding light on three momentous events: the creation of the monetary union, the 2008 financial crisis and the covid-19 shock. the first decade following the introduction of the emu saw continuity in the process of europeanisation embarked upon as from the formation of the common market, based on financial liberalization and market globalization. as argued in celi et al. (2018 celi et al. ( ,2019 , europeanisation meant eu-wide application of a policy of deregulation of goods, labour and capital markets that affected the timing, shape and direction of the european integration process, halting the process of convergence between the core and the sp of the eu. the more developed core (centred on germany) increased its productive and technological capacity; the sp, caught between product competition within the eu and cost competition from emerging economies in the international markets, saw a decline in its manufacturing capacity. 2 with the fall of the soviet union and the entry of the former socialist countries of central and eastern europe in the eu, the eastern periphery (ep) became a key gear of germany's manufacturing matrix (stehrer and stollinger 2015) . a huge flow of direct investments, primarily in the automotive sector, transformed the economies 1 merkel: germany must help other eu states get back on their feet, euractiv.com with reuters 13 mag 2020 https ://www.eurac tiv.com/secti on/econo my-jobs/news/merke l-germa ny-must-help-other -eustate s-get-back-on-their -feet/. 2 these diverging trends are likely to increase as a result of the slow, small and asymmetric response that europe is giving to the ongoing pandemic-driven economic crisis, as confirmed by the macroeconomic evidence provided in this forum by heimberger et al. of the visegrad pact (poland, hungry, slovakia, and check republic) into an essential source of intermediate goods (medium and medium-high quality) for the german industry. a well-qualified, extremely cheap workforce, generous subsidies and tax breaks, as well as geographical proximity and historical links, are among the determining factors of the increasingly tight links between the core and its ep. the impressive growth in manufacturing capacity in the east led to a restructuring in the hierarchical organization of the supply chains across europe: the weaker suppliers in the south were displaced by their cheaper competitors in the east, while the highly specialised suppliers of components in the industrial regions of the south maintained, and even increased, their close links with the german producers. 3 the crowding-out of the less dynamic firms in the sp did not take the form of efficiencyenhancing market selection but rather a generalized reduction of production capacity, contributing to fuel a well-documented (see, among the others, guarascio and simonazzi 2016; dosi et al. 2019 ) process of 'poor tertiarisation' of the sp. on the other hand, the ep's industrial miracle was created by foreign, mostly german, direct investment, with the automotive sector taking the lion's share. so far, we have seen no comparable development of other productive sectors, nor has the automotive sector created spill-over effects in the rest of the economy (krzywdzinski 2019). on the contrary, the surge in the production of components for the automotive sector has partly displaced other productions, leading to an increasing 'mono-specialization' of these economies. despite a growing shortage of skilled labour, wages have remained modest. threats of production shifting further east, to romania, turkey, or to north africa, (pavlinek et al. 2017) 4 are reflected in the adoption of a wage containment policy at home, driving young people with high educational qualifications to emigrate, and weakening the countries' skills base. with domestic demand subdued, the high growth rates recorded by these countries are entirely led by the growth in exports of local production by foreign multinationals (i.e., the so-called "integrated peripheral markets"). while their intensive specialisation in the automotive industry makes them totally dependent on the health of the german automotive industry, the foreign control of production decisions, innovation processes and markets makes it extremely difficult to undertake an independent, less unbalanced development path (celi et al. 2018) . to conclude, the two peripheries-the southern one, made up of the mediterranean economies, and the eastern one, with the prominent role of the visegrad countries-suffer from different fragilities, which descend from their common, albeit diverse, economic and financial dependence on the core. however, the core itself is dependent for its growth on the pattern of specialisation within the eu: the southern markets providing an outlet for its increasing surplus of manufactures, the eastern countries supplying cheap inputs for its industries. this combination of structural divergence and economic interdependence lies behind the fragility of the union as well as of the improbability of its disintegration given the high costs it would entail for core and peripheries alike. in the first period of the emu (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) , the core-sp structural divergence was partly hidden by massive financial flows to the periphery. the 2008 financial crisis, and the ensuing international liquidity crunch, prompted a "sudden stop" of capital flows and a collapse in demand and imports. at that point, the structural and institutional flaws of the emu became evident: the reaction to the crisis aggravated the divergence. with the blame for the crisis put squarely on borrowers, austerity policies were advocated (or imposed) to ensure debtor countries' public and private solvency. with austerity killing demand, growth and imports in the sp, germany, which had built most of its huge trade surplus between 2003 and 2008 by exporting to the periphery, had to find new outlets for its goods. special international conditionsnamely, china's huge growth, which gobbled up german capital goods and highquality durable consumer products (particularly cars), and the vigorous american recovery-supported germany's ability to redirect its trade flows, expand its market shares outside the emu, and make a speedy return to its pre-crisis production levels. the united kingdom, the united states, but above all china, became the most important markets for german exports. the rapid recovery of the german economy pulled the ep along with it: the visegrad countries recorded unparalleled growth in europe. with the abrupt change in the international scenario in 2016, germany's (and the entire emu's) mercantilist strategy was up against the ropes. the brexit referendum, trump's election, and the u-turn in chinese economic policy inaugurated a phase of retreat in international trade. trade with the uk began to suffer due to the increasing uncertainty in future trade relations. when the united states took action to reduce the external deficit, china and germany, the countries with the largest trade surpluses vis-à-vis the united states, were caught in the crosshairs. trade tensions between the us and china put further pressure on international trade. the export-led growth model that had so far supported germany's leadership began to creak. the change in world trade took its toll on german (and eu) growth rates. from the second quarter of 2017, the slowdown in german exports hit industrial production and the gdp, widening the growth gap with china and the usa and dragging the whole emu along with it ( fig. 1) . as the escalation of trade disputes affected relations between the united states and germany 5 (and by extension the eu), the negative effects on europe's (exportled) growth intensified. in the last quarter of 2019, just a few months before the outbreak of covid-19 in the eu, germany's growth rate zeroed. income growth estimates for the rest of europe were consequently reduced. the pandemic arrived in europe from the south: italy was the first country to suffer the contagion. its abrupt, dramatic effects exposed the fragility of the periphery and the crippling effects of austerity policies. since 2010, across the board cuts in social spending had hit the entire range, from health to education, from social assistance to social investment. 6 figures 2, 3 and 4 show the evolution of the share of public expenditure on education and health (divided between general expenditure and hospitals) relative to gdp in the emu, germany and the sp between 2008 and 2018. many hospitals had been closed, the number of beds reduced, medical and nursing staff cut back (for a detailed analysis of the impact that austerity policies had on the italian health care system, see prante et al. 2020 ). it is not surprising that the death toll was higher where intensive care facilities were scarcer. on the eve of the covid crisis, public health accounted for 6.5 percent of the social product in italy and spain, and almost 10% in germany, where per capita healthcare spending did not suffer cuts due to austerity (though it was not completely spared self-imposed restrictions). the covid-19 exposed another aspect of the 'divisive' union (celi et al. 2020) : different capacities to respond to the pandemic crisis. economic ideology shares with austerity the responsibility for the scant endowment of medical equipment and health staff. efficiency, understood as cost reduction, has been taken as the guiding principle. the obsession with competitiveness and reliance solely on the export-led growth model accounts for the almost exclusive emphasis on "tradable" sectors, to the detriment of "non-tradable" sectors (housing, health, education, welfare services in general), considered of lesser importance for international competition. this means that, in the era of austerity, these items have been the first to be sacrificed, in debtor and creditor countries alike. chazan (2020) reports that for years, politicians and health economists in germany have complained that the country has too many hospitals, with the bertelsmann foundation recommending halving the number of hospital, from 1400 to fewer than 600 (chazan 2020 ). only such a radical consolidation-the bertelsmann study arguedwould "improve patient care and mitigate the shortage of doctors and nursing staff". the pandemic succeeded in transforming this "oversupply" into an asset. the same logic of pursuing the lowest cost guided the international location of production, which displaced domestic production and weakened production capacity in the sp. from a regional (european) point of view, this process resulted in a reorganisation of production and trade relations between core, ep and sp. on a global scale, core and peripheries entered into very long and complex gvcs that proved extremely vulnerable in the face of the interruptions prompted by the pandemic. personal protective equipment, respirators, medicines: the emergency has made it clear what it means to lose the capacity to produce domestically, both in quantity and quality, what is urgently needed, bringing the problem of self-sufficiency back to the attention of economists and policymakers. there is no such thing as a symmetric shock. in addition to the grim toll of victims and the incredible pressure on the health systems of all countries, the lockdown of activities to reduce contagion meant a tremendous plunge in production and incomes and enormous pressure on public finances all over the world. however, the lockdown is expected to affect economies differently. the central and eastern european countries have been less affected by covid than the western european countries: not trusting the resilience of their fragile health systems, they have had to rely on rigid social distancing (walker and smith 2020) . even within this group of countries there are differences: thanks to their more robust health systems, the czech republic and slovenia were less constrained by rigid social distancing and able to start economic recovery earlier. moreover, due to their strong productive links with austria-a country relatively less affected by the pandemic which came out of the lockdown earlier-and their favourable positioning in the development of digital economy (wiiw 2020) , their economic outlook is rather better. conversely, it will be tougher for the economies, like those of the sp, which are more dependent on services-tourism and hospitality in particular (fig. 5) -and for cee countries and southern regions that rely to a greater extent on production of intermediate products for final producers, since the latter can better defend themselves from fall in demand by cutting down orders to their suppliers (the so-called "whip effect"). policies have also differed widely across countries and regions. while all the central banks of the developed world promptly intervened to provide almost unlimited . although the stability pact has been temporarily suspended, 7 there are obvious differences in how much member states can spend, depending on their fiscal space. member states are making use of the new flexibility granted by the ec on state aid rules, strictly enforced beforehand to ensure fair competition within the internal market (rios 2020) . germany, which accounts for about a quarter of the eu's gdp, accounts for more than half (52%) of the emergency coronavirus state aid approved by the ec, prompting concerns that countries with the deepest pockets might be getting an unfair advantage by such a sudden (and temporary) abandonment of one of the common market's key pillar (france and italy each account for 17% of the total). an eu official, speaking on condition of anonymity, observed that "if you look at the scale of what germany in particular, but also some others, are doing-any notion of level playing field or single market integrity has gone out of the window." 8 these concerns underpin the ailing south's demand for a joint eu financial plan. in the absence of a prompt and massive common effort, the sp will pay the highest price to the health crisis. indeed, the different firepower will entail a still greater asymmetry in the economic and power relations between the various member states. the ecb, alone among the eurozone institutions, is doing as much as it can to avoid breakdown of the emu. to address the covid-19 crisis, it launched a new asset purchasing programme: the eurosystem's balance sheet shot up from 4692 billion euros on 28 february to 5395 billion by 1st may 2020. despite this massive monetary injection (700 billion in two months) the spread on italian bonds, which had fallen in mid-march following the ecb's announcements, again rose very rapidly, fluctuating in response to political developments. indeed, as tooze and schularick (2020) point out, if, in the 2008 crisis, the liquidity injected into the system by the ecb was enough to prevent deflagration of the banking system, 9 the current crisis would require a coordinated fiscal policy of enormous proportions. despite some recent moves (inaugurated by a merkel-macron agreement), this still does not seem to be looming on the horizon. the newly released 'next generation' (ng) plan, based on the 2021-2027 budget, celebrated by some as a "hamiltonian moment", has yet to qualify as forerunner of an eu-wide up-to-the-challenge fiscal capacity. 10 first of all, it is meant to be temporary and, moreover, it is too little, too late. the plan should mobilize 750 billion euros, 500 in the form of grants and 250 in loans. 8 quote reported by the website euractiv.com. 9 the eurosystem balance sheet (the network of european central banks, guided by the ecb) rose from 1150 billion euros at the beginning of 2007 to 4675 billion euros by the end of 2018; that is, from barely 10% to almost 40% of the euro zone gdp (12 000 billion euros). 10 the ng plan money will be spent over the 2021-2024 period. with an even subdivision over the period, the package amounts to an annual 0.56% of the eu's 2019 gdp, over four years. 7 several parties, including most recently the president of the ecb, christine lagarde, are urging the ec to review the pact before its temporary suspension expires on december 31, 2020. apart from the fact that these are gross figures-once the member states' contributions to the eu budget are subtracted, the net amount received by the neediest countries is much smaller-their disbursement will not start before 2021, will be distributed over a 4-year period, with amounts that grow over time, and, as stated in the ec's "proposal for a regulation" the financial contribution will "be paid in instalments once the member state has satisfactorily implemented the relevant milestones and targets identified in relation to the implementation of the recovery and resilience plan" (ec 2020, art. 17.4.a). as darvas (2020) emphasizes, the incorporation of the ng plan into the eu's next multiannual budget would take advantage of a well-established framework, 'already subject to various checks and balances'. on the other hand, ng resources risk to be trapped in a 'slow-moving machine'. in order to be financed, ng-related projects need to be designed, approved and implemented as part of a process that can take several years. as a result, the timing of disbursements is just the opposite of what would be required to respond to the urgency imposed by the current situation and, even more so, by the expected collapse of incomes that the european economies are going to face. 11 however, the commission expects that barely 24.9% of the total new firepower for grants would be spent in 2020-2022, when the recovery needs will be greatest (darvas 2020) . far from being a tool to counter the immediate effects of the crisis, the ng plan is more similar to the juncker plan, and shares all its weaknesses. 12 it is highly unlikely that countries like italy, severely hit by the pandemic and in persistent financial distress, will be able to afford to refrain from asking for other funds (namely, esm, sure and others for a total amount of about 59 billion euros) which could be paid out immediately, subject to the usual conditionality. the merkel-macron agreement has been hailed as the first step towards a more supportive union. behind the good intentions, there are the concrete interests of both france and germany for the survival of the emu: they look with growing concern at the rise of euroscepticism in the sp. the french economy has been hit hard by the pandemic, and was already in difficulty before. gdp forecasts for 2020 vary widely, but all agree in estimating a fall in the french gdp of much the same proportions as in the case of italy. on the other hand, germany was, together with the netherlands, the main beneficiary of the creation of the euro, and italy and france were the main losers (gasparotti and kullas 2019) . 13 as chancellor merkel told the german lawmakers, "it is essential for germany, as an export nation, that its eu partners also do well". 14 indeed, the history of the eu has taught that excessive german surpluses are deleterious for the south of the eurozone. greater government action, retreat from hyper-globalism, and lower growth rates predate the pandemic. the covid-19 crisis has given yet more voice to calls for protectionist and "beggar thy neighbours" types of policies. it has led countries to prioritize resilience and autonomy in production over cost savings and efficiency through global outsourcing. the same powerful german production platform, so disproportionately export-oriented and dependent on imports of intermediate goods, finds itself vulnerable to a type of shock (the covid-19 pandemic) that disrupts gvcs and threatens to change the existing economic order through permanent disruption of the patterns of demand and production. although transition from an industrial platform designed for export to one for the internal market (a sort of transition from a war to a peace economy) is a formidable challenge, this transformation would benefit germany itself, considering the winds of trade war and the growing uncertainty about the future developments of the global value chains. the european countries are at a crossroad between either letting the union dissolve or radically reforming it. today's darkened geopolitical environment requires europe to act as a whole. however, the emu will remain fragile as long as it chooses to continue to delegate control over its policies to market surveillance. a true "hamiltonian moment", which involves adopting a common fiscal policy in support of the common monetary policy is a matter of urgency. we still have a long way to go. divisions between member countries marked by opposition between debtors and "frugal" creditors, as well intra-country political struggles and conflicting interests, have-even in the face of this dramatic crisisled to the paralysis of the european institutions, with the one exception of the ecb. faced with what she sees as a serious threat to the eu's survival, the german chancellor (and the commission's president ursula von der leyen) have been driven to action. however, as we argued in sect. 3, little can be expected from the ng plan for immediate support. the ability of the sp to emerge from the crisis will increasingly depend on its ability to take advantage of the greater flexibility of eu rules for an efficient use of industrial policy, helping companies and the whole economy to respond to the challenge posed by social and technological innovation, the restructuring of production and the reorganization and shortening of gvcs. the pandemic will have significant repercussions on the international organization of production and gvcs (on this point, see also the contributions to this forum by strange and coveri et al.) . indeed, the countries initially most affected by covid (china, korea, italy) are among the most important suppliers of intermediate goods at the international level. studies on the propagation of economic shocks triggered by natural disasters (such as the earthquake that hit japan in 2011) along the value chains (boehm et al. 2019 ; inoue and todo 2019) found significant supplier substitution effects. anecdotal evidence signals numerous cases of supplier substitution in some countries as a result of the coronavirus (baldwin and tomiura 2020). the extent of these effects depends on the degree of complexity of the production chains, which affects the degree of input substitutability. propagation effects also depend on the presence of "hub" companies interconnected with a large number of supplier and customer firms (inoue and todo 2019) . future developments are uncertain, depending on the relative strength of two opposite effects. on the one hand, greater coordination afforded by digitalisation of production networks could favour substitution effects (especially in cases where value chains are less regionalised and the search for new suppliers is more difficult) (zhenwei quiang et al. 2020 ). on the other hand, processes of reshoring and shortening of value chains could occur, especially where production chains are less complex or automation is more advanced. the second possibility could represent an opportunity to reverse the processes of deindustrialization that have impoverished, above all, the productive fabric of the peripheral countries. a third perspective, probably utopian, could contemplate coordination of coalitions of producers across eu member states. in a situation of strong productive complementarities between countries, the fortunes of the producers (workers and firms) in one country are bound to those in the other. this would call for a coordinated industrial policy at the european level aiming at ensuring a balanced development of the economies of its members through their integration in the european production networks. in emergency situations where production activities are reduced or temporarily suspended (as in the case of coronavirus shock), bilateral agreements (mediated by governments) between producers in different countries should aim at stabilizing employment levels and pre-existing supply contracts between firms through "mutualisation" of the required financial effort. after all, having surprisingly spoken out in favor of the eurobonds, the ceo of volkswagen herbert diess could-at one remove-be also supportive of such a project! material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. thinking ahead about the trade impact of covid-19 input linkages and the transmission of shocks: firm-level evidence from the 2011 tōhoku earthquake crisis in the european monetary union. a core-periphery perspective unravelling the roots of the emu crisis. structural divides, uneven recoveries and possible ways out un'unione divisiva. una prospettiva centro-periferia della crisi europea germany's oversupply of hospital beds aids pandemic fight, the financial times next generation eu: 75% of grants will have to wait until 2023 neodualism in the italian business firms: training, organizational capabilities, and productivity distributions proposal for a regulation of the european parliament and of the council establishing a recovery and resilience facility germany gains most from relaxed eu state aid rules re-prima -tranc he-4-milia rdi-780f3 570-a447-11ea-b19d-c1248 28d4b 5b_previ ew.shtml ?reaso n=unaut henti cated &cat=2&cid=17219 14576 &pids=po&credi ts=1&origi n=https %3a%2f%2fwww .corri ere. it%2fint ernat ional %2fpre mium%2f20_giugn o_01%2frec overy -plan-tutti -ostac oli-fondi -europ eiralle ntato re-prima -tranc he-4-milia rdi 20 years of the euro: winners and losers. an empirical study, cep study a polarized country in a polarized europe: an industrial policy for italy's renaissance firm-level propagation of shocks through supply-chain networks globalisation, decarbonisation and technological change: challenges for the german and cee automotive supplier industry foreign direct investment and the development of the automotive industry in eastern and southern europe decades of tight fiscal policy have left the health care system in italy ill-prepared to fight the covid-19 outbreak eu countries use looser state aid rules to uphold troubled firms the central european manufacturin core: what is driving regional production sharing? (no. 2014/15-02) the shock of coronavirus could split europe-unless nations share the burden. the guardian why has eastern europe suffered less from coronavirus than the west? the vienna institute for international economic studies foreign direct investment and global value chains in the wake of covid-19: lead firms of gcv acknowledgements open access funding provided by università di foggia within the crui-care agreement. key: cord-304282-om2xc4bs authors: berhan, yifru title: will africa be devastated by covid-19 as many predicted? perspective and prospective date: 2020-05-17 journal: ethiop j health sci doi: 10.4314/ejhs.v30i3.17 sha: doc_id: 304282 cord_uid: om2xc4bs nan since the novel coronavirus disease 2019 (covid-19 or sars cov-2 infection) has been declared as pandemic, several mathematicians and statisticians have developed different trajectory curves for africa, with the assumption that the virus can have an exponential pattern of transmission. according to economic commission for africa, 300k-3.3 million covid-19 related deaths may occur in africa (1) . a large body of literature and international media have also predicted that africa is going to be flooded, much higher than europe and the united states of america (usa). for ethiopia alone, some estimated 28-33 million with full mitigation and 70-107 million people without mitigation actions can get infected. when the author of this perspective sees such an easy to do, but hard to conceive figures, he likes to join the closed loop forum and express what his thought is. as of 21 st april 2020, close to 23k confirmed cases and 1000+ deaths are reported from 55 african countries, while the global figure climbs to more than two and a half million and individual countries in the west are reporting the highest ever cases (200k-700k+) and deaths (24k-42k+) in less than three months (2) . the hardest hit countries being the most capable to tackle such kind of infectious outbreak, and the extremely contagious nature of this virus is the puzzle and unprecedented phenomenon. virtually, countries of the globe do not look like they are ordered by the burden of this infection; the actual magnitude of case and death load in each looks as if they are ordered by their economic power and financial muscle. the bottom line is that this infection has been exponentially spreading, and becoming highly prevalent and fatal in the richest countries. that is not yet happening in countries within the tropical climate zone. will it be like that in the weeks or months to come is the core question of this perspective. some may argue that the developed countries testing capacity is what has inflated the case load, citing usa and germany as an example. yes, the high test uptake has helped the developed countries to identify as many cases as possible in a short period of time. rising in the last three months in the western countries of the temperate climate zone was not only case load, but also the staggering mortality figure and the severely morbid cases (hospitalization for pneumonia, icu care, dialysis, and blood transfusion), which are the two key measurements to show how severe the actual magnitude of the covid-19 is. a very important argument is; had the covid-19 transmission been as contagious as in europe and usa, by this time, every health facility in africa and other tropical countries could have been flooded with severely ill patients and deaths. but, that is not the case in any of african and tropical countries. the other side of the coin is; the overwhelming cases and deaths experienced in europe and usa is despite the fact that they started to report covid-19 confirmed cases almost same time or later than many of the countries in the tropical climate zone. up to now, the proportion of mortality in the majority of covid-19 reporting countries is in the lower range (<10%) (2) . the relatively high case fatality rates among countries with larger case load are reported from europe and one north african country (algeria). this observation may lead to pose questions on the predilection of the transmission and the survival of the virus particle outside the human body at different climate zone, as discussed below. on blanket view of the global distribution of the infection, relatively low case and death load is observed across africa, south middle east, south and southeast asia and latin america. since the beginning, the epicenter has moved from east to west along the temperate climate zone, and causes incomparably massive casualties. even in africa, the relatively hardest hit countries are still outside the tropical zone (algeria, egypt, morocco and south africa). countries in the tropical zone of asia and latin america, with relatively high case load, are not yet as hot spot as western countries in the temperate zone, despite the proportional duration of exposure; the cumulative number of deaths is incomparably low. the mathematical modeling result for the stated period using hypothetical numbers and the reported data from several tropical countries is far apart. brazil looks an exception, probably due to the rainy season or high tourist flow just around the outbreak. further, this is despite the fact that some african countries has started reporting covid-19 cases even earlier than some western countries with high case load. many authors have underscored the high mobility of the global population for the rapid spread of covid-19 in hot spot areas. but, the number of cases in many of the african countries is large enough to result in exponential transmission of the virus and be able to make hot spot. age and sex strata are some of the factors determining the prognosis, but not that much strong to justify the exponential transmission. hereunder, some more critical appraisal is presented. what can we learn from history to upkeep the above argument? with our limited knowledge, what history tells us may be in line with what we are observing the covid-19 pandemic at this juncture. as read from chronicles of influenza and other coronaviruses pandemics, the biology of sars cov-2 may have something to do with the climate to have exponential or restricted rate of transmission. it is not debatable that sars cov-2 is the seventh well known new coronavirus that infects humans (after sars-cov, mers-cov, hku1, nl63, oc43 and 229e) (3). sars-cov and mers-cov are also new coronaviruses detected in humans in 2002 and 2012, respectively, and are highly fatal (4) . the mean global case fatality rates of sars cov-2, sars cov and mers cov are 5%, 10% and 35%, respectively (2, 4) . the last four coronaviruses usually cause mild upper respiratory tract infection, with the exception of oc43, which once had caused an outbreak of severe pneumonia in france (5) . like sars cov-2, sars cov originated in china (guandong province), and was subsequently able to disseminate to europe and america, almost similar with the current trend. sars cov has become pandemic by reaching to 33 countries in different continents, while the epicenter was in hong kong, with a total 8,096 infections and 774 fatalities in a year period globally (4). asian and european countries are the ones which are still sporadically reporting sars cov infection. the dissemination of sars cov to countries in the tropical zone along the globe, however, was minimal or none at all. another important milestone that consolidates the origin of the previous and current sars is the emergence of another new coronavirus in 2016 (named sads cov) from china near the origin of sars cov, which killed 25k piglets (6) . the point is; the spread of mers cov and sars cov was predominantly in asia and europe. probing the history of influenza pandemics and the tropical epidemics can also give some clue on the likelihood distribution and proportion of cases and deaths of the current pandemic. since the time of hippocrates (460-377 bc), infectious disease pandemics had ravaged millions of human lives. some of the attributed etiologies for the outbreaks had international and regional propensity. yersinia pestis, which caused the 'black death' of 75-200 million people and the typhus fever which killed more than 3 million in europe alone during the second world war are bacterial etiology, and were not having continental or national boundary. neisseria meningitides (the one causing meningitis outbreak along the meningitis belt), malaria, yellow fever, cholera, shigellosis, dengue fever are still common causes of outbreaks in the tropical climate zone. seasonal influenza outbreaks due to h3n2, h2n2 and h1n1 have been predominantly occurring in the northern hemisphere. the implication is that geographical and climate change may influence the microorganisms' survival outside the human body, and may determine the incubation period of the pathogen in the human body. influenza outbreaks occurred in europe and usa during cold and low humid weather (usually starting in winter and subsiding in spring), while meningitis and cholera outbreaks occurred in the tropics during hot weather and rainy season (usually preceding flood), respectively. although there is a long list of highly catastrophic influenza pandemics at different period of human history, it is worth mentioning those in the late 19 th , early and second half of the 20 th century and early in this century. among others, like the current pandemic, the 'russian flu'/h3n2 (1889-1890) and 'hong kong flu' pandemics/h3n2 (1968) (1969) (1970) which each killed one to four million people, and 'asian flu' pandemic/h2n2 (1957) (1958) which killed 2 million people originated from asia and massively spread to europe and america. 'spanish flu'/h1n1 (1918) (1919) (1920) , which originated from spain, and killed 25-50 million people spread globally. another 'russian flu' pandemic/h1n1 erupted in 1977-1978 and killed around 700k people worldwide (7) . an important observation was that, like the currently observed covid-19 pandemic, the morbidity and mortality of the aforementioned influenza outbreaks were not that much spreading and killing outside the temperate zone, at least in africa. the first 'russian flu', for instance, reached in northern african countries, including egypt and algeria, but the case load and mortality were not as high as the european countries. in england alone, more than 132,000 people died of 'russian flu' in just one year. the 'asian flu' pandemic had also reached to many parts of africa, but was not highly catastrophic as it was in the northern hemisphere. the spanish flu was a bit exceptionally highly fatal in many parts of the world. it was estimated that about 2% of africans died. even then, in south africa (temperate zone) the estimated mortality (500k) was 10-fold higher than ethiopia (40k-50k), which is somehow in line with the current pandemic (8) . as a continuation of the old pandemics, the seasonal outbreaks and casualties of influenza in europe and usa are still devastating. according to the centers for disease control and prevention (cdc) of usa report, the 2017-2018 influenza outbreak killed 61k people in the usa alone, which was higher than the influenza related deaths (56k) in 2012-2013 season (9) . the 2017 global estimate of deaths due to seasonal influenza was between 291k-646k (10). most of these deaths due to seasonal influenza occur in north asia, europe and north america. the 2009 swine flu pandemic that originated from mexico was the third h1n1 influenza pandemic (2009-2010) that resulted in about 150k-575k fatalities predominantly in north and south america, west europe, south and southeast asia, and australia (11) . interestingly, among african countries, only egypt, algeria and south africa were part of the swine flu pandemic. the who annual estimate of mortality due to seasonal influenza is also a quarter to half a million. the bottom line is that, with the exception of the spanish flu, neither of the influenza pandemics seriously affected the african continent. the purpose of citing the above mortality figures is to show that there are infectious disease conditions which follow seasonal changes and are not proportionally distributed across the globe. the common causes of infectious outbreaks in the tropics and temperate zone are not same. otherwise, the influenza viruses and coronaviruses are biologically, pathogenically and epidemiologically completely different. what is probably in-common in the two groups is their potential to cause pneumonia and ability to expose to secondary bacterial infection. from previous coronavirus outbreaks (sars cov, mers cov) and influenza outbreaks as a proxy, one may extrapolate that the tropical zone may not be hit by covid-19 as hard as the temperate zone. the explosive nature of the covid-19 spread to every corner of the six continents, however, may make it incomparable in all parameters with the previous coronavirus and influenza outbreaks. notwithstanding this thought, the already observed rate of spread in the tropics is not as skyrocketing as the temperate zone, despite the virus lands almost two months back in many countries. in other words, the cases and deaths will likely increase, but not with flooding nature as seen in the temperate zone. as noted earlier, the number of confirmed cases may be underestimated due to lack of adequate testing. however, the seriously ill and death rates cannot be underestimated. let alone the covid-19like outbreak, we know how many hospitals are overwhelmed when there is an outbreak of smaller scale. therefore, the severe morbidity and mortality indicators so far reported in the two zones have shown a remarkable disparity. overall, the cumulative cases and deaths will as well increase in africa, and it may even last longer than other types of pandemics, but the chance of exponential increment looks less likely. as sars cov, covid-19 is likely to be endemic in asia, europe and north america. among others, the very crowded day and night social life and the poor personal and environmental hygiene in this zone can be thought as creating a very conducive environment for the spread of covid-19 and any other communicable diseases. the high prevalence of malnutrition, malaria, tuberculosis, stress and non-communicable diseases (including diabetes and hypertension) may also make the majority of the people at higher risk for death. it is probably with this background why many are predicting the worst in africa. there is also a different assumption that the majority of african people and many more in the tropics are already exposed to several viral and bacterial infections (the justification for the planned bcg trial), which could help them to have a herd immunity to be protected from closely related pathogens. however, this theory may not be that much valid as the observed case fatality rate among covid-19 infected persons is not different from other parts of the world. if that is not the case, why the european or the american type of cases flooding into hospitals and overwhelming deaths are not yet observed in africa, in particular, and other countries in the tropics? one may argue that the carriers of this virus are still few in the respective countries. as the international travel of the people in the region is relatively limited, yes, that is partly true. however, it is also hard to accept that many of the first carriers of the virus in asia, europe and usa had a chance to travel to china/wuhan and around; quite significant number of community transmission was noted in europe and usa. it is also not wise to think that the number of the first carriers of this virus was too few to transmit the virus in africa as the transmission is presumed to have an exponential pattern (1 for 3, then 3 for 9, 9 for 27 and the like). nigeria (the first most densely populated african country with highly mobile urban population) reported the first case on february 27 th , but its case load and deaths after nearly two months are 665 and 22, respectively (2). the second most densely populated african country and owner of the famous ethiopian airlines (ethiopia), which has been flying to 130 international destinations till march 20 th /2020 at which time restriction was made to 30 countries, has reported its first case about five weeks back; so far, has 114 cases and 3 deaths. egypt (the third most densely populated african country with large tourist flow before the outbreak and large number of its citizens working in europe) reported the first case one week earlier than italy, but the magnitude of cases and deaths are totally incomparable (italy's deaths are nearly 100 times of egypt). the case load curves of many african countries are also waxing and waning type; a steady type of increment is not yet observed in the last 2-3 months, which is against with an exponential spread. this may not be solely explained by the preventive measures implemented, as there were several inconsistencies and breaches in many parts of africa. some also argue that the absence of community transmission is what has contributed to the low case load in africa and elsewhere with few cases. it is true that the majority of the transmissions occur in the community in europe and usa. however, it is still difficult to take it as a major reason for the low case load in several countries after reporting their respective first case nearly two months back, and with limited containing and mitigating actions. if we take ethiopia as an example, the wisdom of the author is that the covid-19 was imported probably several weeks before the quarantine was initiated for those who were coming from abroad. ethiopian airlines have been flying to more than 75 countries in the world (including china at 5 destinations). therefore, as the very recently confirmed case reports showed, the assumption is that the virus carriers are already within the community, and probably in many other african countries too. the recently reported eight cases in ethiopia came from the community with no contact history. the majority (>60%) of the reported cases had an incubation period for more than two weeks, which is in contrast to the experience in the temperate zone. in literature, with few exceptions (24-27 days), the incubation period is less than two weeks. this is probably another research area on the impact of the climate on the multiplication of the virus in the human body and its survival outside the human body. although it is too early to deduce, the author's assumption is that africa and many of other countries in the tropical zone are less vulnerable to coronavirus and influenza virus infections, primarily because of the weather condition. until proved otherwise, this is probably because of the lower survival of the coronaviruses and influenza viruses in the external environment here in the tropics, whereby the humid weather condition is probably hostile to the virus to live outside the human body, thereby having a limited chance of proliferation and transmission from one person to another one unless it gets access as early as possible it is out. this hypothesis is going to be tested soon, at least for sars cov-2. in 2011, chan and colleagues reported that sars cov viability was rapidly lost (>3log10) at higher temperatures and higher relative humidity (12) . thus, in europe, usa and north asia, in particular, sars cov and sars cov-2 may live longer in the cold seasons outside the human body and be able to proliferate fast in the human body and infect as many people as possible. furthermore, in europe, sars cov-2 is reported as staying viable up to 17-day outside the human body. had this been the case here in africa and other places in the tropics, by this time, the covid-19 related admissions to hospital and deaths could have been overwhelming. with this regard, ethiopia and many african countries may as well benefit from ultraviolet radiation (uvr) b exposure. it is well proven fact that ozone depletion, prolonged sunlight exposure, higher altitude and latitude increase the uvr b exposure, of which ethiopia specifically has double advantage to be protected from covid-19 like epidemics (high altitude and prolonged sun light exposure). living organisms in general and microorganisms in particular are at higher risk for uvr b effect. uvr b is known to kill viruses by chemically modifying their genetic material (dna and rna viruses). during rainy or cloudy season, 70%-90% of uvr b type is blocked, which may be one of the possible reasons for low incidence of covid-19 in the african region at this dry moment (13, 14) . although it is unlikely to be the reason for all, one cannot ignore the timely actions of many of the african governments' role in implementing many of the preventive measures, including lockdown in a few countries. in many places, the public response to the call was also appreciable. here in the ethiopian capital, contact tracing, handwashing and preparations with available resource for the worst ahead are very impressive and commendable. streets are not that much crowded with pedestrians, and traffic jams have significantly decreased, which all have probably played some role in reducing the exposure. here and there handwashing service and practice was looking as the campaign is active, but could not be long-lasting in many places. what is likely to happen next? in the author's opinion, the case load is very likely to keep on increasing in all parts of africa with a bit higher than the current pace; particularly, if the complacence of the people grows along with the slow increment of the cases and the deaths, the risk of transmission of this virus may be a bit higher than the current trend. whatever the risk of transmission is, the cumulative figure is very unlikely to be in several millions as many predicted. the argument is that since the majority of the african population lives in scattered rural area, with the current awareness and the weather condition as described above, the risk of a large area spread in short a while is less likely. the expectation is that, before the spread of this virus reaches a larger scale, the two-three waves of the outbreak will be over. then after, sporadic cases will keep on emerging until the season is favorable for the virus's spread. similar spread and trend is expected in the majority of tropical countries as learnt from the previous pandemics. if that is not the case, this virus will not have a pattern similar to other infectious outbreaks (ascending, flattening and descending pattern). if the latter is true, africa will not be an exception; years long outbreak can occur elsewhere and the destiny will be unpredictable. the experience in the last three months, however, has shown that covid-19 outbreak is almost similar with previous pandemics; some countries like china and south korea are already entertaining the second wave after coming from apex to close to the baseline. therefore, the first scenario is; like many of other viral infections, those infected with covid-19 will develop humoral immunity and be protected from reinfection. as the majority of the population becomes immune (herd immunity) in due course, the chance of outbreak and the incidence rate will be less and less. the coming generation as well will be exposed in their earlier age and similarly develop the herd immunity. the possibility of developing a vaccine is within the domain of this assumption. the second scenario is reinfection. naturally, the majority of viral infections do not recur (with exception of those integrating their genome to the human genome, like hiv, human papilloma virus). covid-19 antigen, however, may not stimulate the human immune system to develop antibody against reinfection. this is much worrying as it may herald the difficulty to develop vaccine. researchers are soon to rule in or rule out whether the first or the second scenario is true. anecdotal evidence from china and south korea shows the possibility of reinfection, but that needs to be verified whether it is reinfection, reactivation or false positive result of the earlier test. african government and health stakeholders should not develop complacence with the slow rate of increment or reduction from recorded apex. apart from the seasonal nature, the character of infectious outbreaks is having two-three waves of mass infection; the latter waves are usually severe, for which complacence takes the major share. as the rainy and cold seasons are coming along the equator, second and third waves may be harder than before. seriously ill patients in hundreds to thousands are not manageable in an african setting. therefore, the already in action preventive interventions have to be maintained or strengthened till this outbreak is declared over (particularly contact tracing, avoiding or minimizing physical contact, hand washing, social distancing and universal mask use when exposure to other persons or patients is inevitable). the lockdown for africa, in particular, is a very controversial and challenging action. the author's opinion is that, as far as the social distancing and other preventive actions are in place, the lockdown action is not a wise decision for africa. the living style in the village and at the household level is already congested type; it is not uncommon to find dozens of people living and sleeping in a room. if lockdown is implemented, it should be complemented by mass testing, which is not economically and technically feasible for africa. therefore, phase by phase, the workforce has to resume the daily activities with stringent application of physical distancing and universal mask use. then after, students may be allowed to attend class on shift base (may be odd/even number on a day) with good advice and in-school close monitoring of the physical distancing. otherwise, the economic and social devastating effect of this virus to the african continent in general and poor countries in particular may not be tolerable and easily reversible. it may even result in social unrest and political crisis. therefore, we should not further delay the resumption of economically rate limiting sectors. if things go significantly in the wrong direction, preventive actions can be retightened as many countries are doing. in the author's opinion, whatever the consequence of this pandemic is in africa or elsewhere, it is another turning point in human history after the spanish flu and the second world war, by bringing about an extraordinary change in the political, economic and social landscape across the globe. from social interaction, international connectedness and travel perspective, i do not think that i am wrong if i say that covid-19 has dramatically changed the so called "world is a village" to 'world is an individual'. the economic crisis described by many, as the deep recession looming, may also hit hard africa and other low income countries with fragile economy. beyond controlling the outbreak, the big lesson for the world is to get ahead better prepared to manage such scale of outbreaks, and to make a significant paradigm shift in resourcing future researches to prevent and treat infectious outbreaks. for decades, communicable diseases are left to low income countries (particularly to sub saharan africa) with limited effort to develop vaccines and antimicrobials in resource rich countries. in short, the lesson acquired from covid-19 pandemic is expected to be the legacy for the generation to come. specific to africa, it is not arguable that covid-19 is a practical test that has clearly shown how much the health facilities are scarce and ill-equipped to handle such scale of public health emergency. when nations in africa are aware of that the expected covid-19 caseload is projected to be in several hundred thousand at a time, they also realized that available hospital beds in each big town are only a few hundred or less. similarly, the available health facilities and the health force to provide intensive care to critically ill patients are either non-existent or rudimentary. it is ahead a very disturbing experience for many of them. as an example of status indicator, the two countries with large population size (nigeria and ethiopia) are each able to test <10,000 individuals in nearly two months. some african countries reported zero, 3, 70 and the like number of ventilators at the national level while the demand is in thousands. this is in contrast to the first and second world where the testing and the basic life support capacity is extraordinary. in one of his briefings, his excellency andrew cuomo, the new york state governor requested the federal government to supply 30k ventilators while he has 11k at hand. the author is not sure whether the 54 nations in africa in total have this number of ventilators. it is, therefore, covid-19 is a learning curve for african governments in the tropical zone to revise their health policy and get better prepared for similar or larger outbreaks in the years to come. covid-19 is not only a deep wake up click, but also a great 'opportunity' to mobilize the human force and financial resource to catch up in a short period of time with affordable cost. around two decades back (2001), african leaders signed the abuja declaration, which was stated as african countries should allocate 15% of their annual budget for health services (15). in practice, however, the majority could not make it even 3%. that is why the health system and health facilities in africa remained crippled despite the staggering case load in every referral hospital. as a result, african countries are enforced to export the financially capable patients (including leaders) to middle east and asia with a yearly increasing number that has exploited the country's scarce resource. in the era of covid-19, however, no way, nowhere to go. this is another reality, what makes covid-19 a breathtaking phenomenon. neither the economic nor the military power enables the abler to escape this invisible disease by traveling somewhere else. invariably, the covid-19 victim or susceptible individuals worldwide are getting help only from the nearby hospitals. luckily, the hospitals and treatment centers in these poor countries are not yet overwhelmed by covid-19 cases. if the worst comes (cases flooding like the europe and usa), there is an extremely low chance of getting medical care in africa. whether we like it or not, it will be a natural death and survival ('survival of the fittest'), like in the time of the old pandemics. african vips and well to do's will not be an exception. it is from this bad experience, what african leaders and every one of us need to take a big lesson to get prepared ahead for the worst to come (taking covid-19 as 'a blessing in disguise'). in general, covid-19 is another 'red flag' for humankind. in other words, the recent 'red flag' for humankind is the emergence of four highly fatal coronavirus strains (sars cov, mers cov, sads cov and now sars cov-2) in less than two decades with extremely fast global dissemination of sars cov-2 in three months and the lack of treatment or vaccine for either. related to this, the sporadically exploding highly fatal viral hemorrhagic fevers in the tropical zone (like ebola and marburg viruses) with on and off migration to other countries and again with no treatment or vaccine are a previously well noted 'red flag' for humankind. above all, the emergence of four new coronaviruses as a human pathogen in the first quarter of the 21 st century is a 'red flag' for the emergence of another new coronavirus in the years to come, whose effect and destiny cannot be predicted. could the climate change have an influence in the mutation of these new coronaviruses and probably many more is not yet well substantiated. overall, the earlier appearance of the third generation of diseases implies that the human battle with the emerging viruses and bacteria will be tougher than before. covid-19 in africa: protecting lives and economies a novel coronavirus from patients with pneumonia in china clarivate analytics solution. diseases briefing: coronaviruses. 2020. accessed on an outbreak of coronavirus oc43 respiratory infection in normandy, france fatal swine acute diarrhoea syndrome caused by an hku2-related coronavirus of bat origin reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. pathogens are we prepared for the next pandemic? estimated influenza illnesses, medical visits, hospitalizations, and deaths and estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the united states influenza vaccines: ummet needs and recent developments the effects of temperature and relative humidity on the viability of the sars coronavirus ultraviolet radiation: how it affects life on earth abuja declaration on hiv/aids, tuberculosis and other related infectious diseases sars = severe acute respiratory syndrome mers = middle east respiratory syndrome sads = swine acute diarrhea syndrome key: cord-268661-a56u5e2o authors: nadeau, s. a.; vaughan, t. g.; scire, j.; huisman, j. s.; stadler, t. title: the origin and early spread of sars-cov-2 in europe date: 2020-06-12 journal: nan doi: 10.1101/2020.06.10.20127738 sha: doc_id: 268661 cord_uid: a56u5e2o the investigation of migratory patterns of the sars-cov-2 pandemic before border closures in europe is a crucial first step towards an in-depth evaluation of border closure policies. here we analyze viral genome sequences using a phylodynamic model with geographic structure to estimate the origin and spread of sars-cov-2 in europe prior to border closures. based on sars-cov-2 genomes, we reconstruct a partial transmission tree of the early pandemic, including inferences of the geographic location of ancestral lineages and the number of migration events into and between european regions. we find that the predominant lineage spreading in europe has a most recent common ancestor in italy and was probably seeded by a transmission event in either hubei or germany. we do not find evidence for preferential migration paths from hubei into different european regions or from each european region to the others. sustained local transmission is first evident in italy and then shortly thereafter in the other european regions considered. before the first border closures in europe, we estimate that the rate of occurrence of new cases from within-country transmission was within the bounds of the estimated rate of new cases from migration. in summary, our analysis offers a view on the early state of the epidemic in europe and on migration patterns of the virus before border closures. this information will enable further study of the necessity and timeliness of border closures. in response to the pandemic potential of the sars-cov-2 virus, many nations closed their borders in order to curb the virus' spread (1). these closures continue to incur high economic and social costs. to weigh the relative costs and benefits of border closures, it will be important to understand the efficacy of these policies. at the early stages of an outbreak, border closures can delay a pathogen's arrival, thereby giving countries additional time to prepare (2). however, the success of this strategy depends on timely implementation and a good knowledge of where the pathogen is already circulating. to evaluate the efficacy of border closures in limiting the spread of sars-cov-2, it is important to reconstruct the timeline of the early international spread of the virus, before such policies were implemented. in this analysis, we aim to estimate the early patterns of sars-cov-2 transmission into and across europe. we also address the more specific question of where the predominant sars-cov-2 lineage circulating in europe originated. we hope that by addressing these questions we can inform further analysis of the efficacy of border closures as a strategy to combat sars-cov-2. the sars-cov-2 virus was identified as the cause of an epidemic in wuhan, china in late 2019 (3) . the epidemic in wuhan was reported to the who on 31 dec. 2019 and within one month, sars-cov-2 was confirmed to have spread to 19 additional countries (4) . by the end of february 2020, the virus was detected in all who regions (5) . currently, several lineages of the sars-cov-2 virus are circulating across the globe. the intermixing of these lineages in different countries and regions suggests that the virus has been transmitted across borders many times (6) . here we focus on estimating the early introductions of sars-cov-2 into europe and the virus' migration across european borders. through national surveillance efforts, the first covid-19 cases in europe were detected in france on 24 jan. 2020 and in germany on 28 jan. 2020 (7, 8) . of the 47 cases detected in europe by 21 feb. 2020, 14 were infected in china, 14 were linked to the initial cases in germany, 7 were linked to the initial cases in france, and 12 were of unknown origin (7) . in addition to the unknown sources of transmission, some early introductions may not have been detected. this is especially probable given that a significant proportion of infected individuals are likely to be asymptomatic (9) . in summary, it is difficult to draw firm conclusions about the source, number, and timing of sars-cov-2 introductions into europe based on confirmed case data alone. viral genomes are an important secondary source of information on outbreak dynamics. if viruses acquire mutations on the same timescale as an outbreak, these mutations can provide information about past transmission events. phylodynamic methods couple a model of viral evolution describing the mutational process to an epidemiological model describing the transmission process. by fitting the combined model to viral genomes sampled from a cohort of infected individuals, we can infer the evolutionary and epidemiological model parameters. here we fit a phylodynamic model with geographic structure to sars-cov-2 genomes from hubei, china and several european countries before the first borders were closed in these regions. we co-infer the transmission tree linking these sequences, the geographic location of ancestral lineages, migration rates of infected individuals between regions, the effective reproductive number, and the proportion of no-longer infectious cases sequenced in each region. in addition to these inferences, we specifically focus on estimating the geographic origin of the predominant sars-cov-2 lineage in europe. this lineage is defined by a characteristic amino acid substitution at position 314 in the orf1b gene from proline to leucine and was provisionally named the "a2a" lineage by the nextstrain team. in the more dynamic, tree-based nomenclature suggested by (10) , this lineage corresponds to the "b.1" lineage described as "a large lineage that roughly corresponds to the large outbreak in italy, and has since seeded many different countries" (11) . as of apr. 1, 2020, two-thirds of the sars-cov-2 sequences collected in europe belonged to this lineage and just 10% of sequences from the lineage were collected outside europe (data from (12) , lineages assigned using (13) ). here, we use the name a2a to refer to the group of sars-cov-2 viruses defined by the orf1b:p314l mutation. where the a2a lineage originated remains unclear. its characteristic orf1b mutation was found in some of the earliest confirmed covid-19 cases in italy, switzerland, germany, finland, mexico, and brazil in late february (14, 15) . intriguingly, a late-january sample from a german case linked to all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. . https://doi.org/10.1101/2020.06.10.20127738 doi: medrxiv preprint business travel from singapore shares a mutation in the s gene with the a2a lineage, but does not have the lineage-defining orf1b mutation. this german sample is part of a smaller "a2" clade that is basal to the larger clade of a2a sequences (6) . as a result, it was hypothesized that a german transmission cluster may have seeded the larger european outbreak (14) (15) (16) . however, it was quickly pointed out that incomplete and biased sampling must be taken into account before this hypothesis can be rigorously addressed (14, 17, 18) . phylodynamic models with geographic structure aim to account for such biases. firstly, parameter estimates are generated by integrating over a distribution of potential phylogenies, which acknowledges that we cannot reconstruct the true transmission tree with certainty. secondly, sampling parameters are allowed to differ between regions, which acknowledges that testing and sequencing resources vary across regions. here, we fit a phylodynamic model with geographic structure to full-length sars-cov-2 genomes to (i) estimate the early patterns of sars-cov-2 spread into and across europe, (ii) weigh genomic evidence for competing hypotheses about the geographic origin of the predominant a2a lineage in europe, (iii) report on the epidemiological parameters, and (iv) compare the rate of new cases arising from within-region transmission versus migration during the early epidemic. we fit a simplified version of the multi-type birth-death model described in (19) . under this model, beginning with a single infected host in a single geographic region (deme), the virus can be transmitted from one host to another (a birth event), die out due to host recovery or death (a death event), be sequenced (a sampling event, assumed to correspond to a death event), or migrate from one deme to another (a migration event). the birth, death, sampling, and migration processes are assumed to occur at deme-specific rates that are constant through time. importantly, this model aims to capture heterogeneity in epidemiological parameters (birth and death rates) and sequencing effort (sampling proportion) among demes. we used a version of the model parameterized in terms of the effective reproductive number, which allows us to additionally infer this epidemiologically relevant quantity for each deme. we analyzed sars-cov-2 genome sequences from five different demes: hubei province in china, france, germany, italy, and a composite deme of other european countries ("other european"). all sequences were accessed from gisaid (12) . to represent the pandemic origin, we randomly chose 10 sequences from hubei collected on or before the lockdown of wuhan city on 23 jan. 2020. to investigate the earliest outbreaks in europe, we considered all available sequences collected in france, germany, and italy on or before the lockdown of the lombardy region of italy on 8 mar. 2020. these countries had the first detected (france and germany) and the largest (italy) early outbreaks in europe (4, 7) . by limiting sampling to before regional lockdowns and border closures went into effect, we hope to (i) satisfy model assumptions that epidemiological and migration parameters are constant through time, and (ii) get a picture of the early, unimpeded spread of sars-cov-2 within europe. to represent the pool of sars-cov-2 circulating in other european countries during this time, we down-sampled sequences from other countries to the cumulative number of confirmed covid-19 deaths in each country by 8 mar. 2020 plus one (table s1 ). we used this quantity as a proxy value roughly proportional to the outbreak size in each country. table 1 characterizes the sequences analyzed from each deme for the main analysis. as a sensitivity analysis, we repeated the analysis while down-sampling based on confirmed death data from 28 mar. 2020, considering that deaths occur with a delay after transmission. this yielded a slightly larger sequence set for analysis (results in supplement). table 1 . analyzed sequence information. location is the location of sample collection, as recorded in the nextstrain metadata (13) . date is the date of sample collection, as given on gisaid (12) (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. we prepared a sequence alignment from publicly available data on gisaid (12) using the nextstrain pipeline for sars-cov-2 (13). short sequences (< 25,000 bases), those without fully specified collection dates, and duplicate sequences from the same case were eliminated, as well as sequences from known transmission clusters or with suspicious amounts of nucleotide divergence (as determined by the nextstrain team). we aligned selected sequences to reference genome genbank accession mn908947. to eliminate suspected sequencing errors, we masked the first 130 and final 50 sites from the alignment, as well as sites 18,529, 29,849, 29,851, and 29,853 (following the nextstrain pipeline). we assume that during the time span considered here, the outbreak in hubei and the different european outbreaks were only sources and not sinks for sars-cov-2 globally. in other words, we assume that (i) once a strain was in europe, the strain could have been transmitted from europe to other global regions, but subsequent re-introductions of this strain did not occur. similarly, we assume (ii) strains were not re-introduced into hubei. these assumptions allow us to ignore sequences from outside of hubei and europe. to justify assumption (ii), we argue there was not sufficient time between the pandemic origin in hubei and jan. 23, 2020 for a significant amount sars-cov-2 export, transmission outside-hubei, and subsequent re-introduction into hubei. furthermore, confirmed case data shows that hubei province was the epicenter of the sars-cov-2 pandemic until this time, with comparatively less transmission occurring outside of the province than within it (4). to justify assumption (i), we tested whether there was evidence for significant migration into european demes by running a separate analysis on a2a sars-cov-2 sampled from all global regions (results in supplement). for inferences, we used the implementation of the multi-type birth-death model in the bdmm package (19, 20) in the beast2 software (21) . since this is a parameter-rich model, we fixed some parameters to improve the identifiability of others. the values for fixed parameters, priors for estimated parameters, and the rationale behind these decisions are given in table 2 . we ran four mcmc chains to approximate the posterior distribution of the model parameters. the first 10% of samples from each chain were discarded as burn-in before samples from the chains were pooled. we used tracer (22) to assess the convergence and confirm that ess was > 200 for all parameters. to weigh the significance of cases from migration versus within-region transmission during the early epidemic, we compare the rate at which new cases migrate into a region (= per-individual migration rate x case count in source region) to the rate at which new cases arise from within-region transmission (= transmission rate x case count in sink region). when signal in the sequence data is low, e.g. for some migration rates, our prior assumptions determine the magnitude of these rates. to assess the sensitivity of our main conclusions to the prior, we additionally analyzed the same sequences using a lower migration rate prior ( figure s12b ). we note that the migration and transmission rates are assumed to be constant through time for this analysis. thus, the temporal trends depend only on the confirmed case data, which we take from the johns hopkins center for systems science and engineering (23). (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. to test our assumption that europe was primarily a source and not a sink of infections before 8 mar. 2020, we analyzed a2a sequences collected from different global regions on or before that date. we aggregated sequences into five demes: africa, asia & oceania, europe, north america, and south & central america (table s3) , and then fit the multi-type birth-death model to these data. the most recent common ancestor of the global set of a2a sequences was inferred to be in europe with 95% posterior support ( figure s9 ). the posterior distributions for the migration rates into europe closely matched the prior, thus the data contains little information on these rates ( figure s10 ). however, in the analyzed dataset, 0 introduction events were inferred from other parts of the world into europe, while in total 24 migration events were inferred from europe to other parts of the world (table s5) . for our main analysis we focused on estimating patterns of sars-cov-2 transmission into and across europe. based on the particular set of sequences analyzed, we infer that sars-cov-2 was introduced from hubei into france, germany, italy and other european countries approximately 2-4 times each before 8 mar. 2020 (table 3 ). the largest number of estimated introductions was 18 from italy to other european countries. importantly, these estimates reflect only introductions occurring in the transmission history of the analyzed cases, not the full epidemic. in contrast, the inferred migration rate parameters should describe more general patterns of spread between regions. the sequence data were informative for inferring some, but not all, migration rates. we highlight here only the rates for which the data is the most informative; see figure s1 for a full comparison of posterior and prior distributions. the highest migration rate was inferred to be from italy into other european countries, with a median rate of 3.7/year. the lowest migration rate was from italy to germany, with a median rate of 0.44/year. the maximum clade credibility tree in figure 1 summarizes the posterior sample of transmission trees linking analyzed sequences. the a2a lineage sequences form a clear clade with posterior support of 1. the most recent common ancestor of the analyzed a2a sequences is estimated to be in italy with 87% posterior support. in contrast, the location of the most recent common ancestor between this clade and the basal, singapore-linked german sequence is less certain. this ancestor is inferred to have been in either germany (40% posterior support), hubei (38%), or italy (20%). we find very little support for this ancestor having been in france or another european country (2%). several epidemiologically relevant parameters were co-inferred along with the transmission tree. firstly, we report on the reproductive number in the different demes, which varied from 1.2 to 1.7 in hubei to 2.5 to 3.5 in france ( figure s2 ). secondly, we report on the prevalence of no-longer infectious cases in each deme as of the collection date of the last analyzed sequence. this quantity can be backcalculated from the estimated sampling proportion (prevalence = # sequences analyzed / sampling proportion). we note that both the sampling proportion and prevalence estimates have large credible intervals ( figures s3 and s4 ). of the european demes analyzed, the outbreak in germany was estimated to be smaller in early march (150 to 490 cumulative cases) than the outbreaks in france (709 to 2,323 cases) and other european countries (719 to 1,806 cases), while the outbreak in italy was the largest (2,600 to 4,988 cases). figure 2 compares the rate at which we estimate new cases to arise in each region from migration versus from within-region transmission. the estimated rates of new cases from migration and withinregion transmission are represented here as point estimates 5 days before the date of case confirmation, which assumes a 5-day delay between infection and onward transmission or migration. beginning with the first day on which we have case data from hubei, we estimate a substantial risk of infected individuals migrating from hubei into european regions. throughout late january to mid-february 2020, cases were sporadically detected in each european region, each of which is associated with a risk of subsequent within-region transmission. sustained within-region transmission is first evident in italy in mid-february. shortly thereafter, sustained within-region transmission occurred in other european countries, in france, and in germany. by 8 mar. 2020, the estimated rate of occurrence of new cases from within-region transmission is within the estimated bounds on the rate of new cases from migration for each region considered ( figure s12a) . we obtain the same qualitative result in our sensitivity analysis using a very different prior on the migration rate ( figure s12b ). we note that the rates in figure 2 are underestimates of the rates of new cases arising due to migration or transmission due to the underreporting in the confirmed case data. however, assuming that the amount of underreporting is comparable across regions, we can indeed compare the rates. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. . https://doi.org/10.1101/2020.06.10.20127738 doi: medrxiv preprint figure 1 . maximum clade credibility tree. the clade of a2a sequences analyzed is highlighted with dashed branches. the values above the branches are the posterior clade probabilities and the pale red bars show the 95% highest posterior density interval for node ages. the pie charts at nodes show posterior support for the ancestor being located in each deme (note that we assumed the root of the tree was in hubei with probability 1). the deme for each tip is the deme in which the sequence was collected, irrespective of travel history. tips are annotated with gisaid accession identifier. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. . https://doi.org/10.1101/2020.06.10.20127738 doi: medrxiv preprint table 3 . median inferred number of introductions from each source deme to each sink deme along the transmission tree linking analyzed cases. hubei is assumed to be a source only. values in brackets are the upper and lower bound of the 95% highest posterior density interval for these estimates. source the median of these rates is show in the "migration" row. we also multiplied the number of newly confirmed cases in each sink region by the posterior sample of transmission rates for the region. the median of these rates is shown in the "within-region transmission" row. dates are lagged 5 days to account for a 5-day delay between infection and migration or onward transmission. case data comes from (23). we inferred the early spread of the sars-cov-2 virus into and across europe as well as the geographic origin of the predominant a2a lineage spreading in europe. to do this, we applied a previously published phylodynamic model to analyze publicly available viral genome sequences from the epidemic origin in hubei, china and from the earliest detected and largest european outbreaks before 8 mar. 2020. after performing bayesian inference, we (i) report on inferred patterns of sars-cov-2 spread into and across europe, (ii) compare posterior support for several hypotheses on the origin of the a2a lineage, (iii) report on epidemiological parameters, and (iv) compare the timeline of new cases resulting from migration versus within-region transmission in europe before borders were closed. genome sequence data indicates that prior to 8 mar. 2020, sars-cov-2 was introduced from hubei province into france, germany, italy and other european countries at least 2-4 times each (table 1) . these estimates, which are based solely on genome sequence data, provide a complementary account of introduction events compared to line-list data (26) . the introduction events we report here are inferred to have occurred along the transmission tree specific to the analyzed sequence set and are not all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. . https://doi.org/10.1101/2020.06.10.20127738 doi: medrxiv preprint attributable to individual cases. in comparison, line-list data (7, 26) attributes introduction events to individual cases but cannot reconstruct previous, unobserved introductions. since we analyze only a fraction of all cases, we expect our estimates to be a minimum bound on the true number of introductions. ideally, we want to go beyond counting migration events amongst the analyzed sequences and investigate general dynamics. to do this, we would interpret inferred migration rates as representing more general patterns of sars-cov-2 spread. however, the sequence data was only informative for inferring some of these rates ( figure s1 ). in regions with few lineages circulating during the period considered, there is little signal for the amount of outward migration. we observe information about the per-individual migration rate from italy to other european countries ( figure s1 ). however, we do not find evidence for preferential migration paths from hubei into different european regions or from each european region to the others, although we cannot exclude this possibility. we estimate that the a2a viruses spreading in europe by 8 mar. 2020 had a common ancestor in italy sometime between mid-january and mid-february 2020 (figure 1 ). in contrast, nextstrain places this ancestor in the u.k. with 100% confidence (27) . however, the nextstrain result may be an artefact of disproportionately high sequencing effort in the u.k. since biased sampling violates the assumptions of the "mugration" method employed (28) . we additionally report that the a2a lineage was most likely carried from hubei to italy or from hubei to italy via germany. both transmission routes have almost equal posterior support under our model assumptions (figure 1 ). since we only consider a few geographic regions, these migration routes are not necessarily comprehensive. rather than reconstructing a complete transmission chain, we compare model support for different a2a transmission routes amongst the analyzed demes and report two equally plausible routes. although it is not the main focus of our analysis, we also report on epidemiological parameters of the early outbreaks considered. estimates for the reproductive number fall roughly within the range of previous estimates (29) , though we mention a particular caveat with respect to the reproductive number in hubei below. unsurprisingly, prevalence estimates in early march generally exceed confirmed case counts by a factor of 1-3 ( figure s4 ). our inferences of epidemiological parameters do not challenge the idea that the early reproductive number in different outbreaks is difficult to estimate precisely, but not hugely variable, and that there is substantial under-reporting in line-list data (30) . finally, we estimated the rate of new cases arising from migration compared with the rate of new cases arising from within-region transmission in the regions analyzed. the magnitudes of these rates are quite uncertain due to uncertainty in the inferred migration and transmission rates ( figure s11 ) and underreporting in case counts, which we implicitly assume to be constant in time and between demes. however, the temporal trends suggested by these data are still compelling and robust towards different prior assumptions. we see that under sustained risk of case migration from hubei, isolated cases were confirmed throughout europe beginning in late january 2020 but did not immediately cause large outbreaks. shortly after the first evidence of sustained within-region transmission in italy, outbreaks in the rest of europe also took hold ( figure 2 ). our results based on the multi-type birth-death model take into account phylogenetic uncertainty and sampling biases between demes, which are two major concerns in genomic analyses of sars-cov-2 (18) . indeed, wide confidence intervals around internal nodes in the maximum clade credibility tree and low clade support near the tips (figure 1 ) indicate a high degree of phylogenetic uncertainty. therefore, it is important that the parameter estimates we report result from integrating over a distribution of potential phylogenies with different geographic locations assigned to ancestral lineages. in comparison, some initial studies that estimated international sars-cov-2 spread constructed a median-joining network instead of a phylogeny to account for this uncertainty (16, 31) . in this approach, identical sequences are collapsed to single nodes and edges represent mutational differences. this disregards information from relative sampling times and means that ancestor-descendent relationships are highly dependent on the choice of the network root (32, 33) . unaccounted-for sampling biases in these analyses may also yield spurious results for the geographic origin of lineages (34, 35) . our analysis, which relies on a mechanistic model of migration and between-deme sampling differences, should be robust to such biases. despite the advantages of the multi-type birth-death model just mentioned, there are also several unique caveats to consider. the birth-death model assumes uniform-at-random sampling from the total all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 12, 2020. . https://doi.org/10.1101/2020.06.10.20127738 doi: medrxiv preprint infected population in each deme. however, particularly in the early stages of outbreaks, infected individuals were identified by health ministries via contact tracing (7) . non-random sampling may be one possible explanation for why we infer markedly different transmission rates in china when analyzing cases from within hubei (as in this analysis) as opposed to cases exposed in hubei but sequenced elsewhere (as in our previous analysis (36) ). furthermore, the multi-type birth-death model assumes that parameters are constant through time and homogenous within demes. as a result, our inferences based on province-, country-, and continent-level demes are only coarse approximations of the true, heterogeneous epidemic dynamics occurring at a local level. in particular, we do not account for a reduction in airline traffic between europe and china beginning in late january, before borders were closed (37) . due to these limitations, we focus on estimating and interpreting particular events along the transmission tree of the analyzed sequences (e.g. table 3 , figure 1 ) and advise caution when interpreting inferred migration rates ( figure s1 ). we expect that our results will be useful in parameterizing more specialized models aimed to understand the efficacy of border closures as a means to fight pandemic disease. so far, such analyses have primarily used line-list data and information on travel networks to estimate sars-cov-2 migration patterns (38) (39) (40) . here we present independent estimates of migration patterns based on genome sequence data. by combining case count data and our estimates for migration and transmission rates, we provide a timeline of early sars-cov-2 introduction and spread before border closures were implemented. despite migration risk from hubei being on the same order of magnitude as later migration risk from italy, we only observe sustained outbreaks in other european regions after the onset of sustained within-region transmission in italy. finally, before the first border closures in europe, we estimate the risk of new cases arising from within-region transmission to be within the estimated range for the risk of new migration cases. 91% of world population lives in countries with restricted travel amid covid-19 updated who recommendations for international traffic in relation to covid-19 outbreak a new coronavirus associated with human respiratory disease in china who, covid-19 situation reports coronavirus disease (covid-19) dashboard first cases of coronavirus disease 2019 (covid-19) in the who european region beschreibung des bisherigen ausbruchsgeschehens mit dem neuartigen coronavirus sars-cov-2 in deutschland estimating the asymptomatic proportion of coronavirus disease 2019 (covid-19) cases on board the diamond princess cruise ship a dynamic nomenclature proposal for sars-cov-2 to assist genomic epidemiology. biorxiv hcov-2019/lineages: resources for calling and describing the circulating lineages of sars-cov-2 nextstrain build for novel coronavirus (ncov) genomic characterization and phylogenetic analysis of sars-cov-2 in italy thanks to rapid global data sharing of #sarscov2 genomic data via https://t.co/tbvb4magpy, we can reconstruct large and small scale patterns of #covid19 spread. this is a thread discussing this intersection of large and sma phylogenetic network analysis of sars-cov-2 genomes a follow up to yesterday's thread on the possible connection between the bavarian cluster and the italian #covid19 epidemic regaining perspective on sars-cov-2 molecular tracing and its implications improved multi-type birthdeath phylodynamic inference in beast 2 phylodynamics with migration: a computational framework to quantify population structure from genomic data beast 2.5: an advanced software platform for bayesian evolutionary analysis covid-19) cumulative cases by day worldwide 2020 download today's data on the geographic distribution of covid-19 cases worldwide early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study inference of transition between discrete characters and 'mugration' models -treetime 0.7.6 documentation the reproductive number of covid-19 is higher compared to sars coronavirus repeated seroprevalence of anti-sars-cov-2 igg antibodies in a population global transmission network of sars-cov-2: from outbreak to pandemic. medrxiv medianjoining network analysis of sars-cov-2 genomes is neither phylogenetic nor evolutionary on the use of median-joining networks in evolutionary biology evolving covid-19 conundrum and its impact sampling bias and incorrect rooting make phylogenetic network tracing of sars-cov-2 infections unreliable airlines suspend flights due to coronavirus outbreak -reuters the effect of travel restrictions on the spread of the 2019 novel coronavirus (covid-19) outbreak. science (80-. ) outbreak dynamics of covid-19 in europe and the effect of travel restrictions impact of international travel and border control measures on the global spread of the novel 2019 coronavirus outbreak s.n, t.v., j.s., j.h., and t.s. thank eth zã¼rich for funding. all rights reserved. no reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted june 12, 2020. key: cord-257358-uoek1pba authors: peset, josé l. title: plagues and diseases in history date: 2015-03-12 journal: international encyclopedia of the social & behavioral sciences doi: 10.1016/b978-0-08-097086-8.62050-0 sha: doc_id: 257358 cord_uid: uoek1pba in spite of the development of the medical science, during the twentieth century, individuals have observed the spread of new or reemerging diseases, from plague, cholera, and flu; measles, cancer, and malaria; to acquired immune deficiency syndrome, west nile fever, resistant tuberculosis, virus of ebola, creutzfeldt-jakob disease, and others. as individual illness is rooted in society and the environment, human life is tied up with the history of main endemic and epidemic diseases. human health is very sensitive and adaptable to changes, so the history of disease and hygiene is the core of the new ecological history. the 'sweating sickness' (sudor anglicus) . on yet other occasions, these changes are merely due to cultural appreciations, as it has happened with certain sexual practices such as masturbation or homosexuality, which used to be framed as stigmatized diseases. on the other hand, disease is not always considered only harmful: thus it may be considered a distinction of the gods, as was the case of epilepsy in ancient times, or among some historical aboriginal tribes. nevertheless, the hippocratic text on the sacred disease established the natural condition of this illness, similar to other medical affections. the same disease was associated with the devil by the christians, and historically, it had always been a supposed distinction of great personages from caesar to napoleon. disease can also be considered a way toward perfection or transformations, leading to the creation of art or to the salvation of the soul, as melancholy or sorrow were for centuries. disease may also have political repercussions: it is claimed that george the third's madness gave rise to problems for the british crown, while roosevelt's fragile health was considered to have placed him in a weak position in the yalta negotiations. socially, disease has sometimes unjustly been considered the stigma of groups (as acquired immune deficiency syndrome (aids) for homosexuals, and poor or marginal groups, or alcoholism for black or aboriginal peoples). medicine and politics have endeavored to preempt social changes by means of the contested eugenic theories and practices of social engineering, inspired by francis galton at the end of nineteenth century, which began with recommendations or laws to avoid marriages entailing risks (real or imaginary), and went on to such processes as sterilizations. heredity is today considered an important predisposition for disease, but mostly not in a deterministic way. hereditary conditions are thus intertwined with cultural, social, religious, and moral ones. besides, in contrast with the stark determination of former times, there is today an attempt to draw new optimism from the possibilities of genetic modifications. yet, in this latter respect, there is fear of a future where such a formidable force could rest in the hands of the rich and powerful. an important renewal in the study of infectious diseases was driven by bacteriological discoveries, and the theories about infection and immunity. in this respect, hans zinsser in rats, lice, and history combined them with human history, proposing biographical interpretations of epidemiological history. the study of the transmission of pathogens through animals and human beings (as vectors and hosts), living in a physical, biological, social, and cultural environment, was crucial in bringing about a new history of disease and also much later in fueling the most recent ecological history. in the meantime, the essential contributions of historical demography and social history licensed the consideration of the history of diseases as 'biographies,' shared by human cultures, living beings, and natural environment. but with the development of accurate technologies of diagnosis, the real identification of old plagues is more and more demanding. paleopathology enables us to discover the high incidence of diseases in the early inhabitants of the earth, especially where such diseases left their mark on bones. it is thus possible to detect remnants of tumors, infections, necrosis, osteoporosis, and malformations, as also traumatisms, dental alterations, rickets, rheumatism, and other diseases of the bones. today, laboratory analysis allows the possibility of detecting remnants of other diseases, germs, or lesions, in animal or human remains, including of course the famous mummies. from the first settlements in the fertile crescent, changes have taken place in the relationship of man and animals with their environment and it is possible to establish an extensive catalog of diseases that have largely subsisted down to this very day. particularly significant are the forms of settlement, the crops and hunting, and the contact of man with cattle, pets, and parasites, as well as the relations between peoples, through mixing and trade, wars, and migrations. malaria originated in tropical africa, accompanying the dawn of humanity, from plasmodia infecting animals and hominids. caused by different plasmodia (plasmodium vivax and plasmodium falciparum among others, with different geographical distribution), its relation with human populations is shaped by migrations and deforestation, hunting and farming, climate and soils, crops, animals and foods, and a complicated immunity resulting from ancient genetic mutations and new infections. thus, with the early human emigrations, it expanded through eurasia, and in the third millennia bc, malaria had already set in the early civilizations in marshy areas where the water, the climate, and the crops provided the conditions for the anopheles mosquitoes to infect in crowded populations. evidence for the existence of intermittent fevers is already to be found in ancient cultures, finding suitable conditions along the yellow, indus, ganges, euphrates, or nile rivers. different interpretations considered the disease to originate from climatic or environmental factors, from particles or small animals, because of spirits or gods, or from unbalanced or disharmonic alterations. the connection between fevers, splenomegaly, and marshy areas appears in the hippocratic texts, such as on airs, waters and places. deforestation, agriculture, temperature, and a greater population density, as well as military and commercial movements, favor the spread of the disease. in italy, in republican times, the disease becomes acute; and it was recommended that the marshy lands be either abandoned or sold and that people should dwell on high groundthe latter being traditional advice and here defense reasons also counted. also, the cleaning and draining of swamps was considered, this being the origin of systems of engineering sanitation. the spread of malaria got worse and worse in rome owing to negligence and flooding, climate and agricultural changes, wars, travels, and migrations, and it reached its zenith at the time of the fall of the roman empire, a cataclysm to which it may have contributed. but when the old empire declined, another frightening ghost traveled through the mediterranean sea. plagues were considered in ancient cultures as diseases originating in god's punishment, with a violent pattern, and quick and terrible diffusion, affecting and killing a large number of persons. destructive epidemic catastrophes were narrated frequently in mesopotamian, biblical, egyptian, indian, or chinese sources, and in 430-426 bc, thucydides describes the plague of athens in the war against sparta, but it is doubtful that this case refers to the bubonic plague. this epidemic death is considered the beginning of the decline of athenian hegemony, the crisis of the democracy, and culture of the pericles era. fear, war, siege of the city, and its maritime port were accompanied by the death of the great ruler pericles. later on, the first reliable description of this disease is that given by rufus of ephesus in the ad first to the second century, in the epoch of trajan; and in the sixth century, the plague of justinian initiates the first great epidemic cycles of bubonic plague. soldiers and merchants, animals and merchandises, and slaves and prisoners all contribute to linking up the extremes of the known world. a consequence of this contact was the antonine plague in the second century. this plague -and othersis attributed to smallpox, a disease that had already existed as far back as 3000 years ago, as certain mummies show. in the middle ages, leprosy spread widely, allegedly as a result of the increasing east-west relations trough trade, travels, and wars. this biblical and present day disease is accompanied by social repulse and malignant connotations since dirtiness and overcrowding provided the conditions for the spread of the otherwise not extremely contagious mycobacterium leprae. in this respect, the way to santiago de compostela where pilgrims slept in groups and under unhealthy and dirty conditions provided a fertile ground for this disease. another markedly religious character is to be found in the 'sacred fire,' 'st anthony's fire,' or ergotism; a disease that developed in people eating rye infected by ergot, it was soon prevented, but reappeared during the course of severe famines. these diseases are linked to many others that owed their spread to squalor and poverty, for example, parasites and infections, scabies, mycoses and lice, anthrax and ophthalmia. natural catastrophes, wars, poverty, and famines were escorted by mental diseases, tuberculosis and pneumonia, traumatisms and poisonings, diarrheal diseases and fevers, as well as smallpox and measles. in the mediterranean basin, malaria continued to be endemic with the population tending to resort to residing on the hills and mountains, far from marshy lands. the extension of malaria involved south and southeast of asia, central china and japan, and also north europe. the plague set in the growing cities with the burden of rats and fleas, making this disease an explicative example par excellence of epidemic history. a second epidemic cycle began with the black death in 1348. commerce and the cities collapsed, giving rise to the origin of the modern european kingdoms. at this time, venice established control over persons and ships, in order to avoid the spread of plague, arriving from distant lands. dark ages are ending, and new worlds are opening in culture and geography. european expansion meant a sudden traffic of diseases mostly toward the new world. the discovery of america, with its scattered population devoted to agriculture, where there were no dirty cities, and where the inhabitants were devoid of immunity to the diseases of old europe, produced an enormous demographic crisis. certain diseases, such as smallpox (and measles) ravaged the indigenous population; this very contagious and harsh illness was introduced in the caribbean and mexico, and destroyed american indigenous populations. syphilis came supposedly from america (although other human treponematoses were present in other continents), brought back by the spaniards and it caused havoc since renaissance in europe and soon all around the world. troop movements spread an unknown disease called 'tabardillo,' or 'typhus exanthematicus,' bringing about serious suffering for armies and poor people. sea voyages led to the development of scurvy, due to the lack of fresh food. other diseases also voyaged overseas, such as yellow fever; although it originated from africa, due to the commerce of slaves and merchandise, special temperature conditions and mosquitoes as vectors were required for the contagion. in the seventeenth century, it took root in brazil and also spread to the caribbean and throughout america, reaching new york and boston and likewise colombia, ecuador, and peru. it affected warm america and europe, through the iberian peninsula. immunity and cutoffs in commerce stalled the disease, but it remains endemic in tropical areas of america and africa. also, malaria arrived to america with the european conquest in sixteenth century, beginning in the caribbean and central america and soon spreading to south and north america, becoming endemic in hot, wet, and low lands. malaria was combated since the seventeenth century by the use of cinchona bark (peruvian bark), found in peru, as an indigenous medical practice. later on, the quininethe alkaloid obtained from the bark in french laboratoriesgave rise to rich industry and trade. trees were cultivated in british and dutch colonies, mainly in java. after being taken in the second world war by the japanese army, synthetic products such as atebrine and chloroquine were obtained. getting worse with agriculture, mining and livestock changes, settlements, and slavery trade, malaria becametogether with yellow fevera scourge along the warm and hot reaches. throughout the american conflicts between european empires, and later during the american independence wars, both diseases played an important role, infecting and killing nonimmune soldiers. plague slowed demographic growth in europe since the wars between modern and powerful nations, the crowded and dirty cities, and the developing trades impeded protection against the disease. the great writer daniel defoe remembered the terrible contagion in london in 1665 in journal of the plague year. after the great european plague of marseille in 1720, the relative peace of the eighteenth century allowed western europe to set up sea and land defenses, with austria becoming a solid bulwark in the face of the ottoman empire, thus sealing off all possible spread of the plague. toward the middle of the nineteenth century, the third wave of the disease broke out and, with the exception of europe, it spread to all countries including asia, africa, and paradises like america and australia, leaving remnants in many places. the eradication of plague in europe was a result of the advent of public hygiene, immunity to disease, and the disappearance of rats and of the old and dirty wooden buildings. the great london fire in 1666 'purified' the city, since the hygienic rebuilding was carried out in stone, eliminating animals and dirt. the disappearance of plague from europe was followed by the outbreak of cholera, which had been endemic in india for centuries. this disease was described by western travelers in the sixteenth century and its spread to europe and america was a consequence of pilgrimages, trade, and a lack of cleanliness in water. a great pandemic broke out in 1817 from india and spread through eastern africa and southern asia, arriving to china and the philippines, and in a second wave, it spread through persia reaching russia and poland in 1830. then this second wave swept across europe and reached america by 1832. throughout 100 years, terrible waves spread from the east. however, the timely and necessary cleansing of urban water supplies helped to progressively stall its advance. nevertheless, as late as 1892, the free hanseatic city of hamburg suffered an outbreak of cholera epidemic, while the neighboring altona, governed by the prussian reich, was able to avoid the disease, thanks to the successful filtering of its water. local and national governments advanced in hygiene and they attempted to bring about healthier cities by means of appropriate public health measures. the nineteenth century sees the beginning of the demographic revolution in europe, followed by developing countries, in america for example, with a sharp decline in mortality, especially maternal-infant mortality. old inoculation and the new vaccination proposed in 1798 by edward jenner fought smallpox successfully. studies about human immunity since the last decades of nineteenth century began a new medical approach to the prevention and understanding of illness, being successful in the contention of many diseases, which have a long record of burdens and deaths. mother care also advanced both throughout pregnancy and at childbirth and during lactation. the rise of great and industrial cities with low-grade outskirts and the emigration of peasants to the city favored the spread of maladies associated with poverty, hard work, squalor, lack of appropriate food, and exposure of people devoid of defenses. some of the diseases were strictly occupational as in the case of miners and textile workers who were exposed to injury, and to industrial poisons that affected the proletariat. sir percivall pott described in the eighteenth century the cancer produced in professional cleaners (chimney sweep) by chemical toxics contained in soot. many other diseases, such as cancers, will be attributed to chemical and physical aggressions, including radioactivity. other diseases were closely related to the harsh and dirty conditions of life such as spread of typhoid fever and pulmonary diseases. tuberculosis spread over the turn between the eighteenth and nineteenth centuries, and while it was represented as the disease in fashion, affecting notable and distinguished people, it struck the proletariat much more severely. the same can be claimed regarding the enormous spread of syphilis, and drug abuse, beginning with alcohol and continuing with cocaine and morphine. the discovery of the microbiological origin of infectious diseases, and of effective therapies against them, and the development of public health changed the pathological landscape in developed countries. the long way between ignaz semmelweis and alexander fleming arrived to the contention of infections in health care. the twentieth century marked the descent of the high mortality rates in countries that reached high standards of sanitary development, investing in health care and public health. such advances have been due to public health services, hospitals, antibiotics, surgery, and vaccination, and they have been reinforced by the developments in immunology and microsurgery, pharmacology, and biotechnology and with the promising future of genetic engineering. the international health solidarity promoted by the world health organization (who), and other governmental and nongovernmental organizations (ngos), including church missionaries, were accompanied by better governance of nations, and internationalization of information and resources. the twentieth century established a serious change in geopathology of diseases. smallpox is the first disease to be considered totally eradicated with only some samples of the virus being kept at a few laboratories for study purposes. a cuban doctor (carlos finlay) found the method by which yellow fever is transmitted through mosquitoes (aedes aegypti). after the cuban war and during the opening of the panama channel, yellow fever and malaria were studied and faced by us army and american sanitarians (walter reed, william gorgas), and later by the rockefeller foundation. impeding mosquito reproduction and avoiding bites and spreading chemical products were useful. fortunately, an effective vaccine against yellow fever was later discovered. during nineteenth century, malaria expanded all around the world, arriving to the central extensions of america and eurasia. emigrations and settlements, wars, famines, climate change, and revolutions in travels, such as railroads and steamships, contributed. during the napoleonic wars and the american civil war, malaria was seriously extended, as it was also during wars and revolutions in twentieth century. in the interwar years, the rockefeller foundation and the league of nations sponsored international campaigns against the disease. many governmental campaigns also fought against malaria; several national programs were effective, from taiwan and china to the united states, brazil, and argentina, passing across the mediterranean basin, from italy to egypt. opinions and campaigns oscillated between quinine treatment, fighting against mosquitoes (by dichlorodiphenyltrichloroethane (ddt)), and improvements in life, education, and land sanitation, clearing up the marshy areas. malaria has been eradicated from europe thanks to drainage, improvements in crop cultivation, mechanical barriers, quinine and modern drugs such as atebrine and chloroquine, and insecticides. colonial settlements entered tropical areas backed by quinine, nets in beds, hygiene, and sanitation, but transmissible diseases were continuously a serious burden for colonial armies, in america, africa, or asia. some chemical products such as ddt were a successful support for soldiers, travelers, merchants, or settlers. nevertheless, in 1955, the world health assembly, meeting in mexico, warned against the resistance of the mosquitoes to insecticides. mosquitoes are still today carrying both diseases, and also dengue. chagas disease produced by trypanosoma cruzi is endemic in america, and sleeping sickness caused by trypanosoma brucei (rhodesiense and gambiense) occurs in africa. today, an effort is being made to involve governments in the fight against malaria, a disease that represents a danger to nearly half of the world's population. in africa, the situation is very serious due to the changes in agriculture and irrigation as well as in work and migrations, the political and economic problems, the severe droughts, famines and wars, the bad sanitary conditions following in the wake of housing expansion and deforestation, and harsh social and economic exploitation. together with the who and the united nations international children's emergency fund (unicef), regional institutions such as the pan american health organization and the us government are financing programs of eradication. the who, through the 51st world health assembly of 1998, set up the program 'roll back malaria' and, with aid from unicef and the world bank, is endeavoring to bring about economic and sanitary improvements in developing countries. in twentyfirst century, the global fund to fight aids, tuberculosis and malaria is attaining important amount of resources and success. nets treated with insecticides are very useful for protection against mosquitoes. today, hope is also placed on vaccination and in the sterilization, or genetic modification, of the mosquitoes. yet, malaria continues to be endemic in warm zones of america, asia, and with severe cruelty, in africa. the rapid increase of world population in huge metropolitan areas was accompanied by new settlements and emigrations, wars, conflicts and revolutions, and marginalization of aboriginal cultures and disinherited peoples. throughout the past two centuries, economical, social, and political expansion of the west led to studies on tropical medicine, creating hospitals and laboratories and institutions on public health and sanitary departments. cholera continues to be feared in asia, between india and the far east, and also in warm zones in america and africa. wars and catastrophes, travels and migrations, as well as famines and unhealthy conditions allowed the expansion of the cholera germ, the vibrio cholerae isolated by robert koch in 1883, as was the case of the recent tragedy of haiti. at the end of nineteenth century, the third outbreak of bubonic plague allowed its bacteriological and epidemiological description. the germ of bubonic plague yersinia pestis, discovered by yersin and kitasato, is still to be found throughout the world. the germ is carried by rats, rattus rattus: rat fleas are the arthropod vectors transmitting 'epizootic' plague to humans from rodent hosts, and related species, but transmission among humans is also possible. almost forgotten in the developed world, with several and very effective antibiotic therapies, there is, nevertheless, always the possibility that the devil may once more send his rats to the old, rich cities. but other viruses have taken its place in the twentieth century. thus the very old and common influenza caused several cruel and heavy outbreaks; among many others, influenza pandemics began in 1918 and reappeared in 1957, 1968, and 2003 : these were known, respectively, as the 'spanish flu,' which perhaps originated in the united states, the 'asian flu,' the 'hong kong flu,' and the 'avian flu,' mostly coming from asia. vaccines are very useful in its prevention, as they are also in the control of many infectious childhood diseases, such as measles, rubella, mumps, chicken pox, whooping cough, diphtheria, and so on. old diseases such as poliomyelitis exploded in the united states and europe, affecting nonimmune children, and this disease has only been controlled in developed countries by means of vaccination. during the past century, individuals have observed astonished the spread of new or reemerging diseases, from plague, cholera, influenza, measles, and malaria, to aids, west nile fever, avian flu, severe acute respiratory syndrome, resistant tuberculosis, hemorrhagic fever (ebola virus disease), transmissible spongiform encephalopathy (creutzfeldt-jakob disease), and others. unfortunately today, many frequent or rare diseases do not have adequate treatment, and many germs are developing resistance to antibiotics, a serious threat for its affectivity. aids has meant a development in the study of viral infections, and this disease has associations with the exploitation of poor people, unsafe sex, and drug trading, but it also affected an elite sector, which has sprung rapid research in the field. the world commotion surrounding this disease has served both to reveal human altruism on the one hand, and, on the other, contempt toward those infected by the disease, since aids became more and more the lot of the poor, mostly in large areas of africa, or india, and of downcast or marginal groups such as the chronic patients, drug addicts, prostitutes, and homosexuals. nevertheless, heterosexual transmission through unsafe sex and transmission from mother to child are today serious dangers. safe sex and antiretroviral treatment are the best contention, while a vaccine will be obtained perhaps in the coming future. mental affections were considered till modern times, as devilish, criminal, or vicious behaviors, more an ethical or social than a medical problem. in the eighteenth century, the natural explanation of mental disease was established, according to alexander crichton, or philippe pinel, and in the nineteenth and twentieth centuries, its psychogenic process, following sigmund freud. from pinel to freud, the possibility of treatment and remedy of mental disease was established, leading the soul of the patient with convictions and health measures to the cure. the discovery in recent times of some effective pharmacological drugs acting on human mind, and conduct, has allowed better treatment. reclusion was considered a doubtful possibility, restricted to some severe problems. the old lunatic asylums, founded since middle ages, were being abolished or completely renewed. nevertheless, mental illnesses wreak serious havoc at present times all around the world, affecting all ages, genders, and conditions, without any distinction. sometimes, the misunderstanding regarding mental diseases still produces cruel treatments, harsh restrictions, or punishment. during the past decades, economic and social improvements led to quick globalization and urbanization, with longer human life and changes in disease patterns. political, sanitary, and economic development managed to stamp out infectious morbidity, and forms of suffering or living illnesses are changing. unicef and who, in collaboration with governments, foundations, and ngos, promote successful campaigns of vaccination, especially focusing on children. the burden of infectious, parasitic, and transmissible diseases changed to chronic diseases and sufferings related with aging and lifestyles, likewise, nutritional disorders, cancer, or heart and brain vascular diseases. on the other hand, the increase in life expectation favors the development of alzheimer and other chronic and degenerative diseases, neurological and muscular diseases, mental affections such as schizophrenia, mania and depression, diabetes, vascular diseases, and of course, the terrible presence of cancer. accidents and traumatisms, due to traffic and sports, factories and radiation, or even home accidents, are something that the twenty-first century is inheriting. blindness, deafness, dumbness, and other frequent physical and mental disabilities, with multiple origins in traumatisms or accidents, genetic, metabolic and degenerative diseases, infectious diseases such as poliomyelitis, or cerebral and vascular affections, make daily life difficult and, at the same time, make economical, institutional, and social support necessary. incapacitating and chronic diseases lead to severe dependency and so the need for protection of disabled individuals is leading to the founding of patients' associations looking for help and justice, creating new rights and demands. ghettos and migrations, hard work, poverty and unemployment, and some of the old drugs such as alcohol, heroine, and tobacco or new synthetic ones are causing havoc even to the rich world. but in developing countries, the old morbidity due to transmissible diseases continues to exist, maintaining a very low life expectation. certainly, the increase of migrations and of urban population are requiring more water, food, and energy, producing climate warming, deforestation and agriculture changes, and dangerous issues such as waste, toxics, and pollutants. potable water, health services (medical care or medical drugs), sanitation and hygiene are urgently requested. environmental degradation and the confrontations between national, social, and ethnic groupings are a serious danger for healthy life. china, japan, and south korea and other expanding countries have lived through these challenges in different ways from diverse british colonies such as australia or india. different traditions and cultures are extremely important to understand the relations between peoples and diseases. death is most rampant amid the least protected and poorest people, especially women, children, and the elderly, with harsh sufferings such as wars, famine, and exploitation. under such circumstances, diseases caused by deprivation and infection continue to be the most rampant, causing high death rates among the population. old and new diseases, such as malaria and aids, are ruining great stretches of africa. leprosy and cholera, tuberculosis and tetanus, and many child diseases, such as mumps, measles, tetanus, or meningitis are in poor countries and populations the salt of the earth. private and public funds, and international solidarity, are always necessary for relieving these harsh sufferings. the united nations millennium development goals are also facing them. according to the who report global health risks (2009), the better or worse conditions for mortality and for the burden of disease are seriously conditioned by several circumstances, related to lifestyles: blood pressure, blood glucose, physical activity, alcohol and tobacco, weight, safe sex, safe water, sanitation, and hygiene. obviously, these circumstances and their consequences are very different, depending on the social level of individuals and the public health governance of nations and peoples. if developing countries are freeing themselves from transmissible diseases, now they are fighting against noncommunicable diseases, related to social level, health organization, and hygienic customs. some american, asian, and african countries are still supporting a terrible burden of disease, which is also shared by low-income population in developed countries. the rio political declaration in the world conference on social determinants of health (who-rio de janeiro, brazil, 21 october 2011) is a new call looking for equity, justice, and universality of health. it has recommended adopting better governance for health and development; promoting information, justice, and participation in policy making and during the implementation process; including civil society like indigenous people; and reducing health inequities in the health sector. this declaration promotes research on the relationships between social determinants and differences (economic, ethnic, and gender inequalities) and health equity. we are all convinced about the relation between poverty, social discrimination, low education and low sanitation, and diseases and death. history of western; science, history of; welfare state, history of plagues in world history the great pox: the french disease in renaissance europe les hommes et la peste en france et dans les pays européens et méditerranéens, 2 vols la malaria tra passato e presente the columbian exchange: biological and cultural consequences of 1492 médecins, climat et épidémies à la fin du xviiie siècle the cambridge world history of human disease public health in asia and the pacific. historical and comparative perspectives plague and the end of antiquity: the pandemic of 541-750 mosquito empires: ecology and war in the greater caribbean plagues and peoples inescapable ecologies: a history of environment, disease, and knowledge humanity's burden: a global history of malaria rats, lice and history. printed and pub. for the atlantic monthly press by little, brown, and company key: cord-309210-3dpnmswf authors: de zwart, onno; veldhuijzen, irene k.; elam, gillian; aro, arja r.; abraham, thomas; bishop, george d.; richardus, jan hendrik; brug, johannes title: avian influenza risk perception, europe and asia date: 2007-02-17 journal: emerg infect dis doi: 10.3201/eid1302.060303 sha: doc_id: 309210 cord_uid: 3dpnmswf during autumn 2005, we conducted 3,436 interviews in european and asian countries. we found risk perceptions of avian influenza to be at an intermediate level and beliefs of efficacy to be slightly lower. risk perceptions were higher in asia than europe; efficacy beliefs were lower in europe than asia. during autumn 2005, we conducted 3,436 interviews in european and asian countries. we found risk perceptions of avian influenza to be at an intermediate level and beliefs of efficacy to be slightly lower. risk perceptions were higher in asia than europe; efficacy beliefs were lower in europe than in asia. t he possibility of an influenza pandemic presents a major public health challenge. since 2003, outbreaks of avian influenza (ai) have occurred in asian, european, and african countries. as of august 21, 2006, the total number of cases was 240 and the number of deaths was 141 (1) . a crossover of current human influenza virus with the avian h5n1 virus could result in a virus capable of human-tohuman transmission and the start of a new pandemic. despite extensive media attention for avian influenza, knowledge about risk perception of ai is scarce. we therefore explored the conditions for effective nonmedical interventions. if an influenza pandemic occurs, public health authorities will be dependent on the willingness and ability of the public to adhere to recommendations regarding personal hygiene, vaccination and prophylaxis, quarantine, travel restrictions, or closing of public buildings (2, 3) . adherence, however, cannot be assumed. evaluation of the outbreak of h7n7 ai in the netherlands in 2003 showed that adherence to antiviral therapy and behavioral measures, such as wearing face masks and goggles, was low (4). our ability to promote health-protective behavioral change depends on our knowledge of determinants of such behavior (5) . the protection motivation theory posits that health-protective actions are influenced by risk perceptions (6) (7) (8) . risk perceptions are defined by the perceived seriousness of a health threat and perceived personal vulnerability. however, the protection motivation theory explicitly states that higher risk perceptions will only predict protective behavior when people believe that effective protective actions are available (response efficacy) and that they have the ability to engage in such protective actions (self-efficacy). we investigated risk perceptions and efficacy beliefs related to ai of a random sample of persons in 8 areas. random digital dialing was used to select the samples, and data were collected by using computer-assisted telephone interviewing. interviews were conducted from september 20 through november 22, 2005, in 5 european countries (denmark, the netherlands, united kingdom, spain, and poland) and 3 east asian areas (singapore; guangdong province, people's republic of china; and hong kong, special administrative region, people's republic of china). at the time the telephone survey was conducted, on october 14, 2005, the media announced the introduction of ai in europe. we therefore ensured that at least 90 interviews were conducted in each country after october 18, 2005. the questionnaire focused on risk perception of ai and other infectious diseases, precautionary behavior, and use of information sources; it was based on our earlier study of risk perception of severe acute respiratory syndrome (sars) (9) . respondents first received a brief explanation of ai. in line with the protection motivation theory (8), a measure of risk perception was constructed by multiplication of seriousness (scale 1-10) and vulnerability (scale 1-5). to make the scores comparable, the seriousness score was first divided by 2. to normalize the skewed distribution of the new variable, a square-root transformation was performed, which resulted in a measure of risk perception on a scale from 1 (low) to 5 (high). a total of 3,436 respondents were interviewed; participation rates varied from 12.9% in asia to 81.1% in poland. most respondents were female (table 1) . european respondents were significantly older than asian respondents (mean age 47 and 39 years, respectively, range 18-75 years, t = 16.2; degrees of freedom [df] = 3,351; p<0.001). overall, 45% of respondents thought they were likely or very likely to become infected with ai if an outbreak occurred in their country. this perception varied from 32% in denmark and singapore to 61% in poland and spain. risk perception scores varied significantly across countries; the highest mean score was in poland and the lowest was in denmark (table 2) . higher scores were observed in europe than in asia (t = 5.2; df = 3,250; p<0.001), and differences between individual countries within europe were significant. multivariate analysis showed that country, sex, and age group remained inde-pendent significant factors and showed a significant interaction between country and sex and between country and age group (figure) . in all countries, except singapore, risk perception was higher among women than men, but this difference was smaller in asian than in european countries. the effects of age also varied by country; mean risk perception levels were higher in older age groups in europe but not in asia. response efficacy and self-efficacy also varied across countries; levels were highest in china and lowest in the netherlands (table 2 ). mean response efficacy and self-efficacy were significantly higher in asia than in europe (response efficacy t = −14; df = 2,868; p<0.001; self-efficacy t = −20; df = 2,701; p<0.001). response and self-efficacy were inversely associated with risk perception (p = 0.013 and p<0.001, respectively). multivariate analysis also showed that country, but not sex or age, was significantly associated with response efficacy. country, sex, and age group were all significantly associated with self-efficacy. self-efficacy levels were lower for women compared with men and for the youngest age group compared with older respondents. risk perception and efficacy levels before and after the introduction of avian influenza in europe did not differ significantly. our study showed that risk perceptions for ai appear to be at an intermediate level and that efficacy beliefs are slightly lower. both differ according to country or region. no evidence was found that the introduction of ai in europe in october 2005 influenced perceptions of risk or efficacy. fielding et al. have reported on risk perception of ai in hong kong with a focus on live chicken sales (10) . although our results are difficult to compare with theirs, our study appears to indicate a higher feeling of vulnerability, with 41.8% of hong kong respondents thinking it likely or very likely that they would become infected with influenza during an outbreak. takeuchi's interviews on food safety practices of consumers in thailand found high levels of knowledge of ai but lower levels of risk perception and behavior change (11) . if we compare our results with those from several studies on perception of risk for sars, we find that perception of risk for sars in some of the asian countries was relatively low compared with that in the united states (12) . in the netherlands, however, perception of risk for sars was low, whereas our present study indicates that it is high for influenza (9) . the lower level of risk perception for ai in asia may be related to the proximity to the current outbreak and the experience with the sars epidemic. these experiences may have resulted in the notion that new epidemics of infectious diseases can be controlled. also, despite the fact that the first cases of h5n1 influenza among humans in asia were reported in 2003, a larger outbreak did not ensue. accordingly, risk perception research has shown that the public may be more optimistic when familiar risks are perceived to be largely under volitional control (13, 14) . our study has several implications for public health policy and research. although in all countries an influenza pandemic is perceived as a real risk, the level of self-efficacy appears to be rather low. when developing preparedness plans for an influenza pandemic, specific attention should therefore be paid to risk communication and how perceived self-efficacy can be increased; otherwise, adherence to preventive measures may be low. world health organization. cumulative number of confirmed human cases of avian influenza a/(h5n1) reported to who nonpharmaceutical interventions for pandemic influenza, international measures nonpharmaceutical interventions for pandemic influenza, national and community measures avian flu epidemic 2003: public health consequences. bilthoven: national institute for public health and the environment (rivm) and institute for psychotrauma health promotion planning, an educational and ecological approach the precaution adoption process factors in risk perception cognitive and physiological processes in fear appeals and attitude change: a revised theory of protection motivation sars risk perception, knowledge, precautions, and information sources, the netherlands. emerg infect dis avian influenza risk perception, hong kong avian influenza risk communication emerg infect dis the public's response to severe acute respiratory syndrome in toronto and the united states the social amplification of risk and risk communication the british 2001 foot and mouth crisis: a comparative study of public risk perceptions, trust and beliefs about government policy in two communities interventions for hiv, sexually transmitted infections, and viral hepatitis. key: cord-274045-0npcun9p authors: nan title: note from the editors: don’t stop thinking about tomorrow date: 2020-01-09 journal: euro surveill doi: 10.2807/1560-7917.es.2020.25.1.2001091 sha: doc_id: 274045 cord_uid: 0npcun9p nan as we are now starting a new decade and thinking about tomorrow, we would like to take stock of selected events in 2019. one memorable event was the worldwide movement of young people for the climate. even if not directly related to infectious disease prevention and control, it reminded us of our collective obligation to the upcoming generations. disease prevention is about improving future health outcomes. continuous vigilance and surveillance are necessary elements in ensuring the best possible protection of the heath of the population as a whole. pathogens continue to evolve in their ability to cause human disease. this was demonstrated by the recent detection of pneumonia cases of unknown origin in wuhan, china since mid-december, for which an unknown, novel corona virus has been preliminarily determined as the cause [1, 2] . an example of how pathogens are able to escape tools and technologies developed to control and stop their spread is antimicrobial resistance (amr). amr has been a worldwide concern for some time already and has featured prominently in eurosurveillance. in 2019, we covered various aspects of amr such as the emergence of multidrug-resistant neisseria gonorrhoeae related to international travel [3] , an outbreak of extensively drug-resistant klebsiella pneumoniae in a german hospital [4] , and the surveillance of antimicrobial consumption and prescribing for example in belgium, israel and switzerland [5] [6] [7] . another aspect driving spread and severity of communicable diseases is human behaviour. the continued spread of measles in europe over the past decade has been facilitated by insufficient vaccine coverage in specific population groups or regions. over the past year, vaccine hesitancy and mandatory vaccination were covered in several eurosurveillance articles [8] as were interventions to improve confidence in vaccines, for example, motivational interviews conducted with parents of newborns on maternity wards in canada resulted in lower hesitancy and greater intention to vaccinate [9] . as usual, food-and waterborne diseases, hiv/aids and blood-borne diseases, emerging and vector-borne diseases, influenza and other respiratory diseases were the subject of several articles in the categories, 'outbreak reports' and 'surveillance articles'. these two article types have different structures and collectively replaced the former category 'surveillance and outbreak reports' at the beginning of 2019. the associated new instructions for authors have led to greater consistency and completeness of information in submissions in these article categories. a special issue published in january 2019 illustrated how advanced diagnostics support public health policy development [10] . we also published articles on less frequently encountered topics such as a skin rash outbreak traced to a portable floating tank [11] and urban brown rats as the possible source of multidrug-resistant enterobacteriaceae and meticillin-resistant staphylococcus [12] . in 2019, we published 220 articles (65 rapid communications, 155 regular articles and 21 other items such as editorials, letters and meeting reports). the 2019 acceptance rate of 25% was similar to previous years. as a reflection of the european focus of eurosurveillance, the vast majority of published articles were from europe, even though 15% of accepted articles in 2019 were from non-european countries. we will continue to welcome contributions from around the globe that are relevant for public health in europe in the year ahead. our rapid communications on ongoing or emerging threats were published within 2 to 3 weeks of submission, creating awareness and providing evidence to support rapid public health action. some examples of the rapids we published included the worsening epidemiological situation of carbapenemase-producing enterobacteriaceae in europe [13] , a case of extensively drug-resistant typhoid fever imported from pakistan to denmark [14] and the detection of a chlamydia trachomatis variant escaping detection by a widely used assay in finland that was found in other european countries thereafter [15] [16] [17] . an activity close to our heart is the eurosurveillance lunchtime seminar that is organised every year on the margins of the european scientific conference on applied infectious disease epidemiology (escaide). the 2019 seminar about pointof-care testing (poct) and its impact on surveillance of communicable diseases and public health was well received and we look forward to publishing a respective special issue sometime in early spring. the call for the next special issue on food as a vehicle for amr will be launched in the second half of 2020. other 2019 activities by the eurosurveillance editors comprised several workshops on publication ethics, tools to increase transparency in scholarly communications, and on how authors can improve their chances of getting published. last but not least, we started to post educational article-related quizzes on twitter. all this could not have been achieved without the involvement of so many amazing supporters and constructive critics: our editorial board members, colleagues at the european centre for disease prevention and control (ecdc), public health experts and scientists in the field of infectious diseases and other disciplines in europe and elsewhere who respond when we ask for assistance and who remain unnamed here. we owe you a heartfelt thank you! we also thank our publisher, the ecdc, and its director who provide us with continued funding and editorial independence. we also value the contributions of our reviewers who go the extra mile, often on short notice and in their spare time, to help us select the right articles and guide authors in how they can improve their manuscripts. we are indebted to each of them. to acknowledge the ca 550 experts who reviewed for us in 2019, we are publishing a list with their names in this issue [18] and sent certificates to all those who supported us with more than one review. in his 2020 new year message, united nations (un) secretary-general antónio guterres pointed out that we enter the new decade "with uncertainty and insecurity", but he also stated that there is hope, addressing young people as "the greatest source of that hope" as they demand a role in shaping the future and encouraging them to challenge those in charge by "speaking out", "thinking big", "pushing boundaries" and "keep[ing] up the pressure". he also noted that the un will be launching a blueprint for further action for the sustainable development goals [19] . also, the president of the european commission ursula von der leyen's agenda for europe contains an "aspiration of living in a natural and healthy continent" and a "world full of new technologies and age-old values" [20] . sustainability and evolution within scholarly communication are important to us editors. together with our contributors and supporters, we are constantly working to maintain eurosurveillance as a useful means to provide sound and trustworthy evidence for communicable disease prevention and control also in the future. in 2020, we will discuss with our editorial board our strategy and goals for the years 2021 to 2027; we envisage to further advance to follow new developments and meet the demands of our diverse audience to the best of our abilities also in the time to come. to get a better idea of the various needs and interests, we launch a satisfaction survey today. the results should inform our strategy by identifying areas of particular interest to our audience. we hope that many of you will respond and help us shape the future of the journal, so that eurosurveillance continues to be interesting for readers, attractive for authors and useful for strategic and day-to-day public health decision-making. pneumonia of unknown cause -china. geneva: who who statement regarding cluster of pneumonia cases in wuhan collection: emerging multidrug-resistant neisseria gonorrhoeae related to international travel. stockholm: ecdc extensively drug-resistant klebsiella pneumoniae st307 outbreak, north-eastern germany antibiotic consumption in belgian acute care hospitals: analysis of the surveillance methodology, consumption evolution 2003 to 2016 and future perspectives antimicrobial use trends antimicrobial use in acute care hospitals: national point prevalence survey on healthcare-associated infections and antimicrobial use special edition: tackling vaccine hesitancy and improving immunisation delivery promoting vaccination in maternity wards ─ motivational interview technique reduces hesitancy and enhances intention to vaccinate, results from a multicentre non-controlled pre-and post-intervention rct-nested study advanced diagnostics to inform public health policy an outbreak of skin rash traced to a portable floating tank in norway urban brown rats (rattus norvegicus) as possible source of multidrug-resistant enterobacteriaceae and meticillin-resistant staphylococcus spp worsening epidemiological situation of carbapenemase-producing enterobacteriaceae in europe, assessment by national experts from 37 countries ceftriaxone-resistant salmonella enterica serotype typhi in a pregnant traveller returning from karachi chlamydia trachomatis samples testing falsely negative in the aptima combo 2 test in finland finnish new variant of chlamydia trachomatis escaping detection in the aptima combo 2 assay also present in örebro county the 'finnish new variant of chlamydia trachomatis' escaping detection in the aptima combo 2 assay is widespread across norway eurosurveillance reviewers in 2019 un) regional information centre -europe. un secretary-general's 2020 new year's message. brussels: un. 31 political guidelines for the next european commission 2019-2024. a union that strives for more. my agenda for europe. brussels: european commission this is an open-access article distributed under the terms of the creative commons attribution (cc by 4.0) licence. you may share and adapt the material, but must give appropriate credit to the source, provide a link to the licence and indicate if changes were made.any supplementary material referenced in the article can be found in the online version. key: cord-266628-7gyy2c52 authors: sanchez-ramos, juan r. title: the rise and fall of tobacco as a botanical medicine date: 2020-05-25 journal: j herb med doi: 10.1016/j.hermed.2020.100374 sha: doc_id: 266628 cord_uid: 7gyy2c52 a forgotten and valuable chapter in the history of tobacco concerns its role as a botanical medicine. for three hundred years following its importation into europe, tobacco came to be considered a universal remedy highly prescribed by physicians. in the early history of tobacco, the literature on its medicinal benefits was voluminous. nonetheless, bitter opposition to its use for non-medicinal purposes began to arise. there was little doubt of its medicinal efficacy at first, but with time, as the concepts and practice of medicine changed, the tide of medical opinion turned against it. medical support for the therapeutic use of tobacco reached its nadir during the mid-nineteenth century, when it was dropped from most medical pharmacoepiae. medical opinion on the health hazards of recreational smoking required another 100 years to arrive at the contemporary opinion that cigarette smoking is the single most important preventable environmental factor contributing to illness, disability and death in the u. s. soon after tobacco was introduced into europe as an ornamental plant, it came to be regarded as a remarkable medicinal plant. spanish sailors and the chroniclers of the indies observed and recorded the widespread use of tobacco. they were impressed by the esteem with which it was held by the natives of the new world. tobacco played a very important role in the mystical, social and medical rituals of the american natives. based on the medical applications of the herb by the natives, european herbalists believed that most herbs of the new world possessed some medicinal virtues. by the end of the 16 th century, tobacco was in widespread use in europe to treat a variety of diseases. some medical authorities popularized tobacco as a panacea for treating over 65 different ailments. over time, excessive use of tobacco led to the first great well-documented "drug" controversy. awareness of the inability to give up smoking of tobacco long after recovery from the illness led some to see the habit as sinful, simply because the individual indulged in the practice for "pleasure". puritans in england saw non-medical use and dependence on daily tobacco smoking as a sign of a weak and immoral character. a more rational view against the medical use of tobacco argued that a single medication could not possibly cure so many different ailments. it was not till the 20 th century that the deleterious health consequences of chronic tobacco smoking became strongly evident and led to efforts to suppress tobacco use. identification of nicotine and its physiological effects led to insights into the neurochemistry of the autonomic nervous system. more recently nicotine and the nicotinic receptors in brain are being explored as agents that might enhance cognition. review of tobacco's history is relevant to the contemporary problem of differentiating socially or medically-approved use from substance abuse and addiction. j o u r n a l p r e -p r o o f methodology the methodology used to prepare this review was based on the study of selected publications on the history of tobacco. many of these books were long out of print but were available at the university of chicago regenstein library. the books selected for study included significant sections on medical use and abuse, as well as the social history of tobacco. primary documents from the early spanish chroniclers and physicians were not available and so the author relied on secondary sources, books written in early to mid-1900s. from the very outset, tobacco was smoked by the spanish because it was considered pleasurable, but at the same time it was attributed with exceptional medicinal qualities. the j o u r n a l p r e -p r o o f chroniclers of the indies also noted that once spaniards began to smoke, it was difficult to give up the practice (corti 1932) . in 1610, francis bacon stated this succinctly: "tobacco conquers men with a secret pleasure, so that those who have once become accustomed thereto can later hardly be restrained therefrom (corti 1932) the use of tobacco for pleasure alone would not have been palatable to the europeans at home, who would have found the habit both primitive and sinful (ortiz 1947) . interestingly, tobacco was introduced into spain as an ornamental medicinal plant. "pleasure sought tobacco, but medicine justified it for reasons of its own, and sensuality was able to hide behind the cloak of curative science" (ortiz 1947) in england, smoking became fashionable at a time when puritanism was taking hold. the puritans did not deny tobacco's medicinal qualities but objected when smoking was indulged in for non-medical reasons. they noted that tobacco "drinking" (as smoking was then termed) was not confined to specific doses at certain times of the day like other medicines, and therefore might be harmful, especially to the young (apperson 1914) . the puritans in the colony of connecticut, in attempting to set controls on the consumption of tobacco, passed laws (around 1650) prohibiting persons under the age of 21 from smoking, and ordering that no smoker could enjoy his pipe unless he obtained a doctor's certificate (apperson 1914) . even with a doctor's permission, smokers of the colony at that time were not allowed to take tobacco publicly in the "street, highways, or any barnyards" (apperson 1914) . during the 17th century many writers and physicians condemned the use of tobacco for non-medicinal purposes and attempted to differentiate legitimate use from "licentious" abuse. tobias venner j o u r n a l p r e -p r o o f in his "brief and accurate treatise concerning the taking of the fume of tobacco, which very many in these days do too licentiously use" (london, 1637) denounced the common mode of smoking tobacco which most men took "like tinkers drank ale" (apperson 1914) . he listed 10 precepts for the correct use of tobacco. for example, that "you drink not between taking of fumes, as our idle and smoakie tobacconists are wont" and "that you goe not abroad into the aire immediately upon taking of the fume, but rather refrain therefrom the space of half an hour, or more, especially if the season be cold or moist" (apperson 1914 ). many people associated recreational smoking with idling. in the rules of the grammar school at essex, england, founded in 1629, it was prescribed that "the master must be a man of sound religion, of grave behavior, of sober and honest conversation, no tippler or haunter of alehouses, no puffer of tobacco" (apperson 1914) . in spite of condemnation of recreational use, the smoking of tobacco was practised more for pleasure than for its medicinal value in western europe and the american colonies. tobacco did continue to be employed as medicine, especially in forms other than smoke, until mid-nineteenth century. from the american civil war to the present, tobacco has been used almost exclusively as a recreational substance. the attacks on its abuse in the late 19th and early 20th centuries were linked to temperance movements and based on moral arguments. only in the last 50 years has the opposition to smoking been based on strong medicinal arguments. the last attacks on the use of tobacco re-introduced a moral component to the medical argument: non-smokers are subject to some deleterious health consequences of smoke pollution generated by smokers. the point is made that it is immoral to smoke since innocent non-smoking victims (including children) may be hurt. j o u r n a l p r e -p r o o f it has been suggested that the tobacco epidemic was due to a lack of prior restraints on grounds of convention, religion, morality or law simply because neither the substance nor the technique of smoking was previously known (laufer 1924) . it was up to medical profession to provide "restraints" in the form of a set of rules for appropriate consumption of tobacco. it should be emphasized, however, that there undoubtedly was a real belief in the medicinal efficacy of tobacco, especially within the context of the fifteenth and sixteenth century notions of health and disease. for example, certain diseases were seen as a disturbance in the balance of four qualities: hot, dry, cold, wet. catarrh (the common cold), particularly prevalent in the northern countries, was believed to be due to excess of cold and wet, so that applications of hot and dry tobacco smoke was seen as beneficial. purgation of the head by nasal irrigations and fumigations, or by provoking sneezing, was commonly practiced. "caput pungia" or clearing of the head was the latin term applied to this practice (ortiz 1947) . purgation of the gastrointestinal tract by eliciting vomiting or promoting bowel movements were popular medical remedies for which tobacco in one form or another was efficacious (ortiz 1947) , the practice of medicine from antiquity to the renaissance was based therapeutically on plant-derived substances. during the renaissance, prior to the discovery of tobacco, there was great interest in identifying the lost panacea of antiquity, the sylphium, described in great detail by the ancient physicians, hippocrates, galen and celsus. this plant, indigenous to desert regions of north africa, had been reported to be useful in treating fever, bronchitis, scrofula, tumors, toothache, bites of rabid animals, wounds from poisonous weapons, sore throats, pertussis, pleurisy, icterus and epilepsy . this wondrous plant, still j o u r n a l p r e -p r o o f not unequivocally identified, had disappeared, so that the introduction of tobacco was hailed as a substitute for the long-lost panacea of legend. two other factors helped perpetuate the notion that tobacco was a panacea. spanish sailors and the chroniclers of the indies observed and recorded the widespread use of tobacco and were impressed by the esteem with which it was held by the natives of the new world. tobacco played a very important role in the mystical, social and medical rituals of the american natives. based on the medical applications of the herb by the natives, european herbalists believed that most herbs of the new world possessed some medicinal virtues. a few influential books on the medical benefits derived from tobacco generated a host of literature on the san sancta (holy cure), the panacea of panaceas . tobacco was mentioned for the first time in the very first book written about the discovery of the new world, the diary of columbus. an entry in his diary, dated october 15, 1492, mentions dry leaves carried by an "indian" in a canoe, who valued the leaves for their healthfulness (corti 1932) . columbus later wrote, in november 1492, that 2 members of his crew, sent out to explore the island of cuba, saw many people who carried a burning torch to kindle fire and to perfume themselves with a certain herb. later it was learned that the herb was smoked in a rolled cylindrical form (cigar) and employed to lessen fatigue and as a disinfectant (corti 1932) . on the second voyage, columbus left father ramon pané on the island of hispaniola to convert the taino indians. pané described the use of a snuff, cohoba, derived from an intoxicating plant, by a medicine man in a healing ritual. the "doctor" followed the same diet and assumed the same aspect of a sick person. both doctor and patient would j o u r n a l p r e -p r o o f purge themselves by inhaling the snuff intranasally. the use of cohoba was also referred to by many chroniclers, including oviedo, las casas and columbus himself (corti 1932) . the identity of cohoba has been disputed, but most agree that the effects of the powder might not be due to tobacco alone, but to the addition of powder derived from grinding products of the hallucinogenic plant piptadenia peregrine (ortiz 1947) . in 1500, the portuguese explorer cabral reported the use by brazilian natives of a medicinal herb called betum (later identified as tobacco) for a variety of ailments including abscesses, fistulas, sores, and polyps (corti 1932) . in 1535, the first official chronicler of the indies, oviedo y valdes, published "the general history of the indies" in which he described the use of tobacco as a medicine by the indians, and also that some spaniards on the island used it for treating the disease of syphilis, unknown to europeans until this time (corti 1932) . oviedo was the first to use the word tabaco correctly in print. tabaco was the word for the instrument with which the natives of hispaniola inhaled the smoke or powder of the herb. the word tabaco (or the anglicized tobacco) came later to mean the plant itself (corti 1932) . the actual amount of tobacco introduced into europe between 1500 and 1600 is not recorded, but the growing importance of tobacco is reflected in the literature of the period. between 1503 and 1600, the number of books published in europe which referred to the medicinal use of tobacco increased markedly (see table 1 ). the two most influential books on the medicinal use of tobacco were by nicolas "this plant, which is commonly called tobacco, is a very ancient herb and known among the indians, especially those of new spain. after these lands were conquered by our spaniards, they, being taught by the indians, made use of it in wounds suffered in war, healing themselves with it, to the great benefit of all. it was brought to spain a few years ago more to adorn gardens with its beautiful appearance than for the marvelous medical virtues which it has; now we use it more for these virtues than for its beauty, for they are certainly such as to attract admiration its quality is hot and dry in the second degree. it has the virtue of heating and dissolving, with some astringency and invigoration. it glues together and closes up fresh wounds, so they say, at the first application. it cleans and purifies infected sores, and brings them to perfect health, as we shall describe later. and now i shall speak of the virtues of this plant and the things which it is useful for, one after another …." monardes then systematically listed all the ailments which can be cured by either smoking, chewing, or drinking tobacco, or applying hot leaves or tobacco ointments onto skin (ortiz 1947) . for-example, ailments of the breast are alleviated by tobacco syrup; smoke taken by mouth expels the causes of most complaints. the use of warmed leaves, salves, clysters (enemas) is prescribed for internal congestion, stomach aches, constipation, kidney stones, and flatulence. for ailments of pregnancy and labor pains a leaf of the plant, very hot, is applied to the navel. to expel worms, tobacco is invaluable. tobacco is also recommended for rheumatism, abscesses, toothache, and venomous wounds; furthermore, application of tobacco is sufficient to restrain any flux of blood. monardes advertised tobacco as a household remedy and it was due primarily to his authority that the new herb was accepted by physicians and laymen alike as one of the most popular remedies ). the book on horticulture "maison rustique" by liebault and estienne published in 1567 (paris) included a chapter entitled "nicotiane" which says that tobacco was introduced into france by jean nicot and was called by some the "queens herb". nicot sent seeds of tobacco to queen catherine de medici, who later became a great advocate of tobacco, and was supposedly the first promoter of medicinal snuff. catherine treated her ill young son, francois ii with an unction of tobacco. the young prince died with symptoms of poisoning and it was generally believed to be a consequence of the tobacco ointment . in any case, the book by liebault and estienne became very popular among physicians and laymen, containing information about tobacco and its various applications in disease. "tobacco will heal all old sores and cancerous ulcers, ringworms, great scabies, and what evil so ever may be, by stamping the leaves in a clean mortar and applying the herb and juice together upon the sore" the book also mentions a host of other virtues of the plant including its efficacy in treating dropsy . as early as 1565, the plant was called nicotiane in honor of jean nicot, who as was mentioned, introduced the plant into france, but also performed medicinal experiments with the herb, demonstrating its effectiveness in shrinking a cancerous growth on the face ). the bubonic plague was endemic almost every year of the 16th century in some part of europe. a number of serious outbreaks in great britain popularized the use of tobacco as a disinfectant, documented in 1572 in the book by dr. antoine sarracin "de peste commentarius " published in geneva and lyons ). in addition to all of the books by physicians attesting to the wondrous cures produced by tobacco, a great number of poets, historians and botanists bolstered the panacea image of tobacco. of the total of 254 diseases and other conditions reported as treated with tobacco between the years 1492 and 1860, 71 were reported as treated with tobacco between the years 1586 and 1600 . in these 15 years, physicians invented new formulae using tobacco and also found new uses for it, since they also applied it to patients' eyes and ears. j o u r n a l p r e -p r o o f before the year 1600, there were only four medical authorities who warned of possible harmful effects of the herb (stewart 1967) . by 1600 tobacco was at the height of its fame as a medicinal herb, but the first book published about medicinal tobacco in london in 1602 (work for chimney-sweepers) emphasized its harmful effects. the author, writing under a pseudonym, "philartes", probably found it expedient to avoid using his real name since his book was exposing the harmful effects of tobacco. he argued that no one remedy could be applied to all maladies any more than one shoe could fit all men's feet. tobacco purged its users too violently and dried up the sperm of a man so that if used too long, "the propagation and continuation of mankind will be abridged". moreover, philartes declared tobacco had a stupefying effect, not unlike opium, and it increased melancholy greatly and wasted the liquid part of the blood and much more (stewart 1967 ). this book elicited 3 more books in defense of tobacco, setting the stage for the london tobacco controversy which lasted 65 years (stewart 1967 ). in england, as opposed to the continent, tobacco was seen less as a medicinal herb than as a recreational social habit (apperson 1914) . sir walter raleigh is generally credited with introducing tobacco smoking to queen elizabeth and the english court, thereby making it the latest fashion in london. by the end of elizabeth's reign (1603) smoking was popular among all classes of society: but it was especially the mark of the young man of fashion: "at the end of the 16th century, london was infested with strutting, affected dandies, and these gallants adopted smoking as something especially devised for them. their extravagances in this art, the elaborate smoking equipment they carried about with them, and their insolent claim that only they knew the correct method of smoking made them the butt of many literateurs." (dickson 1954) on the continent the use of tobacco by smoking was hardly known. a german visitor to england in 1598 could scarcely believe his eyes when he saw everyone smoking even in the theatres (apperson 1914 (austin 1978) . aside from the attacks on the abuse of tobacco, there was another reason for condemning its use. the tobacco trade was largely in the hands of the spanish, the enemies of england, and represented great economic loss for the country. king james raised the duty on tobacco in an attempt to diminish importation. despite the king's opposition in words and deeds, the use of tobacco increased rapidly during his reign. the increased duty imposed by the king suppressed the regular trade and developed a great traffic in smuggling from spain and the colonies and also promoted the cultivation of tobacco in england. the outbreak of the plague again in 1614 in london helped overcome the king's opposition. doctors declared that steady smokers were less subject to infection than others and recommended tobacco as a disinfectant, with the result that smoking increased enormously in spite of the king's antipathy (corti 1932) . by 1615, there were upward of 7, 000 apothecaries, grocers, chandlers and inn-keepers living by the trade of selling tobacco in and near london(macinnes 1926). from 1620 to 1758, the production of tobacco in the english american colonies increased exponentially from 20, 000 lbs. per year to 22,050,000 per year (jacobstein 1907) . the spread of tobacco to japan, china, turkey and russia is beyond the scope of this essay. it should be noted that the most severe penalties in the form of torture and death failed to suppress the use of tobacco in those countries, and eventually tobacco use became worldwide (brooks 1952 , austin 1978 . by the beginning of the 18th century, tobacco was being used more for pleasure than for its medicinal value both in western europe and the american colonies. before tobacco was j o u r n a l p r e -p r o o f to become abandoned as a medicine altogether another twist of fashion propelled it, in the form of snuff, as the primary medicinal form. in 1655, a book had been published in france dealing with the preparation and use of snuff for medicinal purposes (brooks 1952) . snufftaking became fashionable among the upper classes in france and rapidly disseminated among the upper classes of western europe. the habit took such a hold of the governing classes, the nobility, and clergy in france and england, that it almost supplanted smoking. smoking "was relegated to the middle and lower classes during this period (corti 1932 ). one of the books of the time, "grundlicher unterricht" (ulm) by frederick hoffman, physician to the king of prussia, devoted a chapter to the correct use of snuff. he believed that snuff was particularly advantageous in curing head ailments caused by "moist humours" and in the treatment of certain conditions of the eyes and ears . he prescribed snuff powders mixed with balsams and different herbs, which were able to "relieve the nose of germs and offensive odors and also have a beneficial effect in gout" . he also warned that constant, careless use of snuff affected the sense of smell and produced throat ailments and its abuse resulted in deafness, insanity and fatal illness . while hoffman's assertions of the therapeutic value of tobacco was weak, the arguments against its abuse were no better founded . a pupil of hoffman, frederick camel, also published a dissertation in which he analyzed the different qualities of snuff and attempted to explain the action of the different constituents of tobacco. a small controversy arose in europe over snuff, which was used as much for pleasure as for medicine. proponents presented case histories to prove snuff had cured bronchitis, consumption, apoplexy and other diseases. opponents to the use of snuff called snuffers snivellers and snorters, and that they were digging an early grave with their noses. the controversy which ended around 1750 did have the effect of reducing snuff taking for both medicine and social purposes, but the habit did not entirely disappear from medical practice until more than a century later (stewart 1967) . in 1753, linnaeus published his "species plantarum" in which tobacco was classified as a member of the nightshade family (solanaceae) and the modern scientific terms for the chief species of the genus nicotiana, tabacum and rustica were first included . physicians who continued to use tobacco as a medicine found two new applications. dr. tissot suggested introducing tobacco smoke into a patient's lungs to resuscitate the apparently drowned (stewart 1967) . a second new application was the procedure for giving tobacco j o u r n a l p r e -p r o o f smoke clysters, again for resuscitating drowning victims (stewart 1967) . by 1799, medicinal tobacco was being abandoned and deleted from some but not all materia medica. several pharmacoepiae continued to include tobacco leaves up until the beginning of the 20 th century. the swiss pharmacoepia still mentioned "folium nicotianae" in 1893. the german pharmacopia mentioned tobacco for the last time in 1901 (vanproosdy 1960). as early as the 17th century, experiments were carried out with extracts of tobacco "essential oils of tobacco"; its poisonous effects were demonstrated by showing that one drop of tobacco oil would kill a dog or cat . by 1809, louis lauguelin, a french chemist discovered, but was unable to completely isolate the active principal of tobacco, which he called "nicotianine". other chemists continued the work until 1828 when posselt and reimann, at lille, france, isolated the constituent of tobacco now called nicotine (volle and koelle 1970) . with the discovery of this potent poisonous alkaloid, the attacks on the medicinal and recreational use of tobacco were intensified. in 1851, a summation of the effects of tobacco was published by l. b. coles, in the united states. he emphasized the dependence liability of tobacco, noting that tobacco was never taken like other medicines and then lain aside. "a man takes this so-called medicine for forty years perhaps, but gets no cure." (stewart 1967 ) he also cited many, many case histories to prove tobacco never cured diseases for which it was prescribed and noted the harmful effects of nicotine. the first pharmacological studies of nicotine were initiated by orfila in 1843, and was followed by a sharp increase during world war ii when widespread adaptation of the cigarette by women was added to large -scale consumption by american troops(surgeon-general's 1979). it has been noted that since the introduction of tobacco in europe, any major war has invariably been associated with an enormous increase in the prevalence of smoking (corti 1932) . the deleterious effects of tobacco on health had been suspected, and alluded to, for centuries before appropriate tools for scientific investigation were developed. the relationship between cancer of the lip and tobacco use was noted as early as the 18th century, but it was not until 1920 that the first systematic approach to that association was made(surgeon-general's 1979). in 1900 statisticians began to note increases in the incidence of lung cancer. in the dangers of involuntary (passive) smoking was described: "levels of carbon monoxide which can be reached in cigarette smoke-filled rooms have been shown to decrease the exercise duration required to induce angina pectoris in patients with coronary artery disease. side-stream smoke, which comes from the lighted tip of the cigarette between puffs, has higher concentrations of some of the irritating and hazardous substances than does mainstream smoke (that smoke inhaled by the smoker." (surgeon-general 1964) the most recent opinion on passive smoking appeared in a prestigious journal of medicine, reporting that chronic exposure to tobacco smoke is deleterious even to the non-smoker, significantly reducing small-airway resistance (white and froeb 1980) . over the last 40 years, the health hazards associated with cigarette smoking have been communicated to the public by the mass media. according to the 1979 report of the surgeon general, the increased awareness by the individual smoker of the deleterious effects of tobacco smoke has resulted in a decrease in the prevalence of smoking in the general population. however, the percentage of teenagers who smoke has not declined in the last 2 decades, and the number of teenage females who regularly smoke has increased(surgeon-general's 1979). the historical record on tobacco has demonstrated that establishment of the most severe penalties for smoking in the past, including torture and death, failed to suppress smoking in the long run in turkey, russia and japan (brooks 1952) . it is no surprise, then, to see that the threat of delayed physical harm, in the form of disease, has failed to suppress smoking among the youth of the u.s. today. it is clear that tobacco has reinforcing properties that motivate its user to continue smoking even when aware of the possible health consequences. nicotine appears to be the compound in tobacco which is most likely responsible for these effects. when the nicotine and tar content were varied independently, it was the nicotine content that correlated with ratings of strength and satisfaction(surgeon-general's 1979). moreover, laboratory research has demonstrated that animals will self-administer nicotine (surgeon-general's 1979). an approach to this problem has been suggested recently by an english physician(s), j o u r n a l p r e -p r o o f an approach that has a ring of familiarity. they argue that tobacco snuff would be an acceptable and less harmful substitute for cigarette smoking. they note that in the 400 years of tobacco history, during which time tobacco has been chewed, snuffed or smoked, no population gave up one form of tobacco use without replacing it with another. the only time that the british decreased the frequency of smoking was in the 18th century when they switched to snuff. snuff, they report, produces peak blood levels of nicotine comparable to those produced by smoking tobacco. in addition, there are no products of combustion such as tar carbon monoxide and oxides of nitrogen. the pollutant effects of tobacco smoke would be eliminated by the use of snuff. these physicians postulate a new age for snuff is ahead, predicting that snuff could save more lives and avoid ill-health more than any other rational preventative measure likely to be available well into the 21st century (russel, jarvis et al. 1980 ). in the last few years, a new way to inhale nicotine (e-cigarettes or e-pens) is growing in popularity especially among youth. e-cigarettes are electronic devices that heat a liquid and produce an aerosol or mix of small particles in the air. e-cigarettes can deliver a high level of nicotine. according to one manufacturer, a single refillable cartridge in an e-pen contains as much nicotine as a pack of 20 regular cigarettes. a national health interview survey reported: "overall, 15.3% of adults aged ≥18 years had ever used an e-cigarette, and 3.2% currently used e-cigarettes in 2016. adults aged 18-24 years were the most likely to have ever used an e-cigarette (23.8%); the percentage declined steadily to 4.4% among adults aged ≥65 years. adults aged 18-24 years (4.7%) and 25-44 years (4.2%) were more likely to be current e-cigarette users than adults aged 45-64 years (2.8%) and those aged ≥65 years (1.0%). across all age groups, fewer than one fourth of adults who had ever used an e-cigarette reported being a current user." (mmwr 2017) an e-cigarette aerosol is not harmless, but it generally contains fewer toxic chemicals than smoke from burned tobacco products, like regular cigarettes. nicotine interacts with a group of receptors that are normally targeted by the neurotransmitter acetylcholine. nicotinic acetylcholine receptors (nachrs) are transmembrane ion channels. when activated, either by acetylcholine or by nicotine, they allow selected ions j o u r n a l p r e -p r o o f to flow across the cell membrane. nachrs are distributed in the autonomic and central nervous systems and at the neuromuscular junction. acetylcholine and nicotine act at these receptors to alter electrochemical properties at a variety of synapses, which can in turn affect the release of several other neurotransmitters. nicotine has been shown to enhance attention, the ability to concentrate on particular stimuli and screen out the rest. researchers at the national institute on drug abuse have shown, using neuroimaging methods, that nicotine activates specific brain areas in subjects performing tasks that demand attention (powledge 2004) . researchers are beginning to study the efficacy and safety of nicotine patches for treating mild cognitive impairment, thought to be a precursor of alzheimer disease (powledge 2004) . interestingly, smokers have lower rates of neurodegenerative disorders, and nicotine improves cognitive and motor functioning in people with alzheimer's disease and parkinson's disease (newhouse, potter et al. 2004 ). the mechanism is not clear, but it is hypothesized that nicotine modulates release of neurotransmitters depleted in those diseases. nicotine is also being studied for its analgesic actions and for treating obesity. development of synthetic drugs by pharmaceutical companies that mimic nicotine actions at selective receptors may lead to novel therapeutics to enhance cognition, alleviate pain and to promote weight loss. however, there are those who advocate for less expensive nicotine products like a transdermal patch, chewing gum, or nasal spray. these formulations are generally intended for smoking cessation but are widely available, usually without prescription (powledge 2004). since the late 1980s, the tobacco plant has been used as a natural living laboratory to generate bio-pharmaceutical agents. plant molecular "pharming" or farming (pmp or pmf) is the practice of using plants to produce human therapeutic agents. many therapeutic proteins have been produced in plants, and some of them have are close to commercialization (yao, weng et al. 2015 , dirisala, nair et al. 2017 . the tobacco plant has the potential to massproduce pharmaceutical products with less cost than traditional methods. the first application of plant pharming was for the generation of human growth factor in tobacco (barta, sommergruber et al. 1986 ). tobacco-derived proteins have been tested and used to combat mers-cov and prevents the virus from infecting lung cells (yao, weng et al. 2015) . other examples of therapeutic agents produced in tobacco include a number of vaccines directed against malaria, anthrax, hepatitis and influenza. in addition to harnessing the power of the plant to produce useful bio-pharmaceuticals, the tobacco plant continues to reveal new molecules that had not previously been identified as biologically active. recently, a plant defensin (nad1), a cationic antimicrobial peptide, was isolated from the flowers of the ornamental tobacco plant (nicotiana alata) (poon, baxter et al. 2014 ). nad1 exhibits potent antifungal activity against pathogenic fungi. the potential of the tobacco plant to yield novel therapeutic agents or facilitate production of antigens and antibodies is an expanding frontier for this versatile plant. in tracing the gradual transformation of medical opinion on the use of tobacco, it is clear that medical opinion evolves with increasing information and technology, but it is also molded by contemporaneous social, economic and political circumstances. although most of the concepts of medicine from before the 19th century are no longer tenable or valid in modern times, man himself has not changed from a biological point of view. the propensity to ingest plant or chemical substances has been a characteristic of man since before recorded history and will remain with him as long as he lives social attitudes and medical opinion are subject to relatively rapid change. future decisions on the regulation of tobacco and of newer synthetic substances with abuse potential must be approached with this in mind. man will continue to self-administer psychoactive substances. the responses of society and of the medical profession will most likely undergo the transformations described for tobacco. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. conflict of interest: the author has no conflicts to declare. j o u r n a l p r e -p r o o f the social history of smoking perspectives on the history of psychoactive substance use the expression of a nopaline synthase -human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue the mighty leaf; tobacco through the centuries, little, brown and co introduction of tobacco in europe magic plants in primitive medicine use of tobaco among the american indians a history of smoking, harcourt, brace and co panacea or precious bane: tobacco in 16th century literature recombinant pharmaceutical protein production in plants: unraveling the therapeutic potential of molecular pharming the tobacco industry in the united states introduction of tobacco into europe percentage of adults who ever used an e-cigarette and percentage who currently use e-cigarettes, by age group -national health interview survey effects of nictoinic stimulations on cognitive performance cuban counterpoint phosphoinositide-mediated oligomerization of a defensin induces cell lysis a new age for snuff a history of the medicinal use of tobacco 1492-1860 report on smoking and health report on smoking and health ganglionic stimulating agents. pharmacological basis of therapeutics small airways dysfunction in nonsmokers chronically exposed to tobacco smoke plants as factories for human pharmaceuticals: applications and challenges key: cord-272536-bl8bdrcm authors: de vito, andrea; geremia, nicholas; mameli, sabrina maria; fiore, vito; serra, pier andrea; rocchitta, gaia; nuvoli, susanna; spanu, angela; lobrano, renato; cossu, antonio; babudieri, sergio; madeddu, giordano title: epidemiology, clinical aspects, laboratory diagnosis and treatment of rickettsial diseases in the mediterranean area during covid-19 pandemic: a review of the literature date: 2020-09-01 journal: mediterr j hematol infect dis doi: 10.4084/mjhid.2020.056 sha: doc_id: 272536 cord_uid: bl8bdrcm the purpose of the present review is to give an update regarding the classification, epidemiology, clinical manifestation, diagnoses, and treatment of the rickettsial diseases present in the mediterranean area. we performed a comprehensive search, through electronic databases (pubmed – medline) and search engines (google scholar), of peer-reviewed publications (articles, reviews, and books). the availability of new diagnostic tools, including polymerase chain reaction and nucleotide sequencing has significantly modified the classification of intracellular bacteria, including the order rickettsiales with more and more new rickettsia species recognized as human pathogens. furthermore, emerging rickettsia species have been found in several countries and are often associated with unique clinical pictures that may challenge the physician in the early detection of the diseases. rickettsial infections include a wide spectrum of clinical presentations ranging from a benign to a potentially life treating disease that requires prompt recognition and proper management. recently, due to the spread of sars-cov-2 infection, the differential diagnosis with covid-19 is of crucial importance. the correct understanding of the clinical features, diagnostic tools, and proper treatment can assist clinicians in the management of rickettsioses in the mediterranean area. considered to be absent in obligate intracellular bacteria. 9, 11 the transmission of the infection depends on the group. sfg is transmitted by the bite of an infected tick; whereas, organisms of typhus group are transmitted through inoculation via infected louse or flea faeces (rickettsiae prowazekii and rickettsia typhi, respectively) through a bite, wound or mucous membranes. once inoculated into the skin, organisms are phagocytized by dendritic cells and transported via lymphatics to local lymph nodes where they replicate. subsequently, the bacteria spread in the bloodstream and disseminate to infect the endothelium of the microcirculation, where the rickettsiae can infect vascular endothelial cells of the small and mediumsized blood vessels. the damage of the endothelium and the subsequent endothelial dysfunction is followed by alteration in coagulation and the cytokine network. the endpoint of this pathogenetic results in a reduction in circulating peripheral cd4 t lymphocytes and perivascular infiltration by cd4 and cd8 t lymphocytes, b cells, and macrophages, causing a vasculitis. [12] [13] [14] epidemiology. there are several pathological rickettsia species in europe, and in the last years, new species and subspecies have been implicated as human pathogens, and new rickettsial syndromes have been described. 15 mediterranean spotted fever (msf) caused by rickettsia conorii subsp. conorii is the most frequent rickettsiosis in europe. it is endemic in southern europe, but sporadic cases have been reported in all the continents. 15, 16 the first cases were first described in tunisia in 1909 by conor and buch. the brown dog tick, rhipicephalus sanguineus, is the vector and the potential reservoir of rickettsia conorii subsp. conorii in the mediterranean area. 15, 17 most msf cases occur in summer when climatic conditions seem to be an essential factor in increasing the aggressiveness of rhipicephalus sanguineus ticks to bite humans. [15] [16] [17] [18] rickettsia conorii subsp. israelensis is the agent of israeli spotted fever (isf), which was first reported in 1946 in the haifa bay area, israel. [17] [18] [19] [20] in europe and the mediterranean region, the brown dog tick, rhipicephalus sanguineus, is recognized to be the vector of rickettsia conorii subsp. israelensis. 21 the geographic distribution of the disease appears to be spread more widely in the mediterranean countries than previously thought. cases have been reported in italy, portugal, tunisia, and libya. [22] [23] [24] [25] other rickettsia conorii subspecies reported in the mediterranean area are rickettsia conorii subsp. caspia and rickettsia conorii subsp. indica. the first one is the agent of astrakhan fever, endemic in the astrakhan region, adjacent regions of the caspian sea, and described in rhipicephalus sanguineus ticks in kosovo and southern france. 16 rickettsia sibirica subsp. mongolitimonae, the microorganism that cause of lymphangitis-associated rickettsiosis (lar), was isolated for the first time in china, from hyalomma asiaticum ticks collected in mongolia in 1991. 16 rickettsia sibirica subsp. mongolitimonae was detected in hyalomma anatolicum excavatumt ticks in greece and cyprus; in rhipicephalus pusillus ticks in france, portugal, and spain; and in rhipicephalus bursa ticks in spain. [26] [27] [28] [29] [30] the first human infection with rickettsia sibirica subsp. mongolitimonae was reported in france in 1996. 31 rickettsia sibirica subsp. mongolitimonae is implicated in human pathogen in different countries, as france, spain, turkey, and egypt. [32] [33] [34] [35] rickettsia slovaca and rickettsia raoultii are associated with a syndrome characterized by scalp eschars and neck lymphadenopathy following tick bites (senlat). these microorganisms have been found in dermacentor marginatus and dermacentor reticulatus ticks in a vast majority of european countries. [36] [37] [38] [39] [40] [41] [42] after msf, senlat is the most prevalent tick-borne rickettsiosis in europe. it has been reported in different countries, including hungary, spain, france, germany, italy, bulgaria, and portugal. [43] [44] [45] [46] [47] [48] senlat occurs most frequently from march to may and from september to november, which corresponds to the periods of most considerable activity of dermacentor adult ticks in europe. [47] [48] [49] rickettsia helvetica is transmitted by ixodes ricinus, which is the primary vector and the natural reservoir. however, human infection is rare, and it has been documented only in austria, denmark, france, italy, sweden, slovakia, and switzerland. 16, 50, 51 other rare rickettsial pathological species in europe and the mediterranean area are rickettsia massiliae, rickettsia monacensis, rickettsia aeschlimannii, and rickettsia sibirica subsp. sibirica. clinical manifestation. rickettsiosis is a rare disease: the incidence is around 1 case per 100.000 people by year, but it has been increasing during the last years, probably due to better diagnostic techniques. 15 in europe, the most important diseases are three: mediterranean spotted fever (msf), lymphangitisassociated rickettsioses (lar), and scalp eschar and neck lymphadenopathy (senlat). 19 the other significant disease caused by rickettsia rickettsii is the rocky mountain spotted fever (rmsf), but no cases have been reported in europe to date. 19 apart from these three pathologies, there are other minor forms caused by different pathogens. mediterranean spotted fever. msf, caused by rickettsia conorii, is the most common rickettsialdisease in europe, where the highest incidence is during summer. 52 not all people who come into contact with this bacterium develop the disease. a spanish study, indeed, shows that 4-8% of the population carry antibodies against rickettsia but without a previous clinical history of msf. 53 the most common symptoms are fever (93-98%), myalgia (64-75%), headache (48-65%), and asthenia (27%). the maculopapular rash is present in 85-94% of the patients; the tache noir has been noticed in 58-64% of the patients. the classic triad, fever, maculopapular rash, and inoculation eschar, is present in 40-50% of the patients. [54] [55] [56] in most cases, msf is a self-limiting disease but sometimes could be life-threatening. it was estimated that about 5-10% of msf cases could be severe. [78] [79] [80] and arthritis 81, 82 have been reported. the most frequent hematological and biochemical modifications are thrombocytopenia, leukocyte count abnormalities, elevated hepatic enzyme levels and an increase of c-reactive protein. 54, 83 mortality was around 1-3% 84 before the antimicrobial drug era. thus, it has been considered a benign illness. in some recent studies, msf appears to be more severe than it has been thought. mortality rates were 5.4% in france, 3.6% in portugal, 3.2% in algeria, 0.8% in spain and 0.36% in italy. 52, 54, [84] [85] [86] risk factors for severe msf include advanced age, immunodeficiency, chronic alcoholism, g6pdh deficiency, diabetes, prior prescription of an inappropriate antimicrobial drug, or delay in treatment. 84, 85 scalp eschar and neck lymphadenopathy after a tick bite. senlat 87 syndrome is also known as tibola 88 (tick-borne lymphadenopathy) or debonel 44 (dermacentor-borne necrotic erythema and lymphadenopathy), and it is caused by rickettsia slovaca and rickettsia raoultii 19 but also by other bacteria such as bartonella henselae. 87 this disease is developed mostly during spring and autumn. 49 the clinical description of senlat includes asthenia, headache, painful adenopathies (especially to the neck's lymph nodes), and a painful scalp eschar surrounded by a perilesional erythematous halo. low fever, rash, and face edema have also been reported less frequently. 45, 87, 89 no malignant or fatal cases have been described in the literature. after the therapy, alopecia could potentially last for several months, with persistent asthenia. 89 lymphangitis-associated rickettsioses. lar is caused www.mjhid.org mediterr j hematol infect dis 2020; 12; e2020056 by rickettsia sibirica subsp. mongolitimonae. just a few cases have been reported in europe. in particular, until 2013, only 24 cases have been reported in the mediterranean area. 19 the typical period of this disease is spring. commons symptoms include fever, headache, an eschar (frequently more than one) on the site of inoculation, and lymphangitis, which starts from the eschar and reaches an enlarged lymph node. the difference between lar and the other two diseases are the period of occurrence (spring), and the presence of lymphangitis and multiple eschars. 90 until now, no deaths have been reported in patients that have been infected by rickettsia. however, some severe cases have been reported, in particular: a retinal vasculitis, 91 sepsis with disseminated intravascular coagulation, 92 myopericarditis 93 and a septic shock. 94, 95 mediterranean spotted fever-like. other rickettsiae in europe could infect humans; most of them cause a disease very similar to msf. for example, rickettsia conorii subsp. caspia causes an illness called "astrakhan fever." this disease is typical of the caspian sea area, but some cases have also been reported in france. 96 astrakhan fever diverges from msf in the percentage of patients who present with an eschar (only 20%) and because it could cause thrombocytopenia and bleed. 97 another similar disease is the israeli spotted fever (isf), caused by rickettsia conorii subsp. israelensis. in europe, this bacterium has been found only in portugal and in italy. the symptoms are quite similar to msf except for the presence of gastrointestinal symptoms in half of the patients. the main difference is the malignity; indeed, the mortality is higher (more than 25%). 24, 40, 56, 98, 99 other rickettsiae who could cause a msf-like illness are rickettsia monacensis, 100, 101 rickettsia massiliae, 102, 103 rickettsia aeschlimannii, 104, 105 and rickettsia helvetica which could be malignant. 51, 106, 107 differential diagnosis with other infectious diseases including covid-19. clinically, the patients with msf present the classic triad, fever, tache noir, and maculopapular rash in 40-50% of cases. in the absence of this typical clinical picture, the diagnosis could be challenging. a small percentage of patients could present only the tache noir, which is generally pathognomonic of rickettsial diseases. however, clinical cases in which the tache noir was present in other zoonoses have been reported in the literature. [108] [109] [110] the presence of fever without other signs is, probably, the most difficult challenge for clinicians because it is the expression of many diseases, both infective (bacterial, viral, fungal, and parasitic) and not infective. in these patients, a proper anamnesis, laboratory findings, and radiological features are mandatory to permit the correct diagnosis. blood cultures should be collected at the fever peak to exclude a bacterial or fungal infection. furthermore, in the area where sars-cov-2 is circulating in the population, the nasopharyngeal swab, together with acute phase serology, is recommended to rule it out. indeed, the common symptom in patients with coronavirus disease (covid-19) is the fever. 111, 112 the other symptoms that these two diseases have in common are headache, asthenia, and myalgia. the associations of dysgeusia, anosmia, and gastrointestinal symptoms could suggest the diagnosis of covid-19. [113] [114] [115] the maculopapular rash is an expression of several diseases. 116 in these cases, clinicians should pay attention to the distribution, the pattern, and the relationship between the localization at the start of it and other clinical signs, especially the fever. although respiratory symptoms are the most frequent in covid-19, skin involvement should always be considered. galván casas c et al. 117 described the most common cutaneous pattern, and magro et al. 118 demonstrated how sars-cov-2 is associated with microvascular damage and thrombosis. moreover, different cutaneous vasculitis-like patterns correlated with covid-19 or sars-cov-2 therapy have been described. 119, 120 diagnosis. nowadays, the majority of reference laboratories in developed countries can provide quick identification of rickettsial pathogens thanks to molecular and serological assays. in many cases, the diagnosis could be made by the clinical manifestation, but the laboratory tests are necessary at the support of it. the choice of the most appropriate diagnostic technique requires consideration of the suspected pathogen, the timing of symptoms onset, and the type of sample available for testing. 121 serological tests remain essential diagnostic tools, 122 but rickettsiae can be isolated from or detected in clinical specimens. the diagnostic tools available include serologic assays, molecular testing, cultures, immunochemistry, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof). 123 the diagnostic technique could be divided into two groups: 1) diagnostic techniques used as routine. diagnostic techniques used as routine (table 1) serologic tests: indirect immunofluorescence antibody assay (ifa) is a widely accepted serologic test for the detection of rickettsial infection. 124, 125 it is considered the most indirect immunofluorescence antibody assay (ifa) serologic high sensitivity and specificity for igg [124, 125] . low sensibility for igm; operatordependent [129, 130] the enzyme-linked immunosorbent assay (elisa) serologic more sensitive than ifa for the detection of low antibodies level; absorbance of the enzyme reaction is measured with a spectrophotometer [131, 132] . could be negative during the early phase [131, 132] . nucleic acid amplification tests (naats) (molecular methods) quick response; could be used during acute disease [123] ; provides the differentiation between different species [136] . high costs; low sensitivity if used peripheral blood and serum [139] ; antibiotics reduce the sensitivity [116] . sensitive and specific method among serological assays. 126 ifa consists of rickettsial antigens fixed on a slide and detected by specific antibodies present in the patient's serum, which can be identified by a fluorescein-labeled conjugate. serum of patients with clinical manifestation of disease must be collected on the day of the admission and 2-4 weeks after illness onset. 127 ifa assays are highly sensitive at detecting antibodies after 2-3 weeks after illness onset, and their results are best interpreted if serum samples collected in acute and convalescent phases are tested at the same time. 128 most laboratories test for igg antibodies because igm antibodies reactive with rickettsia rickettsii are frequently detected in patients with no other supportive evidence of a recent rickettsial infection. therefore, the detection of igm during the acute phase should not be considered diagnostic for an ongoing illness as there could be cross-reactivity with other species and persistence of igm beyond acute status. 129, 130 the enzyme-linked immunosorbent assay (elisa) detects the binding of specific antibodies to antigens in a serum sample. when secondary anti-human antibodies conjugated with an enzyme are bound to antibodies from a serum sample and subjected to a substrate, an enzymatic reaction will be measurable in a positive specimen. 131 elisa is sensitive, reproducible, and allows the differentiation of igg and igm antibodies. the results are more sensitive than ifa for the detection of low antibodies level, such as during late convalescence. 121 elisa has the advantage, compared to ifa, of eliminating the subjective evaluation since the absorbance of the enzyme reaction is measured with a spectrophotometer. the inhibition elisa has been used only for the diagnosis of scrub typhus and seems to be more sensitive than ifa in the early phase of the disease. 132 these assays are more appropriate than serology in the diagnosis of acute infection; a sample collected early at disease onset, before the development of antibodies, is more likely to produce a positive result in pcr assays. when antibody production has increased to detectable levels, bacteria are rarely found in the bloodstream or at the inoculation site. furthermore, if antibiotic treatment has been initiated, the sensitivity of pcr assays decreases for the same reason. 133, 134 the most used method is nucleic acid amplification tests (naats), such as pcr, which has acquired increasing importance over the past few years. the quick response allows a prompt diagnosis without the need to wait for seroconversion or cell culture's growth time, which can take from 10 to 30 days. 123 amplification of species-specific dna by pcr provides a useful method for the differentiation between the several rickettsia spp. and to gain knowledge about the genomic differences within the genus. 124 the conventional pcr format, due to a large number of pcr products, is more prone to contamination. for this reason, a single-use primer pcr has been introduced. 135 another molecular method is real-time pcr that offers the advantage of speed, reproducibility, quantitative capability, and reduced risk of contamination compared with conventional pcr assays. 136 several clinical samples are suitable for pcr amplification: skin biopsy, eschar, swab, or csf. peripheral blood and serum could also be used, but pcr on these samples has a lower sensitivity compared to skin samples or eschar collected on the bite site. 137, 138 pcr detection of rickettsia rickettsii in the blood is possible. still, its sensitivity is lower because of the small numbers of rickettsiae in the blood in the first stages of the disease. 139 for this reason, during the acute phase, it is better to use the sfg tissue specimen. 116, 140 doxycycline treatment decreases the sensitivity of pcr; therefore, obtaining blood before starting antibiotic therapy is recommended to minimize false-negative results. 116 shell vial: this method requires a large number of bacteria and specific cell lines to proliferate, such as vero e6 cells, human embryogenic lung fibroblast, and the promyelocytic hl-60 leukemia cell line (the most widely used cell line for growing a. weil-felix test serologic easy to use; low cost. it is still used in developed countries [125] . cross-reaction with other antigens. low sensitivity, low sensibility [122, 168] western blot serologic highest sensitivity to early antibody, high specificity [144] . expensive, technically difficult to perform, longer procedure [144] . line blot serologic high specificity and sensitivity; a large number of antigens tested [121] . no quantitative titers available; expensive [121] . more sensitive than either the complement fixation or weil-felix [126] rarely used, low sensitivity, long preparation [143] . rarely used for the high cost[145]. hight sensitivity and specificity; tests multiple rickettsial antigens simultaneously [123] cross-reactivity [123] ; high costs. serologic very specific; used for seroepidemiologic studies [143] poor sensitivity, especially during the early stage of the disease [126] indirect immunoperoxidase assay (ipa) serologic similar to ifa; very sensitive and specific [143] needs specific instrument and trained personal [143] shell vial culture highest specific; could be used during acute disease [121, 141] . long times [141] .; low success rate; needing specific cell lines [141] ; low sensitivity [142] circulating endothelial cells (cecs) other not influenced by previous antibiotic treatment; cecs level detected could be correlated with the severity of the disease [127] low sensitivity; not easy to perform [146] . high sensitivity [123, 143] need bioptic sample, not easy to perform [123, 143] . early diagnoses, differentiation between species [123] high costs; not always available [123] . only used to identify infections inside the arthropods [123, 147, 148] phagocytophilum). 141 specimens for cell cultures should be collected before starting antibiotic treatment and should not be frozen. 121 to identify the cultivated small intracellular rickettsiae, the laboratories should label bacteria by fluorescent antibodies or staining with the gimenez method. the low success rate and the complexity of this method do not permit the routinely use of this methodic. 142 serologic methods: the weil-felix test, based on the detection of immuneresponse to different proteus antigens that cross respond with rickettsia 125 should not be considered a first-line testing method anymore, even if it remains an option developing countries. it allows the detection of igm antibodies 5-10 days after clinical manifestations. western blot assay (wba) was demonstrated to be more sensitive than ifa for the detection of early antibodies in rickettsia spp. nevertheless, it is generally more expensive and technically challenging to perform than other serological methods. 143 furthermore, rickettsia cultures are required. for these reasons, its use is limited to only a few reference laboratories. 144 the line, or dot, blot immunoassay, may be particularly useful for screening the many antigens that might be considered for patients with nonspecific or atypical clinical presentation. this test can be regarded as valuable only as a first-line test for the rapid diagnosis of acute cases in areas with high prevalence. 121 the microagglutination test could be divided into two different methods, which included the indirect hemagglutination test and the latex agglutination method. the first one is specific for the detection of igg and igm for all rickettsiae. 143 the latex agglutination permitted the directed detection of the r. conorii, r. prowazekii, r. rickettsia, r. typhi, and infections. this method has a high sensitivity, but it is not routinely used for the high cost. 126, 145 micro immunofluorescence (mif) assay is similar to ifa except that wells are spotted with multiple rickettsial antigens for simultaneous detection. the negative aspect of this method is cross-reactivity, and its costs. 123 complement fixation (cf) test permitted the identification detection of antibodies specific for rickettsiae. it is peculiar, but it has shown a reduced sensitivity, especially during the early stage of the disease. for this reason, it is only used for seroepidemiological studies. 126 indirect immunoperoxidase assay (ipa). the procedure is the same as ifa, but it used the peroxidase instead of fluorescein. it needs a specific instrument and trained personal. for this reason, it is not commonly used. 143 other tests: circulating endothelial cells (cecs) method allows the detection of r. conorii in circulating endothelial cells isolated from whole blood by using immunomagnetic beads coated with an endothelial cell-specific monoclonal antibody. 127 the sensitivity is about 50%, and it is not influenced by previous antibiotic treatment. furthermore, the cecs level detected correlates with the severity of the infection, so it can be considered a prognostic indicator. 146 immunohistochemistry (ihc) permits the rickettsia's detection directly from biopsy specimens, but it could only be used during the acute phase and only if there is a rash or tache noir. 123, 143 the most recent diagnostic tool is the matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof). this technique has been using with promise application for the tick-borne infections inside the arthropods. 123 the future role of this new method could be applied to help the clinical decision. the identification of rickettsiae inside the vector 147 or in the hemolymph 148 is showing great potential but remained a niche method. 123 biosensors emerging technology allows the fast detection of rickettsia-induced immune response. for example, the ompa antigen, an outer membrane protein present in the r. rickettsia, the agent responsible for the spotted fever, allows the detection of anti-ompa human igg. this is possible through an amperometric immune-sensor by using a synthetic peptide, obtained from the h6pga4 r. rickettsia protein, homologous to ompa. 149 treatment. rickettsiae spp. are obligate intracellular bacteria; therefore, the standard treatment is based on tetracyclines or chloramphenicol. the gold standard therapy is indeed represented by doxycycline 100 mg per os twice daily x 7 days in adults and 2.2 mg/kg of body weight per dose twice daily, orally or intravenously. 140, 150 it has been demonstrated, in several studies, that doxycycline shortens the course of msf and induces a rapid remission of symptoms. the problem is that tetracycline should be avoided in childhood, during pregnancy, 151, 152 in patients who are allergic to it, and in those who have a g6pdh deficiency. an alternative to doxycycline is chloramphenicol. it should be administered at a dosage of 50 mg/kg/day in four doses for seven days. 56 since 2000, chloramphenicol was used only for patients suffering from allergy, those having adverse effects to doxycycline or if fever persisted for more than five days or in those that relapsed after the therapy with tetracycline. however, chloramphenicol should also be avoided during pregnancy (grey baby syndrome), and because of the various adverse effects (aplastic anemia, bone marrow suppression), it is not recommended in children. furthermore, in a randomized study on 415 children, the chloramphenicol group had a longer hospitalization. 56 for this reason, in pregnant women and children, the first choice is a macrolide. different randomized studies have shown the macrolides' non-inferiority. in particular, meloni et al., bella et all and cascio et al., in their randomized studies, have demonstrated the non-inferiority, respectively, of azithromycin, josamycin, and clarithromycin vs. doxycycline. [153] [154] [155] on the contrary, munoz-espin et al. have shown that erythromycin is less effective than doxycycline. 156 studies in vitro have tested the efficacy of fluoroquinolones against rickettsiae spp., showing encouraging results. 150, [157] [158] [159] furthermore, randomized studies have shown that there is no difference between tetracycline and fluoroquinolones. 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a randomized controlled trial erythromycin versus tetracycline for treatment of mediterranean spotted fever in vitro susceptibility of rickettsia conorii to ciprofloxacin as determined by suppressing lethality in chicken embryos and by plaque assay susceptibility of rickettsia conorii and r. rickettsii to pefloxacin, in vitro and in ovo susceptibility of rickettsia conorii, r. rickettsii, and coxiella burnetii to pd 127,391, pd 131,628, www.mjhid.org evaluation of ciprofloxacin and doxycycline in the treatment of mediterranean spotted fever randomized double-blind evaluation of ciprofloxacin and doxycycline for mediterranean spotted fever ciprofloxacin therapy for mediterranean spotted fever analysis of risk factors for malignant mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect deleterious effect of ciprofloxacin on rickettsia conorii-infected cells is linked to toxinantitoxin module up-regulation antibiotic susceptibility of rickettsia and treatment of rickettsioses randomized trial of 5-day rifampin versus 1-day doxycycline therapy for mediterranean spotted fever deleterious effect of trimethoprimsulfamethoxazole in mediterranean spotted fever the antigenic relationship between bacillus proteus x-19 and rickettsiae: iii. a study of the antigenic composition of the extracts of bacillus proteus x-19 key: cord-018316-drjfwcdg authors: shephard, roy j. title: building the infrastructure and regulations needed for public health and fitness date: 2017-09-19 journal: a history of health & fitness: implications for policy today doi: 10.1007/978-3-319-65097-5_22 sha: doc_id: 18316 cord_uid: drjfwcdg 1. to recognize the importance to the maintenance of good health of adequate public health regulations and an infrastructure that provides clean water and appropriate waste management. 2. to see the lack of such amenities over many centuries, but the progressive development of public health bureaucracies dedicated to provision of an appropriate infrastructure for healthy cities, beginning during the victorian era. 3. to observe how responsibility for the provision of adequate housing for poorer city dwellers has been shared between government, benevolent entrepreneurs and charities. 4. to note the new challenges to public health presented by such current issues as the abuse of tobacco and mood-altering drugs, continuing toxic auto-emissions, the epidemic of hiv/aids, a decreased acceptance of mmr vaccinations, and the ready spread of infectious diseases by air travel. opportunities for the spread of communicable diseases have increased with the growth in size of cities. the success of urban living has depended in great part on governmental ability to maintain population health through the building of an adequate infrastructure to provide clean water and to dispose of waste, as well as the enactment of appropriate regulations to control the prevent the spread of infectious diseases. in this chapter, we will look at success in meeting these objectives in various communities from early history through the classical era, the arab world, mediaeval europe, the renaissance, and the enlightenment to the victorian era, concluding with some comments on current challenges to public health. in the hey-day of the persian empire, heat, cold, dirt, stench, old age and anxiety were all thought to contribute to ill-health. cyrus the great (590-530 bce) thus taught his soldiers not to urinate or spit into running water. dead matter was also carefully removed from water-courses, and the clothing of dead people was systematically burnt. during the mediaeval era, interest in public health was much more advanced in the islamic world than in northern and western europe. ali ibn-rabban (838-870 ce), a well-respected physician living on the south coast of the caspian sea, wrote in his seven-part medical work paradise of wisdom that: "no one should live in any country which does not have four things: a just government, useful medicaments, flowing water and an educated physician." in the eleventh century, the arabic biographer al-mussawir emphasized that the main duty of a monarch was the preservation of health and well-being in his subjects. thus, islamic legislation required physicians to pay regular visits to army units, prisons and people living in outlying areas. the practice of medicine was regulated through a religious office, the hisba, headed by an official called the muhtasib with some of the powers of a modern ombudsperson. one function of the muhtasib was to act as the city medical officer of health. he prevented people with elephantiasis from using the public baths, regulated the cleanliness of public places such as markets, and ensured that garbage collectors did not handle food. one interesting example of applied hygiene was the method used to determine an appropriate location for construction of the main hospital in baghdad (chap. 16). the merits of various sites were compared by hanging up pieces of meat, and noting the location where decomposition proceeded the most slowly. the city of córdoba under moorish rule further illustrates the infrastructure typical of the arab world during the tenth century ce. among other facilities, the city boasted 300 public baths. in northern and western europe, public health infra-structure such as aqueducts and sewers fell into disrepair following departure of the roman garrisons, and during the mediaeval era the sanitary conditions in most cities were appalling. positive developments were the development of quarantine procedures and the re-emergence of a few public baths. food inspectors were appointed, and some cities also introduced zoning regulations, requiring malodorous trades such as tanning to be undertaken outside the city walls. water supply and sewage disposal untreated waste was thrown directly into the rivers of london and paris, and travellers were advised: "wise men go over bridges, and fools go under them." in 1349 ce, king edward iii ordered the mayor of london to: "cause the human faeces and other filth lying in the streets and lanes in the city top be removed with all speed to places far distant, so that no greater cause of mortality may arise…" a fourteenth century ordinance prohibiting the emptying of latrines into a creek near london's city wall remained largely ignored, so that in the fifteenth century the stream was buried underground. substantial populations of hogs and cattle roamed the streets of many large cities, adding to the urban stench. uncontaminated water was a rarity, and a lack of refuse disposal encouraged rat infestations. infrequent bathing and unwashed woolen clothing led to a proliferation of fleas and other insect vectors of infection. during the mid-fourteenth century, two thirds of the european population was killed by the flea-borne bubonic plague (the "black death", 1340-1348 ce). many doctors deserted their patients during this epidemic, and others proposed preposterous remedies. guy de chauliac wrote: "so contagious was the disease…. that no one could see or approach the patient without taking the disease…for self-preservation, there was nothing better than to flee the region… to purge oneself with pills of aloes, to diminish the blood by phlebotomy and to purify the air by fire and to comfort the heart with senna and things of good odor and to soothe the humours with armenian bole and resist putrefaction by means of acid things." chauliac unwittingly kept the rats and fleas away from pope clement vi, by surrounding his bedside with charcoal burners. a few years following the black death, observant physicians hypothesized that ships arriving from overseas were contributing to the recurring epidemics of plague. at first, hostels for sick townsfolk and newly arrived visitors were set up outside the city, but this was not entirely effective in containing infection. thus in 1377 ce, a trentino (30 days) of isolation on an uninhabited island was required at many european ports of entry. subsequently, the isolation period was extended to 40 days, perhaps because of an ancient greek doctrine that a contagious disease became manifest within 40 days. in britain, recently arriving travellers were quarantined on guardships, anchored in the thames estuary ( fig. 22 .1). most of the roman baths in northern europe had been abandoned by the mediaeval era, in part because of the high cost of heating the bath water, and in part because the church considered public bathing as a common prelude to venal sins. the church also had concerns about reinforcing belief in the supposed healing powers of celtic water deities (chap. 14). nevertheless, as prosperity increased in the latter part of the middle ages, public baths were built or reopened in various parts of europe. in britain, the king's bath was built over the sulis minerva temple in the city of bath, and paris had established 26 public baths by the thirteenth century. in germany, the tradition of river bathing had persisted from celtic times, and a growing number of new public bath-houses were constructed during the 14th and 15th centuries. admission to a bath-house was expensive, and poorer germans considered the payment of "bath money" a great blessing. the full luxury package of a spa treatment included washing, scouring and slapping of the body with a sheaf of twigs, a steam bath, rubbing to induce perspiration, swatting the skin with wet rags, scratching, hair washing, cutting and combing, lavendering, and blood letting. unfortunately, some of the baths subsequently became the scene of debauchery, prostitution and infection, and by the sixteenth century, many were closed for fears of spreading syphilis, leprosy and plague ( fig. 22 .2). personal hygiene substantial quantities of soap were traded during the mediaeval era, but this was used more for the washing of wool than for cleansing of the skin. monasteries boasted laundry rooms, and many women listed their trade as "laundry woman." however, the laundering of clothes was an infrequent luxury for poorer people, and indeed many had no spare set of clothing, so that fleas flourished in the poorer households. food inspection basic foodstuffs such as wine, beer, bread, meat, fish and salt were frequently adulterated in mediaeval times. to counter such abuses, several european governments appointed food inspectors. in britain, in 1266, the assize of bread and ale regulated the price of these staples in relation to the price of corn. occasional renaissance scholars expressed some interest in health promotion. the english diplomat and scholar thomas elyot (c. 1420-1546) wrote a book entitle the "castell of health," summarizing the latest medical knowledge for those unfamiliar with greek, and the venetian nobleman luigi cornaro (1464-1566) wrote a book on the art of living a long life. santo santorio (chap. 27) also sought to put hygiene on a mathematical basis. most of renaissance society showed little interest in public health or hygiene, as shown by the outbreak and management of the great plague. however, boards of public health were set up in some cities. two small advances in personal hygiene were the introduction of cotton clothing and a growing use of toothbrushes. diligent housewives adopted a few other simple changes in household management to preserve the health of their families, and cambridge university insisted on a direct control of its food supply, the great plague the london "plague" of 1665 ce was one in a series of european epidemics of bubonic plague dating back to the "black death." the great plague claimed at least 70,000 lives in central london, this being about a half of the population who had not fled from the city. indeed, the death count was probably underestimated, since publically appointed street monitors were open to bribery by those who did not wish to disclose that their house had become infected. samuel pepys commented that the prevalence of the disease was such that corpses could not removed during the hours of darkness ( fig. 22 .3). people were confined to their homes if one family member was infected, thus virtually ensured the death of the entire household. two watchmen were posted at the doors of infected homes for 40 days, at a cost of 16d per house per day, and the victims received a public stipend of 8d per day to pay for food, fuel and medicaments. believing that the disease was conveyed by miasmata, the college of physicians recommended using bonfires to displace the infected air. there was probably some incidental benefit from these fires, since the smoke tended to drive away the flea-ridden rats that were vectors of the disease. the epidemic was eventually checked by the great fire, which consumed both the rats and the plagueinfested slum dwellings. in europe, local boards of public health were established; they adopted various measures for the containment of epidemics and the provision of social support to the community. in some cases, they designated specific physicians to attend plague victims, and in florence, local doctors prepared a public information booklet that summarized current knowledge on plague prevention. a further responsibility of these boards was to deal with doctors who failed to report communicable diseases in wealthy patients. one roman doctor who was arrested for this offence was ordered to serve as resident physician at the local pest-house. outbreaks of the plague placed a severe financial stress upon some municipalities. in milan, extra funding was needed to hire physicians and grave-diggers, to pay for operating a quarantine "pest-house," and to reimburse the infected for two-thirds of the estimated value of their possessions, which were summarily burned. some municipalities set up immigration offices on mountain passes to control the arrival of infected travelers, and others restricted imports, exports, market trading, travel and funerals, although it was unclear how far these costly measures were successful in reducing the toll of disease and mortality. personal hygiene and household management one positive development during the renaissance was the introduction of washable cotton clothing and sheets. this greatly curtailed the spread of insect-borne diseases, particularly among those with sufficient wealth to own several changes of clothing. another innovation was popularization of the bristle toothbrush. this device had been invented by the chinese in the thirteenth century, but did not become popular in england until the late seventeenth century, beginning with the aristocracy. without necessarily knowing why, tudor housewives achieved some sterilization of their dairy equipment by scouring with salt and hot water, and then exposing utensils to bright sunlight. infestation of houses by fleas was also countered by sprinkling appropriate herbs beneath the rush mats that covered their floors. the renaissance saw further occasional attempts to control the quality of food, particularly for the wealthy. cambridge university insisted that the direct supervision of their refectories was important to preserving the health and well-being of their students. one of those promoting hygiene during the enlightenment was the physician james mackenzie, who in 1758 wrote a text on "the history of health and the art of preserving it." the enlightenment saw some improvement of health infra-structure many dwellings for the poorer citizens of europe.were now constructed of brick and boasted glass windows. and samuel johnson (1709-1784) was urging a pro-active response to the prevention of disease:"we must consider how many diseases proceed from our own laziness, intemperance or negligence… and beware of imputing to god, the consequences of luxury, riot and debauchery." the diderot encyclopédie, first published in 1751, included a section on hygiene, which wss defined as: "the things which mankind uses or handles… and their influence on our constitution and organs." gottfried wilhelm leibniz (1646-1716) was perhaps the greatest enthusiast for public health during this era. he strove to establish a pattern of medical training that was oriented towards public health and preventive medicine rather than the treatment of disease. he reminded his colleagues that hippocrates had registered every successful cure, and he urged a similar meticulous recording of outcomes in order to provide a modern preventive medicine data-base. he proposed that standardized questionnaires should be developed to examine eating habits, and that careful mor-the enlightenment tality statistics should be collected so that findings could be correlated with the local climate, air conditions and the nature of the soil. a few other scientists such as hales (who improved the water supply for his village of teddington), and bernouilli (with authored a probability study demonstrating the merits of vaccination) were also interested in public health. but concern about the provision of clean drinking water, adequate treatment of sewage and garbage, and protection against communicable diseases remained the exception rather than the rule, with most countries making a poor showing on indices of population health. francis bacon published studies on the percolation, filtration, distillation and coagulation of water as early as 1627. anton van leeuenhoek described the microscopic animalicules that he had seen in dutch drinking water in 1680, and the french scientist joseph amy patented a water filter in 1746. however, the quality of water in most large cities left much to be desired. philippe de la hire (1640-1718) mapped the area around paris, seeking to improve the water supply to versailles, probably as much to service the palace ornamental fountains as to provide clean drinking water in the town, and he built a massive aqueduct for this purpose (fig. 22.4) . he further suggested that householders should install a sand filter to purify the water collected from the roofs of their dwellings, although he noted that one alternative source of water, from underground aquifers, was rarely polluted. in 1804, paisley, scotland became the first british city to establish a municipal water treatment plant. it used a sand filter that had been developed by robert thom. in 1806, paris also constructed a large water treatment facility on the seine; here, river water was allowed to settle for 12 hours, and was then passed through sponge pre-filters and main filters that contained sand and charcoal. despite these advances, the residents of broad st., in central london, faced a massive outbreak of cholera as late as 1854, because they were drawing water from a shallow well that was located close to a cholera-contaminated cess-pit. too often, the city dwellers of the enlightenment continued to pass sewage into open gullies or cess-pits that were fig. 22.4 ruins of an aqueduct, built by philippe de la hire to improve the water supply to the city of versailles and its royal palace (source: http://en. wikipedia.org/wiki/ canal_de_l'eure) close to wells, and garbage was thrown directly onto the street. however, in 1706, the conseil supérieur of new france ruled that in order to reduce infection, the houses in quebec city must have latrines, and that garbage must be carried to the river st. lawrence, rather than simply thrown out of the door. populatiion health during the enlightenment vital statistics provide simple objective indices of overall population health during the enlightenment. at birth, the average european could expect to live no more than 35 years. a third to a half of the population died before reaching the age of 16 years. those who survived to their mid-teens lived into their 50s or even their early 60s, and at the age of 21 the aristocracy could expect to live a further 43-50 years; this was an improvement over the 25 years of adult survival typical of the fourteenth century. survival prospects were much worse in north america than in europe during the enlightenment. many of the population succumbed to fevers, intestinal diseases, and, in the case of the african slaves, to harsh working conditions. a quarter of european immigrant children did not survive until their first birthday, and half of all marriages ended in the death of one partner before their seventh wedding anniversary. epidemics of beri-beri, smallpox, malaria and yellow fever wreaked havoc among early colonists. two of every three deaths were attributed to typhoid, dysentery or salt poisoning. in an attempt to reduce this terrible toll, newly arrived immigrants were initially isolated in "guest houses." replacement of contaminated water by wine, beer or cider, a reduced consumption of infected clams, and a scattering of the population to areas where there were copious fresh water springs reduced deaths from typhoid and dysentery, but progress in reducing overall mortality was slow. in early canada, dispersal of the population along the major rivers made major epidemics less likely than in the urban settlements of the united states, but isolation, accidents and harsh winters made canadian life expectancy worse than those in either europe or the u.s. only a small fraction of the population lived beyond 40 years, and many of the children suffered from rickets and anaemia. typhus and smallpox were also recurrent problems. the victorian era was marked by growing government responsibility for the health of the public in large european cities. there was a gradual improvement in the quality of housing, and demographics showed a burgeoning birth rate. social reformers also succeeded in abolishing child labour and slavery from western society (chap. 23). in this section, we will discuss the role of boards of health, continued deaths from poisoning, and improvements in housing conditions. major epidemics of influenza, cholera, typhus, typhoid fever and scarlet fever sparked a deep concern about population health in victorian england. in london, england, cholera killed 14,137 people in 1848-49 and 10,738 in 1853 (chap. 24). however, leaders of a new sanitary movement such as edwin chadwick (1800-1890) and thomas southwood smith (1788-1861) began to recognize that ill-health of the individual soon became ill-health of the population. they thus made urgent calls for the provision of clean drinking water, proper removal of refuse and sewage treatment. chadwick and smith sat as commissioners on london's general board of health that regulated the water supply and sewer connections for all new housing in the city, and provided adequate burial grounds for those who died. the quality of london's drinking water was rapidly upgraded, and money was spent on methods of preventing death during childbirth. the public health acts of 1848 and 1875 also established public baths and wash-houses, and by the 1870s, health-conscious municipalities were building public swimming pools. in lower canada (quebec), a physician was appointed as health officer in 1816, with the primary responsibility of monitoring the sick and starving people who were arriving on immigrant ships from europe. by 1823, a strengthened five-member board of health was supervising quarantine arrangements on grosse isle, in the st. lawrence river near to quebec city. nevertheless, the number of immigrants was such that this holding facility was at times overwhelmed, and cholera periodically reached quebec and montreal, killing between 10-15% of the population. in 1847, 5424 people also died of typhus while they were quarantined at grosse isle. a central board of health for both upper and lower canada was created in 1849. compulsory vaccination against smallpox was introduced in the early 1860s. in the united states, organization of sanitary reform began rather later than in canada. the city of new york enacted the metropolitan health bill in 1866, creating a 9-person board of health. immigrants were processed on ellis island, just outside new york city. the original wooden structure was quickly destroyed by a catastrophic fire, but a stone replacement building opened in 1900. many immigrants spent only a few hours in the facility, but those with contagious disease were summarily denied admission to the united states. continued deaths from poisoning many victorians died from eating adulterated or diseased food. one report to the british privy council (1863) estimated that 20% of meat came from diseased cattle. flour was expensive, and bakers frequently adulterated it with chalk (to whiten it) and alum; often, the bakers also kneaded the mixture with their bare feet. an act prohibiting the adulteration of food was passed in 1860, but its enforcement was an option for local authorities, so that it was not very effective. cooking was typically done in tin-lined copper pans; wealthier citizens replaced the pots when the tin had worn away, but the poor could not afford to do this, and in consequence they sometimes developed copper poisoning. other sources of poisoning in the victorian home were leaking gas pipes, lead used in white paint, and arsenic used to colour wallpapers. in the early nineteenth century, the sudden influx of country folk into the major cities of europe created hideous slums: "in big, once handsome houses, thirty or more people of all ages may inhabit a single room." housing gradually improved over the victorian era, as many workers accumulated sufficient funds to purchase modest but well-built homes. enlightened industrialists also constructed model housing estates for their employees. robert owen (1771-1858) organized a model community for his workers at the new lanark mills, in scotland, complete with a nursery school. he envisaged an even more ambitious employee housing project in new harmony, in, but this project failed within two years. the quaker chocolate manufacturer george cadbury (1839-1922) built a model village for his employees around his factory at bournville, near birmingham, and in the u.s. george pullman, the railway carriage czar, built a model town at pullman, il, in 1885. charitable foundations such as the peabody trust began to replace the worst of london's slums with solidly-built if spartan apartments (fig. 22 .5). the first peabody block, at spitalfields, included 57 dwellings for the poor, 9 shops complete with accommodation for the shopkeepers, and on the top floor baths and laundry facilities for a total cost of £22,000. in the united states, building codes were improved during the victorian era, and a national housing association was founded in 1910, under the aegis of the commission on the congestion of population in new york. there were also attempts to persuade philanthropists to build model tenements at low rents; buildings were bought, renovated, and then rented to relocated slum dwellers who were given "friendly instruction" on management of their new households. despite substantial progress in the delivery of public health, there remain a number of continuing challenges in the twenty-first century. current issues include the definitive control of the sales of tobacco and mood-altering drugs, the regulation of automotive emissions and other source of urban air pollution, management of the hiv/aids epidemic, concern over a growing reluctance to accept childhood vaccinations, and the management of infections spread by international air travel. in the edwardian era, cigarette manufacturers had promoted their wares as the cure for various respiratory conditions such as asthma and hay fever. but in 1912, the american physician isaac adler pointed to a growing incidence of lung cancer, and he speculated that the abuse of tobacco and alcohol might be responsible. anti-smoking groups developed in germany following world war i, and a magazine (german tobacco opponents) was published from 1919 to 1935. the nazi regime was opposed to smoking, with hitler declaring it a waste of money. in particular, women who smoked were considered as unsuitable to be german wives and mothers. during world war ii, the axis powers made much propaganda from the fact that hitler, franco and mussolini were non-smokers, whereas churchill, roosevelt and stalin were all heavy users of tobacco. evidence of the toxicity of tobacco steadily accumulated during the modern era. in 1929, fritz linkint dresden demonstrated an increased prevalence of lung cancers in smokers. his research was confirmed in 1939, with a case-control study by franz hermann muller of cologne. during the 1950s, ernst wynder at the sloan-kettering institute in new york and richard peto and bradford hill at oxford university advanced even more compelling evidence that cigarettes were carcinogenic. hill concluded that consuming 35 cigarettes per day increased the odds of dying from lung cancer as much as forty-fold. other damning evidence came from cellular pathology, animal experimentation and the demonstration of toxic chemicals in cigarette smoke. however, for a substantial part of the post-modern era, public health workers had to combat a deliberate campaign by the cigarette manufacturers to confuse and deceive the general public. the manufacturers were well aware of the damning facts by the early 1950s, but their misleading propaganda was able to increase u.s. cigarette sales to a peak of 630 billion units in 1982. as late as 1960, only a third of u.s. doctors considered smoking as "a major cause of cancer," and 43% of physicians were still smoking on a regular basis. beginning in the mid 1970s, there was a dramatic decrease in the social acceptability of cigarette smoking, and growing restrictions were placed on public areas where smoking was permitted. this resulted from demonstrations that passive exposure to cigarette smoke gave rise to small but significant increases in the risks of chronic respiratory disease and asthma in childhood, and carcinoma of the lungs and cardiovascular disease in adults. public polls showed a growing acceptance of public health measures to control smoking in public spaces. cigarette manufactur-ers went to particularly great pains to obfuscate the risks of passive exposure to cigarette smoke, but adverse effects were clearly demonstrated during the 1980s, not only by epidemiological research, but also by the exposure of volunteers to machine-generated cigarette smoke while they exercised in closed chambers. public health workers continue to face many challenges in reducing the sales of tobacco products, as manufacturers doggedly resist measures to reduce consumption through increased taxation, prohibition of sponsorships, and plain packaging. they constantly seek methods of creating new addicts, both through extensive advertising in third world countries and through such tactics as the marketing of electronic cigarettes. as recently as 2015, cigarette smoking still accounted for 11.5% of deaths world-wide. the toll from cigarettes is now compounded by the effects of mood-altering drugs. several countries (including canada) have abandoned attempts to prohibit the marketing of marijuana, with as yet no clear standards of dosages compatible with worker and road safety, and an ever growing segment of the north american population is becoming addicted to powerful opiates, with a high risk of deaths from overdoses. british columbia alone had 914 deaths from opiate overdoses in 2016, despite providing emergency workers with supplies of the antidote naloxone. the modern era saw a dramatic drop in the sulphurdioxide/large particulate smog associated with coal fires in many developed societies, but air pollution problems have continued from coal-fired power station and sautomotive emissions, particularly during thermal inversions. the exposure of cyclists and pedestrians to carbon monoxide was studied during the 1970s. substantial concentrations of carbon monoxide were recorded on congested city streets, particularly if air movement was impeded by tall buildings, but any build-up of carboxyhaemoglobin in the blood stream was reversed quite quickly when the individual moved to a less polluted area. the only adverse clinical effect from carbon monoxide exposure was a somewhat earlier onset of angina if a person with coronary atherosclerosis exercised on a heavily polluted street. chamber experiments by steve horvath in santa barbara, ca, and larry folinsbee in toronto documented acceptable ceilings of exposures to the ozone that was formed by the action of sunlight upon the nitrogen oxides from vehicle and aircraft exhaust. the threshold concentration causing a minor disturbance of respiratory function in healthy exercisers was around 0.75 p.p.m., a level that was exceeded in some north american cities on heavily polluted days. to date, in many cities improved automotive emission controls have done little more than match the increase in vehicle registrations, and places such as paris and beijing have needed to forbid the access of drivers to the centre of cities on alternating days in order to reduce pollution levels. since ozone levels show a marked diurnal cycle, one immediate remedy for the active individual is to exercise at less heavily polluted times of the day (early morning or late at night). the ultimate solution to the problem of automotive exhaust probably lies in the replacement of gasoline-driven by electric or hydrogen-powered vehicles. the hiv/aids epidemic officially began in the u.s. in 1981, when the centers for disease control reported a clustering of cases of pneumocystis pneumonia among homosexual men in los angeles. it was quickly realized that the condition was not limited to homosexual individuals, but was seen also in intravenous drug users, haemophiliacs and others receiving blood transfusions. thus, in august 1982, the cdc coined the new term aids. a year later, luc montagnier and his associates at the pasteur institute in paris discovered the virus responsible for this disease. much effort has since been devoted not only to finding highly effective antiretroviral agents, but also in devising measures to reduce transmission of the disease. particular emphasis has been placed upon the wearing of condoms during sexual intercourse, in providing sterile needles for intravenous drug users through programmes of needle exchange and supervised injection sites, in closer control of blood banks and in ensuring sterility during drug injection treatments of tropical diseases. nevertheless, success in controlling the epidemic has as yet been only partial. in the u.s. the disease had already claimed 575,000 lives by 2006; a further million were living with the disease, and 56,000 fresh cases were diagnosed in that year. in rural africa, the situation remains even worse, with as many as a third of young adults currently infected. during the early part of the post-modern era, successful childhood vaccination campaigns brought the incidence of mumps, measles and rubella to a very low level in most developed countries, and the who set the year 2015 ce for the total elimination of measles and rubella from the european region. however, the percentage of children receiving vaccination has decreased in recent years, with parents weighing the low current risk of infections relative to the supposed dangers of developing meningo-encephalitis and autism. fears that vaccination would cause autism stemmed from a paper published by the british physician andrew wakefield, in 1998. extensive research found no evidence to support his claims, and the british medical journal recently declared that the original article was fraudulent. further, the british general medical council found wakefield had been guilty of serious professional misconduct, and he was struck from the medical register. there have since been small outbreaks of measles consequent upon the decreased proportion of vaccinations in britain and in canada, and unfortunately many of the general public remain convinced that vaccination can cause autism. infectious diseases can now spread very rapidly, due to the ever-growing number of people who engage in global air travel. this problem is well exemplified by an epidemic of sars (severe acute respiratory syndrome). this began in mainland china in november of 2002, and due to delayed reporting by the chinese authorities it spread rapidly around the world. the who issued a global health alert on april 11th 2003. fortunately, application of rigid quarantine measures contained the epidemic, with relatively few deaths in north america, and by july 5th 2003, the who was able to declare that the sars epidemic was over. many of the major epidemics of earlier eras were due largely to poor hygiene-a lack of clean water, poor sewage treatment, and an inadequate control of people who were already infected. although we often assume that these issues have now been resolved, it is important to recognize that in many third world countries supplies of clean water and adequate supplies of food are still lacking, with shortages often exacerbated by ethnic conflicts. the same issues of clean water, waste disposal and burial of the dead could still arise in wealthier countries today if there were to be an earthquake, a typhoon or a tsunami, and emergency services must be prepared to give the highest priority to an early re-establishment of the basic health infrastructure following any natural disaster. issues in the adulteration of food have now been largely overcome in developed society, but the current obesity epidemic underlines that problems still have to be resolved in terms of persuading food processors to avoid tactics designed to persuade consumers to overeat. for those who can afford housing, the modern single-family home is generally well-equiped to optimize the health of those who are living in it. massive tower blocks are less suited to a healthy and active life-style, particularly for families with young children. moreover, ever-increasing minimum specifications for housing, a growing world population and a lack of land is presenting public health agencies with the issue of a growing proportion of homeless individuals in many large cities. globalization is presenting new challenges to public health, not only with the rapid spread of infections, but also with the international enforcement of regulations on issues ranging from emission controls on cars to the quality of foods and medications. the ideal forum for developing appropriate preventive measures would seem the world health organisation, but unfortunately (as with many international bodies) its effectiveness is often limited by political considerations, including threats from some nations to slash funding unless criticism of their practices is shelved. 1. are the infrastructure constraints of an earlier era still compromising public health in third world countries? questions for discussion child against measles, mumps and rubella? what will be the likely new challenges to public health agencies over the next 20 years? public health foundations: concepts and practices cigarette smoking: health effects and challenges for tobacco control plague and the poor in renaissance florence principles of water resources bathing in public in the roman world mission and method: the early nineteenth century french public health movement history of hygiene asian medical systems: a comparative study hygiene in the early medical tradition public health victorian medicine and popular culture private choices and public health. the aids epidemic in an economic perspective health, civilization and the state; a history of public health from ancient to modern times the nazi war on cancer housing in urban britain environmental policy and public health: air pollution, global climate change and wilderness a history of public health shephard rj. the risks of passive smoking on the mode of communication of cholera the new public health the establishment of a board of health for new york city in 1866 further reading some early societies had an infrastructure that provided clean water and the removal of sewage, but since this was usually available only to wealthy citizens, its impact upon the course of epidemics was limited. major cities such as london did not build a comprehensive infrastructure until the middle of the victorian era, when appropriate initiatives were taken by newly formed boards of public health. although the traditional concerns of public health have now been largely met in developed societies, new challenges are constantly arising. these include the control of tobacco products and mood-altering drugs, the reduction of automotive emissions and other forms of urban pollution, management of the hiv/aids epidemic, overcoming a growing reluctance to vaccinate infants, and countering the rapid spread of infections by air travel. key: cord-298052-mbg6e2j1 authors: hardstaff, jo l; häsler, barbara; rushton, jonathan r title: livestock trade networks for guiding animal health surveillance date: 2015-04-01 journal: bmc vet res doi: 10.1186/s12917-015-0354-4 sha: doc_id: 298052 cord_uid: mbg6e2j1 background: trade in live animals can contribute to the introduction of exotic diseases, the maintenance and spread endemic diseases. annually millions of animals are moved across europe for the purposes of breeding, fattening and slaughter. data on the number of animals moved were obtained from the directorate general sanco (dg sanco) for 2011. these were converted to livestock units to enable direct comparison across species and their movements were mapped, used to calculate the indegrees and outdegrees of 27 european countries and the density and transitivity of movements within europe. this provided the opportunity to discuss surveillance of european livestock movement taking into account stopping points en-route. results: high density and transitivity of movement for registered equines, breeding and fattening cattle, breeding poultry and pigs for breeding, fattening and slaughter indicates that hazards have the potential to spread quickly within these populations. this is of concern to highly connected countries particularly those where imported animals constitute a large proportion of their national livestock populations, and have a high indegree. the transport of poultry (older than 72 hours) and unweaned animals would require more rest breaks than the movement of weaned animals, which may provide more opportunities for disease transmission. transitivity is greatest for animals transported for breeding purposes with cattle, pigs and poultry having values of over 50%. conclusions: this paper demonstrated that some species (pigs and poultry) are traded much more frequently and at a larger scale than species such as goats. some countries are more vulnerable than others due to importing animals from many countries, having imported animals requiring rest-breaks and importing large proportions of their national herd or flock. such knowledge about the vulnerability of different livestock systems related to trade movements can be used to inform the design of animal health surveillance systems to facilitate the trade in animals between european member states. electronic supplementary material: the online version of this article (doi:10.1186/s12917-015-0354-4) contains supplementary material, which is available to authorized users. animal trade is an effective way of introducing, maintaining and spreading animal diseases, as observed with the spread of different strains of foot and mouth disease (fmd) in africa, the middle-east and asia [1] and the spread of bovine spongiform encephalopathy (bse), for example into oman and canada through the importation of infected cattle [2, 3] . within a year, millions of live animals of many different species are transported between countries within europe for breeding, fattening, sports, companionship, conservation and slaughter. this creates opportunities for communicable diseases to be spread across the european union (eu), which is the focus of this study, even though animals must be in a fit state to be transported i.e. healthy animals without clinical signs of illness [4] . however, animals with sub-clinical infections may go unnoticed, providing an opportunity to transport disease to different regions. live animal trade complicates tracing the origin of any disease outbreak that may occur due to an infected animal being displaced. for this reason, the eu has established a trade control and expert system (traces) to monitor imports, exports and trade in animals and animal products across the eu and to ensure traceability within the food chain [5] , in addition to livestock movements recorded by the food and agricultural organisation of the united nations (fao). traces records the number of animals and consignments entering and leaving eu countries. despite the availability of this comprehensive database, animal health surveillance systems are rarely based on international live animal movements. to understand better livestock trade within europe with a view to inform disease surveillance we analysed trade networks across the eu for all major livestock species and purposes of movements. animal health surveillance includes the systematic, continuous or repeated, measurement, collection, collation, analysis, interpretation and timely dissemination of animal health and welfare related data from defined populations, essential for describing health hazard occurrence and to contribute to the planning, implementation and evaluation of risk mitigation measures [6] . recent outbreaks and spread of exotic or emerging diseases such as avian influenza (ai), schmallenberg virus (sbv) and bluetongue virus (btv) in previously unaffected territories of the eu have emphasised the need for well-developed and adequately resourced health systems, including surveillance, to ensure early detection and rapid containment, the complexities of which are highlighted by braks et al. (2011) [7] . at the same time investment is being constrained due to significant financial budget reductions in many european countries. livestock disease is important economically with regards to a loss of productivity, its potential impact on human and animal health, and the mitigation activities implemented when disease occurs (for example trade or movement bans, testing and culling). for example, the economic cost of bse in the uk accrued from the value loss in infected carcasses, disposal costs, and, most importantly, the sharp drop in domestic beef demand due to consumer scares (sales of beef products declined by 40% once the possible link between bse and new variant creutzfeldt-jakob disease (cjd) was announced, but the costs were partly offset by an increase in consumption of substitute meat), and a complete loss in export markets [8] . further costs accrued from operating various public schemes, establishment and enforcement of new legislation and the adjustment of the industry to the new structure and markets [8] . livestock disease can be spread directly for example the introduction of fmd from irish calves imported to the netherlands that were also held responsible for the infection of a farm near to the port of introduction to mainland europe [9] . it can be spread by infected equipment, crates or transporter vehicles which can be contaminated by microbes. for example escherichia coli (e. coli) bacteria were detected on the sides and floors of lorries [10] and contaminated transporters were found to be responsible for spreading classical swine fever to different farms in lithuania [11] . by moving animals with latent or asymptomatic infections this enables disease to spread to wherever the animal travels or where the necessary vectors may be present. particularly in the case of epidemic diseases where the reduction of time from introduction of a hazard to its detection can enable early response and thereby lead to a reduction in intervention costs to contain an outbreak [12] , effective surveillance is critical. few surveillance systems however, are designed based on international livestock movement data, even though such data can provide information on the quantity and seasonality of livestock movements, the types of movement (for example flows from production of point of lay birds to laying units), the route the animals take and associated stopover or resting points. surveillance for many livestock species occurs at the farm where it is the responsibility of the farmer (and veterinarian) to report notifiable diseases or at the abattoir where it is the role of the official veterinarian to inspect livestock according to council regulation (ec) 854/2004 [13] and report notifiable diseases to the national authorities, which in the uk is the department of the environment, food and rural affairs (defra), which in turn must inform the european food safety authority (efsa) as stated in council regulation (ec) 178/2002 [14] . network analyses are useful ways of visualising the countries that are importing animals from a great number of other countries (high level of indegree) and countries that are exporting to a high number of countries (outdegree), these are values that can change temporally. they have been used to find out movement between farms of different species, for example, fish movement between farms in scotland [15] and a study of pig and cattle movement between farms in sweden [16] . countries with a high indegree, which for the purposes of this study has a maximum number of 27 (the number of countries, i.e. (nodes, within this study and the eu as of 2011) that could be used to rank countries, can be more vulnerable to introducing disease due to importing animals from a greater number of countries than those with a low indegree whilst countries with a high outdegree may have a great ability to be able to transmit a disease to many countries; this highlights the importance of understanding levels of disease within trading countries. information about the indegree and outdegree of farms was used by frössling et al. (2012) [17] to investigate whether it could be used to target the surveillance of two cattle diseases in sweden, based on a threshold of in-and out-degrees. they found a positive association between a positive test result and the purchase of animals and proposed approaches to design risk-based surveillance based on cattle movement data. networks can also be used to quantify the proportion of international partners trading with each other (dyadic contacts) compared with the maximum number of national trading partners available for trade within an area allowing a comparison to be made between species and production systems [16] . the higher the density the more connected countries are with respect to the animal being traded and the more countries that may be at risk from contracting a disease from buying in infected livestock. a measure of mixing within a network is to look at its transitivity which indicates whether countries that a country is trading animals to are also trading animals with each other (a triad) [18] . the greater the level of transitivity the faster a disease can spread between countries and potentially infect many countries within the european area [19] . transitivity and density for different communities of wild and domestic ungulates were investigated for the propensity to transmit e. coli by vanderwaal et al. (2014) [20] . however, the network may only consider the point of origin and destination and not necessarily consider the route itself that may involve briefly stopping in other countries where a disease transmission event may occur, for example fmd in france [9] . we hypothesise that the description of trade networks can inform the design of more efficient animal health surveillance systems that may enable a more rapid investigation or response to be implemented. different species being transported for different purposes will have networks of different densities and different countries with the greatest indegree or outdegree. the aim of this project was to map live animal trade networks in eu countries and assess potential differences between species and purposes of transport. this was done by illustrating the number of live animal imports and exports between 27 eu countries including the number of country contacts and numbers of livestock units (lsu, a unit that takes into account the age, sex, purpose of animals with dairy cows having a reference number of 1) moved determining the density of networks and similarities of networks between species. table 1 illustrates the median livestock intra-community movements (expressed in livestock units) and the densities of the transport networks. by far the most heavily moved animal species within europe in 2011 were poultry for slaughter and breeding, followed by poultry for 'other' purposes, pigs for fattening, pigs for slaughter and cattle for fattening; goats were the least traded species. generally more lsus were transported for fattening than for slaughter. the density of movement (table 1) shows that there was greater connectivity for cattle than for the heavily traded poultry. breeding networks were found to be denser than those for other purposes. this may be due to the number of consignments needed to move the relative units of animals. the geographical trade flows are shown in figures 1, 2 , 3, 4, 5 and 6. the transitivity indicates that disease would spread more slowly for 'other' purposes of animal movement than for breeding, fattening or slaughter with the exception of poultry and equines. figures 1, 2, 3, 4, 5 and 6 show the in-and outdegrees of livestock unit movements in the eu on the left and the geographical trade flows in the right, which are separated by species and by purpose of trade. the axes of the graphs of the in-and outdegrees reflect the numbers of trading partners. the countries in the top right received and exported animals with the greatest number of countries, whilst the bottom left indicates those that have little or no export or import trade with other countries. some countries are found in the top right corner with regards to many different animal movements e.g. germany, whilst others rarely buy or sell to the other 26 countries considered in this study e.g. cyprus, finland and sweden, whilst other countries import from many countries and export to few e.g. italy. very few shipments of weaned cattle, sheep and goats require a rest period of 24 hours (additional file 1), whereas many unweaned animals would require a 24 hour break in their journey from their point of origin to their figure 1 the outdegree is shown against the indegree for the trade of cattle for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. and exporting high proportions of their national population, the officially recorded number of animals of that species in the particular country. the poultry and pig sectors had the greatest number of lsu movements, which are being used to indicate breeding fattening slaughter other figure 2 the outdegree is shown against the indegree for the trade of pigs for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. the potential opportunities of pathogen introduction and spread, implying that they require more attention in terms of disease prevention and management, while the equine and goat sectors had the greatest and lowest densities of movements respectively. in addition to lsu movements larger proportions of national pig populations are imported breeding fattening slaughter other figure 3 the outdegree is shown against the indegree for the trade of sheep for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. compared with species such as goats increasing the possibility for the introduction of infected animals to an existing population. for poultry, the highest numbers of lsus moved were for slaughter, which may present less of a risk of introducing disease to an existing population, as the animals are likely to be transported from the production site directly to the slaughter point. however, many poultry journeys would require a break in transit emphasising the breeding fattening slaughter other figure 4 the outdegree is shown against the indegree for the trade of goats for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. vulnerability of the chain and need for adequate surveillance. poultry for breeding had the second highest lsu movements overall, which likely reflects the current structure of commercial poultry production. pure line grandparent and parent stock for breeding are produced by only a limited number of breeding organisations worldwide. for example, the two companies aviagen and cobb, have a market share of more than 85% of the commercial broilers produced in the eu and use their global network of distributors to serve almost all european countries [21] . the breeder farms supplied with young breeding stock have links to hatcheries that produce day old chicks, broiler or layer farms, and slaughterhouses. this system leads to transport of young breeders, hatching eggs and day old chicks. in pigs, heavy movements were recorded for fattening, which reflects ongoing changes in production centres in the eu. in fact, more than two thirds of breeding pigs are produced in denmark, germany, spain, france, the netherlands and poland with half of the breeding pigs at regional level being concentrated in eleven regions in these six countries [22] . germany is the main importer of fattening pigs, with an indegree of 7 and denmark is the main exporter with an outdegree of 11. moreover, pigs for breeding and fattening as well as poultry for breeding were shown to have among the highest transitivities, indicating that disease spread in these networks would be fast if uncontained. hence, solely taking into breeding slaughter other figure 5 the outdegree is shown against the indegree for the trade of poultry for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. account trade data, surveillance efforts would need to focus on poultry for breeding and pigs for breeding and fattening. however, a mapping of surveillance in seven european countries showed that the highest proportion of surveillance components in place were for cattle [23] . similarly, a recent literature review on animal health issues (including zoonoses) researched in the eu showed that cattle and buffalo were the species most breeding slaughter other registered figure 6 the outdegree is shown against the indegree for the trade of equines for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [1] austria, [2] belgium, [3] bulgaria, [4] cyprus, [5] czech republic, [6] denmark, [7] estonia, [8] finland, [9] france, [10] germany, [11] greece, [12] hungary, [13] ireland, [14] italy, [15] lithuania, [16] latvia, [17] luxembourg, [18] malta, [19] netherlands, [20] poland, [21] portugal, [22] romania, [23] slovakia, [24] slovenia, [25] spain, [26] sweden and [27] uk. frequently studied in the eu [24] ; this may reflect differences in resource allocation for surveillance and disease mitigation. the reasons for this may be that cattle harbour or are perceived to harbour more pathogens than other species, that outbreaks in cattle systems have higher impact, that cattle receives more attention than other species for cultural or historical reasons, or that disease prevention and management in cattle systems are of lower quality. currently, there are no multipathogen, multi-species systematic risk assessments available at eu level that would allow a comparison of these factors. breeding networks were found to be more highly connected with more trade between countries indicating disease may spread more easily through them. this is of concern as these animals are not intended to be slaughtered on arrival and will produce new animals, therefore stringent precautions are needed to protect these populations, particularly if they are diseases not covered by eu legislation, for example the diseases listed in council regulation (ec) 722/2013 [25] . the density of international agri-trade calculated by ercsey-ravasz et al. (2012) [26] was 0.33 which was comparable with density of many networks in this study. however, in national networks the densities and transitivities are smaller, which are due to the greater number of farms involved in national animal production compared with the number of countries involved in this study. the cattle trade network in france had a very low annual level of transitivity indicating that disease spread would be slower than that between european countries [27] . the pig and cattle networks in sweden had lower transitivities than international networks of these species [16] as did the transitivity of pig movements in denmark [28] and the uk [29] . the location of countries in figures 1, 2 , 3, 4, 5 and 6 gave an indication of where surveillance could be targeted with countries in the upper right quadrant both importing and exporting high numbers of lsu, which means that they need to monitor both production to export healthy animals and import processes to avoid introduction of disease. countries in the lower right quadrant may need to consider strengthening surveillance related to import processes. many national studies have found that the majority of animal movements are between premises with lower indegrees and outdegrees as shown in a study by smith et al. 2013 [29] , this reduces the likelihood of disease transmission to many different areas, reducing the level of surveillance needed. many countries trading cattle were found to have an in or out degree equal or greater than five. this was the threshold that was calculated to require enhanced surveillance for bovine coronavirus in a study on trade and cattle in sweden by frössling et al. 2012 [17] . consequently, there seems to be ample opportunity to take advantage of trade network data to enhance surveillance. the evolution of trade networks over time at the eu level could be monitored using indegrees, outdegrees, and transitivity. such monitoring would provide information at the systems level and allow observations of changes in networks over time and where consequent surveillance efforts should be focused. higher-level surveillance capturing trends or changes in trade patterns could complement existing surveillance systems that are commonly disease centered. the differences across countries in terms of indegrees and outdegrees also bring up the question of who has the responsibility for disease control, including surveillance the buyer, the seller or relevant food business operator depending on the stage of livestock production [30] . while the draft new eu animal health law [31] refers to listed diseases and pre-dominantly supports disease centered surveillance, it also creates a framework for the better use of the synergies between surveillance undertaken by the different actors in the field to ensure the most effective and cost efficient use of surveillance resources as well as promotion of data availability and facilitation of data exchange. transportation itself is stressful for animals as indicated in many studies in many species for example cortisol in pigs [32] ; heart rate and cortisol in cattle [33] ; cortisol in lambs [34] ; cortisol in horses [35] ; increasing susceptibility to disease and may enhance the likelihood of shedding pathogenic agents in transit or in the receiving country, which may lead to infection in other animals. it is common to refer to malaise post-transportation as shipping illness [36] . however, pathogens may be introduced or spread from transporters and not just from the animals that they transport. studies have demonstrated that transporters need to be thoroughly cleaned to prevent them from acting as a source of pathogens to subsequently carried animals, for example to prevent transmission of porcine reproductive and respiratory syndrome virus, that can survive in transporters, being transferred to pigs [37] . rest stops are infrequent for some species, however, if animals from more than one origin are rested in the same place it may allow for disease spread. this is most likely to impact animals traded for breeding and fattening purposes that have more lsus and are more highly connected than animals already at slaughter weight. these are animals that will live in the receiving country for a period of time that may enable pathogen transfer. many of the highly connected countries (with high in and out degrees in the top right of figures 1, 2 , 3, 4, 5 and 6) for example germany are geographically located in an area (central europe) that minimises the distances and therefore time that animals have to travel reducing the need for rest breaks and the consequent potential for pathogen transfer. many of the long distances are from countries that rarely trade with mainland europe for example cyprus. many animals undergo long journeys between countries. the time in transit is a concern with regards of the potential for disease to spread along trade routes [9] . this has implications for policy around the planning of livestock production and slaughter. ideally, large production facilities would not be placed adjacent to well-known and used trade routes and or resting points. however, such information is only of use to policy makers if it is captured in a systematic and continuous way allowing to monitor trends, change and modify policies accordingly if deemed necessary. the analyses have only considered the spatial aspect of trade and not taken into account temporal variations that may occur altering the relationships between the countries (nodes) and the respective network, and affect the likelihood of an animal being infectious with a disease. animal populations fluctuate within a year and the population recorded in december was used to calculate the proportion of animals being imported or exported into a country, therefore it may have under or overestimated the actual population at the time of movement. for example the majority of lambs are born between january and april increasing the sheep population until they reach slaughter weight and are culled, which occurs before december. networks are highly dynamic and these changes in movements between countries will need to be considered by surveillance programs using this approach. one method that may address this is to use exponential random graph models that can incorporate a range of different distributions of connectivity between the nodes to create many different networks, which can be compared with the data to find a model that best fits the current trade pattern [38] . the distances that animals are transported between countries may be shorter or longer than the distances between centroids. in addition, there are many different routes across europe that may be used and this may be worth investigating in future analyses with regards to distance, time and mixing between countries. this means that our calculations for whether particular species need a rest break for movement between particular countries are generalised so that there may be fewer or greater numbers of animals being rested en-route to their destination country altering the potential for pathogen exposure. the analyses did not take into account the numbers of convoys or animals and the mixing of animals: from different farms per convoy, at resting places, at borders, when received by individuals and at markets in the country of destination. these factors will have an impact on contact between potentially naïve and infectious animals, pathogen exposure and susceptibility. the analyses could not take into animals being bought and sold on to more than one country i.e. the chain of infection [16] and assumed that an animal moved once between countries in its lifetime. creating networks has enabled us to visualise the countries that have a higher level of involvement in animal trade. using network analysis we were able to determine the extent to which a disease may spread, the production systems where disease spread may be more rapid, for example registered horses and breeding cattle, pigs and poultry, and facilitates comparisons with networks in other areas. similarities between countries, species and production purposes has the potential to inform international surveillance policies that take into account trade patterns. the study has highlighted the vulnerability of the pig network to disease, which is of increasing concern due to the proximity of african swine fever to the eu and the potential for wildlife to introduce the disease [11] . this information could complement the national movement recording systems that are mandatory for cattle throughout the eu [39] that will soon be implemented in sheep and goats now that their form of identification tags have been decided upon [40] , and being planned for porcines [41] to produce a more robust surveillance plan. data on numbers of live cattle, goats, horses, pigs, poultry and sheep movements in 27 eu countries were obtained from directorate general sanco animal health dg sanco unit g2 activity report for the year 2011 obtained from http://ec.europa.eu/food/animal/resources/publications_en. htm. the data obtained related to the production purpose of the animals, which fell into five categories: breeding, fattening, slaughter, registered and other (e.g. pets, show animals). these categories were analysed separately and combined for each species. the numbers of animals were converted into livestock units to enable comparison between species using the following conversion factors derived from the eurostat glossary on statistics (2013) [42] : pigs 0.5 (breeding), pigs 0.3 (other), goats 0.1, sheep 0.1, horses 0.8 and poultry 0.014. all data were obtained at a national level from publically accessible databases and no animal experimentation occurred nor consultation with animal owners therefore ethical approval was not needed. all the analyses and associated network figures were created and carried out using r 3.0.1. [43] . networks were created from adjacency matrices and their densities were calculated using network function found in r package network [44] . the in and out degrees were calculated and respective graphs were produced using the degree and network.layout.degree functions in r package network [44] . the transitivity of each network was calculated using the gtrans function in the sna package [45] . trade maps in the figures 1, 2 , 3, 4, 5 and 6 were produced by merging shapefiles of all the countries of europe downloaded from maplibrary.org (www.gadm.org/, 2010, gadm version 9) into one polygon (europe) using arcgis 10.1 [46] . the map of europe was then read into r using the function readshapepoly found in the maptools package [47] . centroids (the co-ordinates for the centre of a country) were calculated for each country and linked with respective importing and exporting countries were calculated using the calccentroid function in r package pbsmapping [48] . curved lines and arrows were drawn between the centroids for each movement using the gcintermediate function found in the geosphere package [49] . to be able to relate the numbers of animals being traded with the animal populations of the countries, the numbers of animals of each species were obtained for 2011 from the eurostat database. the data used was for december as this was the only calendar month available for all species. a movement:standing population ratio was calculated for both animal imports and exports through adding the total number of breeding, fattening, slaughter, registered and other animals being moved and dividing by the total population of animals of that species in the exporting or importing country. to illustrate the number of animal journeys that require 24 hour rest periods during transit, distances that animals would have to travel were approximated by estimating arc distances from one capital city to the other using www.timeanddate.com. the time in transit before animals are required to have a 24 hour rest period were obtained from council regulation ec 1/2005 [4] . the regulation states that unweaned cattle, goats, sheep, pigs and horses require a 24 hour rest period after 18 hours of travel. weaned cattle, goats and sheep can be in transit for 28 hours without a rest, whereas weaned pigs and domestic horses need to be rested after 24 hours of transportation. any animal being transported by boat should be rested for 12 hours at the port after being unloaded. the law for poultry and rabbits states that they can travel for up to 12 hours without food or water and whereas chicks within 72 hours of hatching can travel for up to 24 hours without food or water. to gauge whether a journey between two rest points would need a break the following equation was used given the assumption that a vehicle would be travelling at an average 80 kilometres an hour. 24 hour rest period ¼ distance between cities duration of travel before 24 hours rest period ã80 km=h combining livestock trade patterns with phylogenetics to help understand the spread of foot and mouth disease in sub-saharan africa, the middle east and southeast asia bovine spongiform encephalopathy identified in a cow imported to canada from the united kingdom-a case report european union council regulation (ec) 1/2005. the protection of animals during transport and related operations and amending directives 64/432/ eec and 93/119/ec and regulation (ec) no 1255/97 l3 european union council regulation (ec) 623/2003. commision decision of 19 august 2003 concerning the development of an integrated computerised veterinary system known as traces proposed terms and concepts for describing and evaluating animal-health surveillance systems towards an integrated approach in surveillance of vector-borne diseases in europe the economic impact of bse on the uk beef industry the foot-and-mouth disease epidemic in the netherlands in 2001 the effects of transport and lairage on counts of escherichia coli o157 in the feces and on the hides of individual cattle international disease monitoring economic principles for resource allocation decisions at national level to mitigate the effects of disease in farm animal populations european union council regulation (ec) 854/2004. the laying down specific rules for the organisation of official controls on products of animal origin intended for human consumption council regulation (ec) 178/2002. laying down the general principles and requirements of food law, establishing the european food safety authority and laying down procedures in matters of food safety small-and large-scale network structure of live fish movements in scotland network analysis of cattle and pig movements in sweden: measures relevant for disease control and risk based surveillance application of network analysis parameters in risk-based surveillance -examples based on cattle trade data and bovine infections in sweden collective dynamics of "small-world" networks disease evolution on networks: the role of contact structure quantifying microbe transmission networks for wild and domestic ungulates in kenya chapter 3 production and consumption of poultry meat and eggs in the european union pig farming in the eu, a changing sector mapping of surveillance and livestock systems, infrastructure, trade flows and decision-making processes to explore the potential of surveillance at a systems level review of the emerging animal health and food security issues council regulation (ec) 722/2013 approving annumal and multiannual programmes and the financial contribution from the union for the eradication, control and monitoring of certain animal diseases and zoonoses presented by the member states for 2014 and the following years complexity of the international agro-food trade network and its impact on food safety vulnerability of animal trade networks to the spread of infectious diseases: a methodological approach applied to evaluation and emergency control strategies in cattle relationship of trade patterns of the danish swine industry animal movements network to potential disease spread descriptive and social network analysis of pig transport data recorded by quality assured pig farms in the uk european union council regulation (ec) 853/2004. laying down of specific hygiene rules on the hygiene of foodstuffs council regulation (ec) 722/2013. approving annual and multiannual programmes and the financial contribution from the union for the eradication, control and monitoring of certain animal diseases and zoonoses presented by the member states for 2014 and the following years shipping stress and social status effects on pig performance, plasma cortisol, natural killer cell activity, and leukocyte numbers a comparison of the welfare and meat quality of veal calves slaughtered on the farm with those subjected to transportation and lairage effects of weaning and 48 h transport by road and ferry on some blood indicators of welfare in lambs effects of transport, lairage and stunning on the concentrations of some blood constituents in horses destined for slaughter isolation of respiratory bovine coronavirus, other cytocidal viruses, and pasteurella spp of shipping fever an evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures an introduction to exponential random graph (p*) models for social networks council regulation (ec) 1760/2000: implementing regulation (ec) no 1760/2000 of the european parliament and of the council as regards eartags, passports and holding registers report from the commission to the council on the implementation of electronic identification in sheep and goats council regulation (ec) 71/2008: the identification and registration of pigs eurostat glossary: livestock unit (lsu) -statistics explained r core team: r. a language environment for statistical programming package network package sna desktop: release 10. environmental systems research institute maptools: tools for reading and handling spatial objects pbsmapping: mapping fisheries data and spatial analysis tools submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution acknowledgements bh acknowledges financial support from the leverhulme centre for integrative research on agriculture and health (lcirah). additional file 1: journeys that would require rest breaks due to being over 28 hours long or over 24 hours long. these data are displayed in tables.additional file 2: journeys that would require rest breaks for unweaned animals. the data are displayed in a table.additional file 3: journeys that would require rest breaks for poultry other than chicks <72 hours old. the data are displayed in a table.additional file 4: the proportions of national animal imports and exports compared with the national population. these data are displayed in separate tables for each species. the authors declare that they have no competing interests.authors' contributions jh obtained the data and undertook the analyses. jh, bh and jr interpreted the results and had an equal contribution to the manuscript. all authors have read and approved the final manuscript. key: cord-268564-5qhumjas authors: brown, lisa; murray, virginia title: examining the relationship between infectious diseases and flooding in europe: a systematic literature review and summary of possible public health interventions date: 2013-04-01 journal: disaster health doi: 10.4161/dish.25216 sha: doc_id: 268564 cord_uid: 5qhumjas introduction many infectious diseases are sensitive to climatic changes; specifically, flooding. this systematic literature review aimed to strengthen the quality and completeness of evidence on infectious diseases following flooding, relevant to europe. methods a systematic literature review from 2004–2012 was performed. focused searches of the following databases were conducted: medline, scopus, pubmed, cochrane library, and evidence aid. personal communications with key informants were also reviewed. results thirty-eight studies met the inclusion criteria. evidence suggested that water-borne, rodent-borne, and vector-borne diseases have been associated with flooding in europe, although at a lower incidence than developing countries. conclusion disease surveillance and early warning systems, coupled with effective prevention and response capabilities, can reduce current and future vulnerability to infectious diseases following flooding. defining what constitutes a flood can be quite complex as floods can take many forms; therefore, no universal definition exists. generally and in the context of this review, a flood is defined as the overflow of areas that are not normally submerged with water or a stream that has broken its normal confines or has accumulated due to lack of drainage. 3 overall, different flood characteristics affect the severity of the flood event; specifically, regularity, speed of onset, velocity of flow, and depth of water. quantifying the level of flooding has proven to be difficult; however, the emergency events database (em-dat) provides information about flood events and the impact of floods. for a flood to be classified as a disaster or flood event by em-dat one of the criteria must be fulfilled: either ten or more people killed; 100 or more people affected; declaration of a state emergency; and/or call for international assistance. em-dat defines a flood as a significant rise in water level in a stream, lake, reservoir, or coastal region and includes general river floods, flash floods, and storm surges or coastal flooding. flood disasters hit some european regions very frequently, and in some circumstances every year. in europe from 2003-2012, 19 flash floods and 162 general floods were reported by em-dat. in terms of the number of people affected, 7 out of the 20 most important floods ever recorded in europe occurred during the 2000-2010 decade. 4 a study concluded a rising number in flood disasters from 1950-2005 in the european union (eu). 5 according to frei et al. 6 there has been a significant trend toward increased intense winter rainfall events in europe. other studies do not find a rising incidence of flooding. for example mudelsee et al. 7 examined river flood patterns in central europe, and despite the occurrence of two flood events exceeding the 100-year flood level in 1997 and 2002, found no increased trend in extreme flood frequency over recent decades. analyzing the more frequent, small-magnitude flood events as well as high-magnitude floods can make it easier to detect shifting trends in flood frequency. 6 flood trend analysis is essential to understand future flood risk and vulnerability. • what evidence-based public health interventions are used to minimize infectious disease incidence following flooding. • knowledge gaps and issues for further research. the initial search generated 7,861 relevant articles. after reviewing the abstracts, 106 full-text articles were examined in more detail for eligibility. of these 106 articles, 38 peer-reviewed articles were found to fit the inclusion criteria. increased infectious disease transmission and outbreaks following global flood events have been documented ( table 2 ). the study design and main results of all papers found meeting the inclusion criteria are listed in detail in appendices a-d. some articles and gray literature not meeting the specific inclusion criteria were incorporated into the conceptual framework to give a better contextual outline. water-borne outbreaks are an acute aftermath of flood disasters, mainly as a result of contaminated drinking water supply. intense precipitation can mobilize pathogens in the environment and transport them into the aquatic environment, increasing the microbiological agents on surface water. [17] [18] [19] [20] chen et al. 21 found extreme torrential rain (> 350 mm) was a significant risk factor for enteroviruses (rr = 1.96; 95% ci 1.474-23.760) and bacillary dysentery (rr = 7.703; 95% ci 5.008-11.849). globally, water-borne epidemics have shown an increasing trend from 1980-2006 which coincides with the increasing number of flood events. 2 according to a global systematic literature review performed by cann et al. 17 the most common water-borne pathogens to be identified following flooding were vibrio spp. the most common water-borne pathogens associated with heavy rainfall were campylobacter, followed by vibrio spp. appendices a, b list published studies which have reported post-flood increases in cholera, cryptosporidiosis, non-specific diarrhea, rotavirus, and typhoid and paratyphoid. [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] several studies have implicated excess rainfall in water-borne disease outbreaks because of the transportation of bacteria, parasites, and viruses into water systems. marcheggiani et al. 18 showed a potential association between flood events and a range of water-borne infectious diseases in italy; including, legionellosis, salmonellosis, hepatitis a, and infectious diarrhea. reacher et al. 28 performed a historical cohort study following a severe flood in 2000 in lewes, both climatic and non-climatic impacts, such as land-use dynamics, are expected to influence future flooding in europe. although considerable limitations remain in the ability to make robust projections of changes in flood size and frequency due to climate change, common projections appear to be emerging. according to the latest intergovernmental panel on climate change's (ipcc) srex report 8 there is a 66-100% probability that the intensity of heavy precipitation and the proportion of total rainfall will increase particularly in northern mid-latitudes and high latitudes of europe. the highest total precipitation increases are projected to occur during the winter months. although the ipcc states a general decrease in mean precipitation in the southern european region, rainfall may become more irregular and intense. however there remains low confidence in projections of changes in riverine floods. climate change is likely to increase the frequency of storm surges and coastal flooding due to rise in sea levels, and threaten an additional 1.6 million people per year in europe by the 2080s. 9 overall, changes in the climate that may affect the transmission of infectious diseases include temperature, humidity, altered rainfall, and sea-level rise. flooding can have a range of health impacts but this review focused solely on infectious diseases. the diseases most likely to be affected by flooding are those that require a vehicle for transfer from host to host (water-borne) or a host/vector as part of its life cycle (vector-borne). 10 flood-affected areas serve as ideal breeding grounds for pathogens and may alter vector breeding grounds and zoonotic reservoirs. 11, 12 where infectious disease transmission is endemic, it can present a major public health concern following flooding. 13 the risk of infectious diseases following flooding is exacerbated by the fact many factors work together to increase incidence. 14 the significance of the association between precipitation and disease is potentially amplified when considering the effects of global climate change and land use changes. flooding can alter the equilibrium of the environment and may affect the incidence and geographic range of climate-sensitive infectious diseases. a better understanding of the associations and underlying mechanisms of infectious disease outbreaks following flooding will help support evidence-based flood policies and mitigation strategies. this systematic literature review aimed to identify and examine the relationship between infectious disease incidence and flooding in order to gain a better understanding of: outcome (combined with or) amoebiasis, bacillary dysentery, burul*, campylo*, chikungunya, cholera, communicable disease*, contamination, crypto*, dengue, dengue virus, dermatitis, diarrhea*, diarrhea*, disease*, disease vector*, disease outbreak*, epidemic*, enteric fever, escherichia coli, gastrointestinal, giardia*, hanta virus infections, health, health effect*, health impact*, hemorrhagic fever, hepatitis a, hepatitis e, illness, infectio*, infectious disease*, japanese encephalitis, legionellosis, leptospirosis, lyme disease, lymphatic filariasis, malaria, morbidity, mosquito*, norovirus, naeg*, outbreak*, onchocerciasis, physical health, plague, pollut*, public health, q fever, risk factor*, rodent*, rodentborne, rodent-borne, rodent related, rodent-related, salmonellosis, sars virus, severe acute respiratory syndrome, shigellosis, schistosomiasis, tick*, tick-borne encephalitis, tularaemia, tularemia, typhoid, water, waterborne, water-borne, water related, water-related, west nile fever, vector*, vectorborne, vector-borne, vector related, vector-related, yellow fever, yersini* risk, rising temperatures, overcrowding, poor sanitation, poor health care, poverty, and an abundance of rats and other animal reservoirs. 39 rodent-borne pathogens can be indirectly affected by ecological determinants of food sources which have an effect on the size of rodent populations. for example, lack of garbage management and collection following flooding where rubbish is left on the streets contributes to an increased rodent population. 38 appendices a, c summarize the key studies assessing the relationship between flooding and rodent-borne diseases. outbreaks of leptospirosis were observed in the czech republic following floods in 1997 and 2002. 41, 42 the rate of serologically confirmed cases of leptospirosis was three times higher than usual at 0.9 cases/100,000 inhabitants (average incidence rate was 0.3 cases/1000,000 inhabitants). 41 the first leptospirosis outbreak in austria in july 2010, involved four athletes who swam in recreational waters during a triathlon. 43 heavy rains had preceded the triathlon (22 mm). this outbreak demonstrates a risk of contracting leptospirosis in recreational waters, especially after heavy rainfall. in marseilles, france the incidence of leptospirosis identified in the laboratory increased significantly between january 2001 and july 2011 (p < 0.0001). 38 between 1991 and 2003, the rate of leptospirosis incidence in southern france was very low, 0.09 cases/100,000 inhabitants. in 2008, this incidence increased to england. the risk of gastroenteritis was significantly associated with depth of flooding in people whose households were flooded (rr = 1.7; 95% ci 0.9-3.0; p for trend by flood depth = 0.04). additionally, an outbreak of norovirus in american tourists was linked to direct exposure to floodwater contaminated with raw sewage in germany. 29 earlier research has shown an association between waterborne diseases and flooding in high-income countries. from 1948-1994, more than half of the water-borne disease outbreaks in the united states were preceded by heavy rainfall (p = 0.002). 30 research from finland found that 13 water-borne disease outbreaks from 1998-1999 were associated with un-disinfected groundwater contaminated by floodwaters and surface runoff. 32 surveys in high-income countries where individuals reported their own symptoms have indicated an increase in water-borne diseases following flooding. 28, [30] [31] [32] rodent-borne rodent-borne diseases are climate sensitive and may increase during heavy rainfall and flooding because of altered patterns of human-pathogen-rodent contact. 15 flooding and heavy rainfall have been associated with numerous outbreaks of leptospirosis from a wide-range of countries around the world. 15, 21, [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] areas at the highest risk for leptospirosis outbreaks are those where multiple risk factors are likely to coexist; such as, increased flooding ahern et al. 15 reviewed earlier studies addressing flood-associated outbreaks of leptospirosis from a wide-range of countries: argentina, brazil, cuba, india, korea, mexico, nicaragua, portugal, and puerto rico. in 1997 in the krasnodar territory in russia, a severe outbreak of leptospirosis took place in connection with a high flood. 49 sanders et al. 50 stated that flooding after heavy rain favors leptospires. it prevents animal urine from being absorbed into the soil or evaporating; therefore leptospires may pass directly into the surface water or persist in mud. the evidence of this review, supported by several other reviews, suggests the association between leptospirosis and flooding is fairly robust even in high-income countries. vector-borne precipitation changes are known to effect the reproduction, development, behavior, and population dynamics of arthropod vectors, their pathogens, and non-human vertebrate reservoirs. 10 mosquito-borne infections tend to increase with warming and certain changes in rainfall patterns. vector-borne diseases are unlikely to be a problem during the onset phase of the flood, as many vector breeding habitats are expected to 0.25 cases/100,000 inhabitants. the first three autochthonous cases identified in marseilles (october 2009) were preceded by heavy rainfall. the study showed the first autochthonous case was identified after a period of flooding preceded by heavy rainfall over several days (34.6 mm/day; 79.2 mm/day; 137 mm/ day with an episode of 63 mm/3 hr). similarly, the other two autochthonous cases occurred during a period of high rainfall (13.6-23.8 mm). pellizzer et al. 36 performed a sero-epidemiological study to evaluate the risk of leptospirosis in a population in northeast italy exposed to a severe flood event. this area is endemic for leptospirosis and exhibits and average of 4 cases/100,000 inhabitants. seven out of 44 subjects exposed to floodwaters exhibited anti-leptospira specific igm antibodies and five were confirmed positive by micro-agglutination test. re-testing a few months later found significant antibody titers greater than 100 against serovar copenhangeni in three cases (6.8% seroconversion rate). overall, the rate for seroconversion for leptospirosis appeared to be low, and while flooding appeared to be the sole risk factor, confirmation was not possible due to a lack of a control group. ahmed et al. 69 pakistan, 2010 cross-sectional study-7,814 flood affected individuals interviewed to determine frequency of infectious diseases. gastrointestinal (30%), skin and soft tissue infection (33%), conjunctivitis (7%), ear, nose and throat infection (5%), respiratory tract infection (21%), suspected malaria (4%). no comparative data before flooding. bich et al. 71 vietnam, 2008 cross-sectional study-rural and urban districts interviewed within 1 mo after flood about social, economic, and health impacts. in each district, a flooded commune and a less affected commune (control commune) were selected. no statistically significant differences in proportion of dengue cases in flood affected and less affected communes. higher proportions of pink eye and dermatitis in severely flood affected communes. in flood affected communes, 10/10 urban cases (p < 0.05) and 64/69 rural cases (p < 0.05) contracted pink eye after flood. in flood affected communes, 30/34 urban cases and 221/229 (p < 0.05) rural cases contracted dermatitis after flood. chen et al. 21 taiwan, 1994-2008 routine data-analysis of a database integrating daily precipitation and temperature and an infectious disease case registry. heavy precipitation (130-200 mm) a significant risk factor for enteroviruses (rr = 2.45; 95% ci 1.59-3.78) and dengue fever (rr = 1.96; 95% ci 1.53-2.52). extreme torrential rain (> 350 mm) a significant risk factor for enteroviruses (rr = 5.981; 95% ci 1.474-23.760) and bacillary dysentery (rr = 7.703; 95% ci 5.008-11.849). associations between precipitation levels and enterovirus infections, japanese encephalitis (p < 0.001), and stronger linear relationships between precipitation and bacillary dysentery, dengue fever, leptospirosis (p < 0.001). marcheggiani et al. 18 italy, 1993-2010 routine data-national statistics collected by italian ministry of health. association between hepatitis a, salmonellosis, infectious diarrhea, leptospirosis, cutaneous and visceral leishmaniasis, legionellosis and flood events from 1993-2010 seemed to exist. milojevic et al. 75 bangladesh, controlled interrupted time series-diarrheal incidence of a cohort of 211,000 residents classified as flooded or non-flooded in 2004. after fully controlling pre-flood rate differences and seasonality, no clear evidence of excesses mortality or diarrhea risk during/ after flooding. no evidence of excess risk from acute respiratory illnesses during flood but moderate increase in risk 6 mo after flood (rr = 1.25; 95% ci 1.06-1.47). su et al. 40 taiwan, 2009 routine data-to clarify association between leptospirosis and melioidosis epidemics and flooding. positive correlation for leptospirosis (r = 0.54; p < 0.05) and for melioidosis (r = 0.52; p < 0.05) with cumulative rainfall. increase in melioidosis cases significantly associated with > 500 mm/day (p < 0.05). number of leptospirosis cases positively correlated with 24-h cumulative rainfall (r = 0.71; p = 0.14). appendix b. studies assessing the relationship between infectious diseases and flooding: water-borne apisarnthanarak et al. 70 thailand, 2012 case report-5 melioidosis patients located through active case surveillance. 5 cases reported excess flooding of homes and 0 had traditional risk factors for melioidosis. all cases survived. auld et al. 22 canada, 2000 outbreak investigation-e. coli o157:h7 and campylobacter outbreak. outbreak occurred several days after heavy rainfall (5-d accumulation 130-140 mm). heavy rainfall hypothesized as a causative factor of the outbreak. carrel et al. 72 bangladesh , 1983-2003 longitudinal study-21-y data cluster analysis of health surveillance and geographic information system to investigate temporal and spatial distribution of cholera following flood protection interventions. 8,500 confirmed cholera cases. two clusters of lower than expected cases, 3 clusters of higher than expected cases found (p < 0.001). following flood protection interventions, overall decrease in cholera incidence, differences in the geography of high vs. low spatial clusters of cholera, and shifts in location of unusually high spatio-temporal cholera clusters. harris et al. 73 bangladesh hashizume et al. 23 bangladesh, 1998 routine data-number of observed cases of cholera and non-cholera diarrhea per week during flood and post-flood periods compared with expected numbers. during flooding, cholera cases 5.9 times higher (95% ci 5-7) and non-cholera cases 1.8 times higher (95% ci 1.6-1.9) than expected. post-flood period, cholera cases 2.1 times higher (95% ci 1.9-2.4) and non-cholera cases 1.2 times higher (95% ci 1.1-1.3). ko et al. 74 taiwan, 2009 routine data-melioidosis outbreak. 40 melioidosis cases identified following flooding. onset within 4 d. qadri et al. 76 bangladesh, 2004 routine data-diarrheal stools collected from patients during flooding. of 350 stool specimens tested, 78 positive for v. cholerae o1 (22.2%), 11 for shigella spp (3.4%), 5 for salmonella spp (1.7%). reacher et al. 28 england, 2000 historical cohort study-post-flooding survey interview. flooding associated with significant increase in risk of gastroenteritis with depth of flooding (rr = 1.7; 95% ci 0.9-3.0 p = 0.09, p for trend by flood depth = 0.04). schwartz et al. 24 bangladesh , 1988, 1998, 2004 routine data-diarrheal patients during the 1988, 1998, and 2004 floods compared with non-flood periods. cross-sectional study-1,110 individuals provided flood survey health data. house/yard flooding signficantly associated with gastrointestinal illness (incidence rate ratio = 2.36; 95% ci 1.37-4.07). volume 1 issue 2 appendix c. studies assessing the relationship between infectious diseases and flooding: rodent-borne amilasan et al. 47 the philippines, 2009 hospital-based investigation-investigating risk factors for leptospirosis mortality following flooding. prospective surveillance and retrospective data collection. outbreak of 471 leptospirosis cases, 51 cases died. patients predominately young and male. delayed initiation of treatment, older age, jaundice, anuria, hemoptysis increased risk for death. bhardwaj et al. 33 india, 2006 case-control study-identifying risk factors for leptospirosis during flooding. 62 confirmed cases and 253 age and sex matched fever and healthy controls given a questionnaire. chiu et al. 48 taiwan, 2004-2008 routine data-analyze characteristics of patients with laboratory-diagnosed leptospirosis and correlate onset of symptoms with exposure to floodwater. 6 patients identified with history of contact with contaminated soil/water. 5/6 patients (83%) suffered from leptospirosis after typhoon. dechet et al. 44 guyana, 2005 routine data-laboratory testing on suspected leptospirosis hospitalizations and deaths. confirmed outbreak of leptospirosis after severe flooding. sero-epidemiogical study-evaluated leptospirosis risk in flood-exposed population. 7/44 patients exposed to floodwaters exhibited anti-leptospira specific igm antibodies and 5 confirmed positive. re-testing months later found significant antibody titers > 100 against serovar copenhangeni in 3 cases (6.8% seroconversion rate). flooding appeared to be sole risk factor, verification not possible due to lack of control group. radl et al. 43 austria, 2010 outbreak investigation-leptospirosis. 1st documented outbreak of leptospirosis in austria. four serologically confirmed cases, all triathlon athletes. triathlon preceded by heavy rainfall (22 mm (appendices a, d) older studies have shown associations. in romania, flooded basements were a significant risk factor for wnv in apartment dwellers (p = 0.01). 59 in 1997, heavy rains in moravia, czech republic resulted in flooding, and mosquito populations in the area amplified immediately. 60 wnv activity was reported in the area. hubálek and halouzka 61 stated environmental factors such as flooding can facilitate the re-emergence of wnv. be overwhelmed by the flood waters. 51 while flooding may initially wash out vector populations, they return when the waters recede. receding flood water can provide ideal breeding habitats. therefore, vector-borne diseases are likely to have mid-term to long-term impacts on health following flooding (fig. 1) . vector-borne virus outbreaks are strictly determined by the presence of the pathogen and particular competent disease vectors. 52 the current and future establishment of exotic mosquito species in europe is a cause for serious concern, as the newly introduced species may already be disease vectors or could potentially become vectors. west nile virus (wnv) emerged in europe after heavy rains and flooding, with outbreaks in romania in 1996-1997, the czech republic in 1997, and italy in 1998. 53 the 2002 flood in the czech republic resulted in mass mosquito breeding with a biting frequency peaking at 70 bites per person per minute. 54 specimens from 497 flood-affected residents were examined serologically for mosquito-borne viruses. paired serum samples showed one tahyna virus infection among 150 residents. jiménez-sastré et al. 55 sampled dwellings in tabasco, mexico, post-flood for dengue fever cases and found the geographical distribution of dengue fever cases was associated with the proximity of two permanent bodies of water. chen et al. 21 found heavy precipitation was a significant risk factor for dengue fever (rr = 1.96; 95%; ci 1.53-2.52). additionally, more non-european appendix d. studies assessing the relationship between infectious diseases and flooding: vector-borne hassan et al. 56 sudan, 2007 outbreak investigation-rift valley fever. 747 confirmed human cases including 230 deaths. outbreak followed heavy rainfall with severe flooding. hubalek et al. 54 czech republic, 2002 routine data-specimens from residents in flooded area examined serologically for mosquito-borne viruses. antibodies detected after flood for tahyna, sindbis, and batai viruses, with only activity found for tahyna virus among 150 residents. jiménez-sastré et al. 55 mexico, 2010 cross-sectional study-convenience sampling of dengue fever in flooded colonies. 3 cases with positive serology of igg (0.6%) and 5 cases of positive igm (0.9%). geographical distribution associated with proximity to 2 permanent water bodies. tong et al. 57 australia , 1998-2001 routine data-assessment of variability in environmental and vector factors on ross river virus transmission. wu et al. 58 china, 1979-2000 longitudinal study-review of retrospective data to determine intermediate host snail dispersal patterns and acute and chronic infections of schistosomiasis after floods. average number of acute schistosomiasis cases recorded in flood years 2.8 times higher than in years with little to no flooding. re-emerging and new snail infested areas in flood years on average 2.6 and 2.7 times larger than in years with normal water levels. flooding of marshlands identified as main driver for vector dispersal. responsible for local disease transmission, the factors that influence transmission, location of breeding ground, and which measures of control should be implemented. local destruction of breeding sites after flooding has receded is extremely effective, so individuals should remove unused vessels and stagnant water when possible. water storage containers need to be covered to protect from disease vectors, such as egg-laying female mosquitoes. individuals can protect themselves against mosquito bites by using repellents during biting hours, mosquito nets, and screens in doors and windows. individual and community awareness and participation is essential for successfully reducing the risk of infectious diseases following flooding. understanding the social and cultural influences on response behavior in the time of a flood emergency is crucial to inform the design and targeting of warnings and health education messages. 1 some studies showed the frequency of infectious diseases can increase in the weeks to months after flooding, and figure 1 illustrates when infectious disease outbreaks following flood events are likely to occur. however, there remains scientific uncertainty about the strength of association between infectious disease incidence and flooding. floods can cause population displacement and changes in population density, raise concern about waste management and the availability of clean water, as well as affect the availability and access to healthcare services. all of these are risk factors for an infectious disease outbreak. kouadio et al. 13 and watson et al. 67 suggested that unless there is a substantial population displacement, there is minimal risk of infectious disease transmission and outbreaks following flooding. overall, the risk of infectious disease following flooding is context-specific, differs between countries, and is dependent upon a number of synergistic factors. outbreaks of leptospirosis and diarrheal diseases following flooding have been documented in europe 18, 24, 28, 29, 34, 36, 38, [41] [42] [43] but the evidence of increased incidence of vector-borne diseases following flooding is lacking because the time lag before onset can be several months. 68 past studies have indicated possible associations between vector-borne diseases and flooding in europe. 36, [59] [60] [61] european residents may be exposed to these risks while traveling. foreign relief workers can potentially introduce infectious diseases into an area affected by flooding and these workers may be susceptible to endemic diseases that are more prevalent because of the flood. surveillance in flood-affected areas is fundamental to understanding the impact of flooding on infectious disease incidence. surveillance and early warning systems may reduce current and future vulnerability. a comprehensive risk assessment could help determine priority diseases for inclusion in the enhanced surveillance system and prioritize prevention and control measures. in addition to surveillance and early warning systems to detect epidemic-prone diseases, assuring access to clean water, proper sanitation, adequate shelter, and primary healthcare services is essential. despite a considerable amount of research on the relationship between infectious diseases and flooding, globally and in summary of possible public health interventions public health interventions include those made before, during, and after flooding to reduce vulnerability to infectious diseases. interventions need to take place at a variety of levels: individual, household, community, regional, national, and international. 51 the public health measures cited in the literature to reduce the risk of infectious diseases as a result of flooding focus on: risk assessments, enhanced surveillance systems, and specific prevention and control measures depending upon the type of infectious disease risk. 62, 63 a rapid disease risk assessment should be conducted by a representative multi-agency group within the first week of the flood including: data on the flooded region and displaced persons, the main disease threats for the enhanced surveillance system, baseline data collection, and identification of priority interventions. 62, 63 during a flood event, hand-held devices that allow workers to enter and analyze data in the field can assist the rapid risk assessment. 64 existing disease surveillance systems can be enhanced to target specific diseases or syndromes and to support timely response actions to reduce disease impact and risk of transmission. 62, 63 public health teams need to establish adequate disease surveillance systems which take into account the inherent disruption of the public health infrastructure that may occur during flooding. an enhanced surveillance system should be adaptable and context-specific, monitor key epidemiological data and compare with baseline data, monitor vulnerable groups, identify any emerging outbreaks, and result in timely public health action. in high-income countries, risk assessments and surveillance systems need to be very refined to detect small differences from baseline incidence data. 51 prevention of infectious diseases following flooding involves maintenance of health services, provision of shelter, clean water supplies, proper sanitation, regular and adequate food supply, and in some cases mass vaccination campaigns and control of disease vectors. 62, 63 water and sanitation are vital elements in the transmission of water-borne diseases; hence, providing clean drinking water is a priority in the initial days following flooding. clasen et al. 65 found that household interventions were more effective in preventing diarrhea than interventions at the water-source. interventions at the household level reviewed included: chlorination, filtration, solar disinfection, and combined flocculation and disinfection. ejemot-nwadiaro et al. 66 found hand-washing interventions can reduce diarrhea episodes by one-third. rodent control is another prevention measure that needs to be considered during flooding. the local rodent species and their behaviors should be identified, water and food storage containers should be rodent-proofed, and solid waste should be properly stored, collected, and disposed. 62, 63 according to bhardwaj et al. 33 prompt and vigilant fever surveillance activities in pre-flooding preparedness plans, rodent control programs, and improvement of environmental sanitary conditions may help greatly reduce leptospirosis incidence. vector control can reduce disease transmission by rendering the environment unfavorable for the survival, development, and reproduction of the vector. 62, 63 establishing surveillance for the introduction of new vector species could contribute substantially to vector-control. an expert should identify vectors • papers on unrelated subject areas; such as, biochemistry, molecular biology, and genetics. personal communications between key informants were conducted in conjunction with the literature review. the context of the questions included the current state of knowledge of the association between flooding and infectious diseases and potential solutions to mitigate the risks. because flooding is a natural disaster and cannot be induced experimentally, the research evidence was unlikely to be the considered 'gold standard' of a systematic literature review or a randomized controlled trial. most of the data were observational, and because of the insufficient numbers of similar studies and variations in outcome reporting, no studies were excluded on the basis of study quality. a formal assessment of bias was not possible for each individual study. it is important for health officials and the public to understand that exacerbation of disease risk factors contribute to infectious disease outbreaks following flooding. population and individual vulnerability and resilience factors can worsen or mitigate infectious diseases following flooding. the community needs to be aware of actions that can facilitate or prevent infectious disease. to mitigate infectious disease risk following flooding, those involved in flood planning, response, and recovery should be aware of the results of this systematic literature review. if climate change causes more floods, then the future health burden of infectious diseases from floods could increase. in europe, maintenance and continuous adaptation and improvement of public health measures is important to sustain the low risk of infectious disease outbreaks following floods. presently, there are clear research needs to improve the understanding of the association between infectious diseases and flooding: • more robust epidemiological studies on infectious diseases covering the pre-, mid-, and post-flood periods. • further research assessing the effectiveness of public health interventions minimizing risk from infectious diseases following flooding. • investigation of infectious disease incidence following smaller flood events. • analysis of the differences between summer and winter flooding on infectious disease incidence. • analysis of the differences between flash and riverine flooding on infectious disease incidence. no potential conflicts of interest were disclosed. this work was carried out within public health england's department of extreme events and health protection, funded partly by the eu project "public health adaptation strategies europe, the body of information still remains fragmentary. many studies attempted to collect data retrospectively, had methodological shortcomings, lacked longitudinal data/baseline health data, control groups for comparison, and measures of clear disease outcomes. the studies included in this review were mainly observational studies with widely varying quality levels and study designs. because it is unethical to conduct experimental studies on this topic, rigorous observational studies must be continue to be undertaken. observational studies can present particular challenges because of the unpredictability of the timing and location of floods. reporting and recall bias was very likely in many studies. additionally, many studies relied on data from disease surveillance systems. obtaining relevant disease surveillance data pre-, mid-, and post-flooding is frequently challenging. population displacement can distort the rates of comparison for infectious disease incidence. the quality and robustness of disease surveillance systems can vary from country to country, and a country with a weak disease surveillance system will probably lack pre-flood baseline data. flood damage to pre-existing public health infrastructure can exacerbate weaknesses in a disease surveillance system. furthermore, it is difficult to attribute an increase in infectious disease incidence solely to a flood event, and therefore this issue may be under-investigated and under-reported. finally, this systematic review is not entirely exhaustive, and there may be many other reports in gray literature, but the quality is likely to be lower than the peer-reviewed published reports identified. the search strategy used was adapted from two studies ( table 1) . 15, 16 all papers with the specified search terms in their titles, abstracts, or keywords were searched for. focused searches of the following databases were conducted: medline, scopus, and pubmed. the cochrane database of systematic reviews was searched for further existing epidemiological reviews, as well as evidence aid. further relevant articles were identified manually from cited references from each selected full-text paper. data from gray literature were not systematically searched, but sources and advice from key experts were discussed in the accompanying text. inclusion criteria • papers published from 1 january 2004 to 30 september 2012. ahern et al. 15 included studies associated with infectious disease incidence following flooding up to 2004. • epidemiological studies. • studies conducted in any country, because europe experiences a wide range of climate and geographical variation. • papers in all languages with english abstracts. • all papers where an explicit link is studied between flooding as an exposure and an infectious disease as an outcome. exclusion criteria • papers concerned primarily with mental health effects, flood-related injuries, population displacement, economic costs, and disruption of food supplies. a role of high impact weather events in waterborne disease outbreaks in canada risk factors for typhoid and paratyphoid fever in jakarta, indonesia health impacts of flooding in lewes: a comparison of reported gastrointestinal and other illness and mental health in flooded and non-flooded households outbreak of norovirus infection associated with contaminated flood water extreme precipitation linked to waterborne disease outbreaks. sciencedaily did a severe flood in the midwest cause an increase in the incidence of gastrointestinal symptoms? waterborne epidemics in finland in 1998-1999 a case control study to explore the risk factors for acquisition of leptospirosis in surat city, after flood resurgence of field fever in a temperate country: an epidemic of leptospirosis among seasonal strawberry harvesters in germany in 2007 leptospirosis on oahu: an outbreak associated with flooding of a university campus leptospirosis following a flood in the veneto area later leptospirosis after flood in tabasco, mexico strikes, flooding, rats, and leptospirosis in marseille, france climate change, flooding, urbanisation and leptospirosis: fuelling the fire? infectious diseases following natural disasters: prevention and control measures infectious diseases that pose specific challenges after natural disasters: a review global health impacts of floods: epidemiologic evidence climate change and infectious diseases in europe extreme water-related weather events and waterborne disease risks of water-borne disease outbreaks after extreme events influence of environmental factors and human activity on the presence of salmonella serovars in a marine environment systematic review of waterborne disease outbreaks following extreme water events effects of extreme precipitation to the distribution of infectious diseases in taiwan heavy rainfall and waterborne disease outbreaks: the walkerton example factors determining vulnerability to diarrhoea during and after severe floods in bangladesh medicaid outpatient utilization for waterborne pathogenic illness following hurricane floyd flood hazards and health: responding to present and future risks. tyndall centre for climate change research global trends in waterrelated disasters: an insight for policy-makers. the united nations world water assessment program. international center for water hazard and risk management building human resilience: the role of public health preparedness and response as an adaptation to climate change health impacts of floods in europe: data gaps and needs from a spatial perspective major flood disasters in europe future change of precipitation extremes in europe: intercomparison of scenarios from regional climate models no upward trends in the occurrence of extreme floods in central europe summary for policymakers: managing the risks of extreme events and disasters to advance climate change adaptation protecting health in europe from climate change disease emergence from global climate and land use change infectious diseases in the aftermath of monsoon flooding in pakistan infectious diseases of severe weather-related and flood-related natural disasters we would like to acknowledge carla stanke world health organization regional office for king's college london); and brittany scheckelhoff epidemics after natural disasters the threat of communicable diseases following natural disasters: a public health response frequency of infectious diseases among flood affected people at district rajanpur, pakistan flood-associated melioidosis in a non-endemic region of thailand impacts of flood on health: epidemiologic evidence from hanoi spatiotemporal clustering of cholera: the impact of flood control in matlab shifting prevalence of major diarrheal pathogens in patients seeking hospital care during floods in 1998 melioidosis outbreak after typhoon, southern taiwan health effects of flooding in rural bangladesh enterotoxigenic escherichia coli and vibrio cholerae diarrhea flooding and communicable disease fact sheet mosquitoborne viruses geographic distribution of dengue fever cases in flooded zones from villahermosa, tabasco, in 2010 rift valley fever outbreak in sudan climatic, high tide, and vector variables and the transmission of ross rover virus effect of floods on the transmission of schistosomiasis in the yangtze river valley, people's republic of china risk factors for west nile virus infection and meningoencephalitis, romania west nile fever in czechland nile fever--a reemerging mosquito-borne viral disease in europe public health guide in emergencies communicable disease control in emergencies: a field manual communication, data sharing, and collaboration, at the disaster site. comput in civil eng interventions to improve water quality for preventing diarrhea typhoon-related leptospirosis and melioidosis longitudinal epidemiology of leptospirosis in the czech republic monitoring of the epidemiological situation in flooded areas of the czech republic in year 1997 outbreak of leptospirosis among triathlon participants in langau leptospirosis outbreak following severe flooding: a rapid assessment and mass prophylaxis campaign leptospirosis in mumbai: postdeluge outbreak 2005 leptospirosis following a major flood in central queensland outbreak of leptospirosis after flood, the philippines leptospirosis after typhoon in taiwan anti-epidemic provision for the population in emergency situations in the krasnodar territory increase of leptospirosis in dengue-negative patients after a hurricane in puerto rico in 1996 the health impacts of floods. in: [few r and matthies f] flood hazards and health: responding to present and future risks. tyndall centre for climate change research a review of the invasive mosquitoes in europe: ecology, public health risks, and control options key: cord-018646-fqy82sm6 authors: huremović, damir title: brief history of pandemics (pandemics throughout history) date: 2019-05-16 journal: psychiatry of pandemics doi: 10.1007/978-3-030-15346-5_2 sha: doc_id: 18646 cord_uid: fqy82sm6 intermittent outbreaks of infectious diseases have had profound and lasting effects on societies throughout history. those events have powerfully shaped the economic, political, and social aspects of human civilization, with their effects often lasting for centuries. epidemic outbreaks have defined some of the basic tenets of modern medicine, pushing the scientific community to develop principles of epidemiology, prevention, immunization, and antimicrobial treatments. this chapter outlines some of the most notable outbreaks that took place in human history and are relevant for a better understanding of the rest of the material. starting with religious texts, which heavily reference plagues, this chapter establishes the fundamentals for our understanding of the scope, social, medical, and psychological impact that some pandemics effected on civilization, including the black death (a plague outbreak from the fourteenth century), the spanish flu of 1918, and the more recent outbreaks in the twenty-first century, including sars, ebola, and zika. given to ways plagues affected the individual and group psychology of afflicted societies. this includes the unexamined ways pandemic outbreaks might have shaped the specialty of psychiatry; psychoanalysis was gaining recognition as an established treatment within medical community at the time the last great pandemic was making global rounds a century ago. there is a single word that can serve as a fitting point of departure for our brief journey through the history of pandemics -that word is the plague. stemming from doric greek word plaga (strike, blow), the word plague is a polyseme, used interchangeably to describe a particular, virulent contagious febrile disease caused by yersinia pestis, as a general term for any epidemic disease causing a high rate of mortality, or more widely, as a metaphor for any sudden outbreak of a disastrous evil or affliction [4] . this term in greek can refer to any kind of sickness; in latin, the terms are plaga and pestis (fig. 2.1 ). perhaps the best-known examples of plagues ever recorded are those referred to in the religious scriptures that serve as foundations to abrahamic religions, starting with the old testament. book of exodus, chapters 7 through 11, mentions a series of ten plagues to strike the egyptians before the israelites, held in captivity by the pharaoh, the ruler of egypt, are finally released. some of those loosely defined plagues are likely occurrences of elements, but at least a few of them are clearly of infectious nature. lice, diseased livestock, boils, and possible deaths of firstborn likely describe a variety of infectious diseases, zoonoses, and parasitoses [5] . similar plagues were described and referred to in islamic tradition in chapter 7 of the qur'an (surat al-a'raf, v. 133) [6] . throughout the biblical context, pandemic outbreaks are the bookends of human existence, considered both a part of nascent human societies, and a part of the very ending of humanity. in the apocalypse or the book of revelation, chapter 16, seven bowls of god's wrath will be poured on the earth by angels, again some of the bowls containing plagues likely infectious in nature: "so the first angel went and poured out his bowl on the earth, and harmful and painful sores came upon the people who bore the mark of the beast" (revelation 16:2). those events, regardless of factual evidence, deeply shaped human history, and continue to be commemorated in religious practices throughout the world. as we will see, the beliefs associated with those fundamental accounts have been rooted in societal responses to pandemics in western societies and continue to shape public sentiment and perception of current and future outbreaks. examined through the lens of abrahamic spiritual context, serious infectious outbreaks can often be interpreted as a "divine punishment for sins" (of the entire society or its outcast segments) or, in its eschatological iteration, as events heralding the "end of days" (i.e., the end of the world). throughout known, predominantly western history, there have been recorded processions of pandemics that each shaped our history and our society, inclusive of shaping the very basic principles of modern health sciences. what follows is an outline of major pandemic outbreaks throughout recorded history extending into the twenty-first century. the athenian plague of 430 b.c. the athenian plague is a historically documented event that occurred in 430-26 b.c. during the peloponnesian war, fought between city-states of athens and sparta. the historic account of the athenian plague is provided by thucydides, who survived the plague himself and described it in his history of the peloponnesian war [7] . the athenian plague originated in ethiopia, and from there, it spread throughout egypt and greece. initial symptoms of the plague included headaches, conjunctivitis, a rash covering the body, and fever. the victims would then cough up blood, and suffer from extremely painful stomach cramping, followed by vomiting and attacks of "ineffectual retching" [7] . infected individuals would generally die by the seventh or eighth day. those who survived this stage might suffer from partial paralysis, amnesia, or blindness for the rest of their lives. doctors and other caregivers frequently caught the disease, and died with those whom they had been attempting to heal. the despair caused by the plague within the city led the people to be indifferent to the laws of men and gods, and many cast themselves into self-indulgence [8] . because of wartime overcrowding in the city of athens, the plague spread quickly, killing tens of thousands, including pericles, athens' beloved leader. with the fall of civic duty and religion, superstition reigned, especially in the recollection of old oracles [7] . the plague of athens affected a majority of the inhabitants of the overcrowded city-state and claimed lives of more than 25% of the population [9] . the cause of the athenian plague of 430 b.c. has not been clearly determined, but many diseases, including bubonic plague, have been ruled out as possibilities [10] . while typhoid fever figures prominently as a probable culprit, a recent theory, postulated by olson and some other epidemiologists and classicists, considers the cause of the athenian plague to be ebola virus hemorrhagic fever [11] . while hippocrates is thought to have been a contemporary of the plague of athens, even possibly treating the afflicted as a young physician, he had not left known accounts of the outbreak [12] . it was another outbreak that occurred a couple of centuries later that was documented and recorded by contemporary physicians of the time. the outbreak was known as the antonine plague of 165-180 ad and the physician documenting it was galen; this outbreak is also known as the plague of galen [13] . the antonine plague occurred in the roman empire during the reign of marcus aurelius (161-180 a.d.) and its cause is thought to be smallpox [14] . it was brought into the empire by soldiers returning from seleucia, and before it abated, it had affected asia minor, egypt, greece, and italy. unlike the plague of athens, which affected a geographically limited region, the antonine plague spread across the vast territory of the entire roman empire, because the empire was an economically and politically integrated, cohesive society occupying wide swaths of the territory [15] . the plague destroyed as much as one-third of the population in some areas, and decimated the roman army, claiming the life of marcus aurelius himself [13] . the impact of the plague on the roman empire was severe, weakening its military and economic supremacy. the antonine plague affected ancient roman traditions, leading to a renewal of spirituality and religiousness, creating the conditions for spreading of new religions, including christianity. the antonine plague may well have created the conditions for the decline of the roman empire and, afterwards, for its fall in the west in the fifth century ad [13] . the justinian plague was a "real plague" pandemic (i.e., caused by yersinia pestis) that originated in mid-sixth century ad either in ethiopia, moving through egypt, or in the central asian steppes, where it then traveled along the caravan trading routes. from one of these two locations, the pestilence quickly spread throughout the roman world and beyond. like most pandemics, the justinian plague generally followed trading routes providing an "exchange of infections as well as of goods," and therefore, was especially brutal to coastal cities. military movement at the time also contributed to spreading the disease from asia minor to africa and italy, and further to western europe. described in detail by procopius, john of ephesus, and evagrius, the justinian epidemic is the earliest clearly documented example of the actual (bubonic) plague outbreak [16] . during the plague, many victims experienced hallucinations prior to the outbreak of illness. the first symptoms of the plague followed closely behind; they included fever and fatigue. soon afterwards, buboes appeared in the groin area or armpits, or occasionally beside the ears. from this point, the disease progressed rapidly; infected individuals usually died within days. infected individuals would enter a delirious, lethargic state, and would not wish to eat or drink. following this stage, the victims would be "seized by madness," causing great difficulties to those who attempted to care for them [17] . many people died painfully when their buboes gangrened; others died vomiting blood. there were also cases, however, in which the buboes grew to great size, and then ruptured and suppurated. in such cases, the patient would usually recover, having to live with withered thighs and tongues, classic aftereffects of the plague. doctors, noticing this trend and not knowing how else to fight the disease, sometimes lanced the buboes of those infected to discover that carbuncles had formed. those individuals who did survive infection usually had to live with ''withered thighs and tongues'', the stigmata of survivors. emperor justinian contracted the plague himself, but did not succumb [18] . within a short time, all gravesites were beyond capacity, and the living resorted to throwing the bodies of victims out into the streets or piling them along the seashore to rot. the empire addressed this problem by digging huge pits and collecting the corpses there. although those pits reportedly held 70,000 corpses each, they soon overflowed [17] . bodies were then placed inside the towers in the walls, causing a stench pervading the entire city. streets were deserted, and all trade was abandoned. staple foods became scarce and people died of starvation as well as of the disease itself [17] . the byzantine empire was a sophisticated society in its time and many of the advanced public policies and institutions that existed at that time were also greatly affected. as the tax base shrank and the economic output decreased, the empire forced the survivors to shoulder the tax burden [19] . byzantine army suffered in particular, being unable to fill its ranks and carry out military campaigns, and ultimately failing to retake rome for the empire. after the initial outbreak in 541, repetitions of the plague established permanent cycles of infection. by 600, it is possible that the population of the empire had been reduced by 40%. in the city of constantinople itself, it is possible that this figure exceeded 50 % [17] . at this point in history, christian tradition enters the realm of interpreting and understanding the events of this nature [20] . drawing on the eschatological narrative of the book of revelations, plague and other misfortunes are seen and explained as a "punishment for sins," or retribution for the induction of "god's wrath" [21] . this interpretation of the plague will reappear during the black death and play a much more central role throughout affected societies in europe. meanwhile, as the well-established byzantine empire experienced major challenges and weakening of its physical, economic, and cultural infrastructure during this outbreak, the nomadic arab tribes, moving through sparsely populated areas and practicing a form of protective isolation, were setting a stage for the rapid expansion of islam [22, 23] . the black death "the plague" was a global outbreak of bubonic plague that originated in china in 1334, arrived in europe in 1347, following the silk road. within 50 years of its reign, by 1400, [24] it reduced the global population from 450 million to below 350 million, possibly below 300 million, with the pandemic killing as many as 150 million. some estimates claim that the black death claimed up to 60% of lives in europe at that time [25] . starting in china, it spread through central asia and northern india following the established trading route known as the silk road. the plague reached europe in sicily in 1347. within 5 years, it had spread to the virtually entire continent, moving onto russia and the middle east. in its first wave, it claimed 25 million lives [24] . the course and symptoms of the bubonic plague were dramatic and terrifying. boccaccio, one of the many artistic contemporaries of the plague, described it as follows: in men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg...from the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. as the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves [26] . indeed, the mortality of untreated bubonic plague is close to 70%, usually within 8 days, while the mortality of untreated pneumonic plague approaches 95%. treated with antibiotics, mortality drops to around 11% [27] . at the time, scientific authorities were at a loss regarding the cause of the affliction. the first official report blamed an alignment of three planets from 1345 for causing a "great pestilence in the air" [28] . it was followed by a more generally accepted miasma theory, an interpretation that blamed bad air. it was not until the late xix century that the black death was understood for what it was -a massive yersinia pestis pandemic [29] . this strain of yersinia tends to infect and overflow the guts of oriental rat fleas (xenopsylla cheopis) forcing them to regurgitate concentrated bacteria into the host while feeding. such infected hosts then transmit the disease further and can infect humans -bubonic plague [30] . humans can transmit the disease by droplets, leading to pneumonic plague. the mortality of the black death varied between regions, sometimes skipping sparsely populated rural areas, but then exacting its toll from the densely populated urban areas, where population perished in excess of 50, sometimes 60% [31] . in the vacuum of a reasonable explanation for a catastrophe of such proportions, people turned to religion, invoking patron saints, the virgin mary, or joining the processions of flagellants whipping themselves with nail embedded scourges and incanting hymns and prayers as they passed from town to town [32] . the general interpretation in predominantly catholic europe, as in the case of justinian plague, centered on the divine "punishment for sins." it then sought to identify those individuals and groups who were the "gravest sinners against god," frequently singling out minorities or women. jews in europe were commonly targeted, accused of "poisoning the wells" and entire communities persecuted and killed. non-catholic christians (e.g., cathars) were also blamed as "heretics" and experienced a similar fate [33] . in other, non-christian parts of the world affected by the plague, a similar sentiment prevailed. in cairo, the sultan put in place a law prohibiting women from making public appearances as they may tempt men into sin [34] . for bewildered and terrified societies, the only remedies were inhalation of aromatic vapors from flowers or camphor. soon, there was a shortage of doctors which led to a proliferation of quacks selling useless cures and amulets and other adornments that claimed to offer magical protection [35] . entire neighborhoods, sometimes entire towns, were wiped out or settlements abandoned. crops could not be harvested, traveling and trade became curtailed, and food and manufactured goods became short. the plague broke down the normal divisions between the upper and lower classes and led to the emergence of a new middle class. the shortage of labor in the long run encouraged innovation of labor-saving technologies, leading to higher productivity [2] . the effects of such a large-scale shared experience on the population of europe influenced all forms of art throughout the period, as evidenced by works by renowned artists, such as chaucer, boccaccio, or petrarch. the deep, lingering wake of the plague is evidenced in the rise of danse macabre (dance of the death) in visual arts and religious scripts [36] , its horrors perhaps most chillingly depicted by paintings titled the triumph of death (fig. 2. 2) [37] . the plague made several encore rounds through europe in the following centuries, occasionally decimating towns and entire societies, but never with the same intensity as the black death [2] . with the breakdown of societal structure and its infrastructures, many professions, notably that of medical doctors, were severely affected. many towns throughout europe lost their providers to plague or to fear thereof. in order to address this shortage in times of austere need, many municipalities contracted young doctors from whatever ranks were available to perform the duty of the plague doctor (medico della peste) [38] . venice was among the first citystates to establish dedicated practitioners to deal with the issue of plague in 1348. their principal task, besides taking care of people with the plague, was to record in public records the deaths due to the plague [39] . in certain european cities like florence and perugia, plague doctors were the only ones allowed to perform autopsies to help determine the cause of death and managed to learn a lot about human anatomy. among the most notable plague doctors of their time were nostradamus, paracelsus, and ambrois pare [40] . the character of the plague doctor was drawing from experiences from ancient cultures that had dealt with contagious diseases, medieval societies observed the connection between the passage of time and the eruption of symptoms, noting that, after a period of observation, individuals who had not developed symptoms of the illness would likely not be affected and, more importantly, would not spread the disease upon entering the city. to that end, they started instituting mandatory isolation. the first known quarantine was enacted in ragusa (city-state of dubrovnik) in 1377, where all arrivals had to spend 30 days on a nearby island of lokrum before entering the city. this period of 30 days (trentine) was later extended to 40 days (quarenta giorni or quarantine) [42] . the institution of quarantine was one of the rarely effective measures that took place during the black death and its use quickly spread throughout europe. quarantine remains in effect in the present time as a highly regulated, nationally and internationally governed public health measure available to combat contagions [43] . the spanish flu pandemic in the first decades of the twentieth century was the first true global pandemic and the first one that occurred in the setting of modern medicine, with specialties such as infectious diseases and epidemiology studying the nature of the illness and the course of the pandemic as it unfolded. it is also, as of this time, the last true global pandemic with devastating consequences for societies across the globe [44] . it was caused by the h1n1 strain of the influenza virus, [45] a strain that had an encore outbreak in the early years of the twenty-first century. despite advances in epidemiology and public health, both at the time and in subsequent decades, the true origin of spanish flu remains unknown, despite its name. as possible sources of origin, cited are the usa, china, spain, france, or austria. these uncertainties are perpetuated by the circumstances of the spanish flu -it took place in the middle of world war i, with significant censorships in place, and with fairly advanced modes of transportation, including intercontinental travel [44] . within months, the deadly h1n1 strain of influenza virus had spread to every corner of the world. in addition to europe, where massive military movements and overcrowding contributed to massive spread, this virus devastated the usa, asia, africa, and the pacific islands. the mortality rate of spanish flu ranged between 10% and 20%. with over a quarter of the global population contracting that flu at some point, the death toll was immense -well over 50 million, possibly 100 million dead. it killed more individuals in a year than the black death had killed in a century [46] . this pandemic, unusually, tended to mortally affect mostly young and previously healthy individuals. this is likely due to its triggering a cytokine storm, which overwhelms and demolishes the immune system. by august of 1918, the virus had mutated to a much more virulent and deadlier form, returning to kill many of those who avoided it during the first wave [47] . spanish flu had an immense influence on our civilization. some authors (price) even point out that it may have tipped the outcome of world war i, as it affected armies of germany and the austrian-hungarian empire earlier and more virulently than their allied opponents (fig. 2.4) [48] . many notable politicians, artists, and scientists were either affected by the flu or succumbed to it. many survived and went on to have distinguished careers in arts and politics (e.g., walt disney, greta garbo, raymond chandler, franz kafka, edward munch, franklin delano roosevelt, and woodrow wilson). many did not; this pandemic counted as its victims, among others, outstanding painters like gustav klimt and egon schiele [49] , and acclaimed poets like guillaume apollinaire. it also claimed the life of sigmund freud's fifth child -sophie halberstadt-freud. this pandemic was also the first one where the longlingering effects could be observed and quantified. a study of us census data from 1960 to 1980 found that the children born to women exposed to the pandemic had more physical ailments and a lower lifetime income than those born a few months earlier or later. a 2006 study in the journal of political economy found that "cohorts in utero during the pandemic displayed reduced educational attainment, increased rates of physical disability, lower income, lower socioeconomic status, and higher transfer payments compared with other birth cohorts" [50] . despite its immense effect on the global civilization, spanish flu started to fade quickly from the public and scientific attention, establishing a precedent for the future pandemics, and leading some historians (crosby) to call it the "forgotten pandemic" [51] . one of the explanations for this treatment of the pandemic may lie in the fact that it peaked and waned rapidly, over a period of 9 months before it even could get adequate media coverage. another reason may be in the fact that the pandemic was overshadowed by more significant historical events, such as the culmination and the ending of world war i. a third explanation may be that this is how societies deal with such rapidly spreading pandemicsat first with great interest, horror, and panic, and then, as soon as they start to subside, with dispassionate disinterest. hiv/aids is a slowly progressing global pandemic cascading through decades of time, different continents, and different populations, bringing new challenges with every new iteration and for every new group it affected. it started in the early 1980s in the usa, causing significant public concern as hiv at the time inevitably progressed to aids and ultimately, to death. the initial expansion of hiv was marked by its spread predominantly among the gay population and by high mortality, leading to marked social isolation and stigma. hiv affects about 40 million people globally (prevalence rate: 0.79%) and has killed almost the same number of people since 1981 [52] . it causes about one million deaths a year worldwide (down from nearly two million in 2005) [53] . while it represents a global public health phenomenon, the hiv epidemic is particularly alarming in some sub-saharan african countries (botswana, lesotho, and swaziland), where the prevalence tops 25% [54] . in the usa, about 1.2 million people live with hiv and about 12,000 die every year (down from over 40,000 per year in the late 1990s). hiv in the usa disproportionately affects gay population, transgendered women, and african-americans [55] . being a fairly slowly spreading pandemic, hiv has received formidable public health attention, both by national and by international administrations and pharmaceuticals. advances in treatment (protease inhibitors and anti-retrovirals) have turned hiv into a chronic condition that can be managed by medications. it is a rare infectious disease that has managed to attract the focus of mental health which, in turn, resulted in a solid volume of works on mental health and hiv [56] . by studying the mental health of hiv, we can begin to understand some of the challenges generally associated with infectious diseases. we know, for example, that the lifetime prevalence rate for depression in hiv individuals is, at 22%, more than twice the prevalence rate in general population [57] . we understand how depression in hiv individuals shows association with substance abuse and that issues of stigma, guilt, and shame affect the outlook for hiv patients, including their own adherence to life-saving treatments [58] . we know about medical treatments of depression in hiv and we have studies in psychotherapy for patients with hiv. some of those approaches can be very useful in treating patients in the context of a pandemic. given the contrast between the chronicity of the hiv and the acuity of a potential pandemic, most of those approaches cannot be simply translated from mental health approach to hiv and used for patients in a rapidly advancing outbreak or a pandemic. smallpox was a highly contagious disease for which edward jenner developed the world's first vaccine in 1798. caused by the variola virus, it was a highly contagious disease with prominent skin eruptions (pustules) and mortality of about 30%. it may have been responsible for hundreds of millions of fatalities in the twentieth century alone. due to the wellcoordinated global effort starting in 1967 under the leadership of donald henderson, smallpox was eradicated within a decade of undertaking the eradication on a global scale [59] . the smallpox outbreak in the former yugoslavia in 1972 was a far cry from even an epidemic, let alone a pandemic, but it illustrated the challenges associated with a rapidly spreading, highly contagious illness in a modern world. it started with a pilgrim returning from the middle east, who developed fever and skin eruptions. since a case of smallpox had not been seen in the region for over 30 years, physicians failed to correctly diagnose the illness and nine healthcare providers ended among 38 cases infected by the index case and first fatality [60] . socialist yugoslavia at the time declared martial law and introduced mandatory revaccination. entire villages and neighborhoods were cordoned off (cordon sanitaire is a measure of putting entire geographic regions in quarantine). about 10,000 individuals who may have come into contact with the infected were placed in an actual quarantine. borders were closed, and all non-essential travel was suspended. within 2 weeks, the entire population of yugoslavia was revaccinated (about 18 million people at the time). during the outbreak, 175 cases were identified, with 35 fatalities. due to prompt and massive response, however, the disease was eradicated and the society returned to normal within 2 months [60] . this event has proven to be a useful model for working out scenarios ("dark winter") [61] for responses to an outbreak of a highly contagious disease, both as a natural occurrence [62] and as an act of bioterrorism [63] . severe acute respiratory syndrome (sars) was the first outbreak in the twenty-first century that managed to get public attention. caused by the sars corona virus (sars-cov), it started in china and affected fewer than 10,000 individuals, mainly in china and hong kong, but also in other countries, including 251 cases in canada (toronto) [64] . the severity of respiratory symptoms and mortality rate of about 10% caused a global public health concern. due to the vigilance of public health systems worldwide, the outbreak was contained by mid-2003 [65] . this outbreak was among the first acute outbreaks that had mental health aspects studied in the process and in the aftermath, in various part of the world and in different societies, yielding valuable data on effects of an acute infectious outbreak on affected individuals, families, and the entire communities, including the mental health issues facing healthcare providers [66] . some of the valuable insights into the mental health of patients in isolation, survivors of the severe illness, or psychological sequelae of working with such patients were researched during the sars outbreak. "swine flu" or h1n1/09 pandemic the 2009 h1n1 pandemic was a reprise of the "spanish flu" pandemic from 1918, but with far less devastating consequences. suspected as a re-assortment of bird, swine, and human flu viruses, it was colloquially known as the "swine flu" [67] . it started in mexico in april of 2009 and reached pandemic proportions within weeks [68] . it began to taper off toward the end of the year and by may of 2010, it was declared over. it infected over 10% of the global population (lower than expected), with a death toll estimated varying from 20,000 to over 500,000 [69] . although its death rate was ultimately lower than the regular influenza death rates, at the time it was perceived as very threatening because it disproportionately affected previously healthy young adults, often quickly leading to severe respiratory compromise. a possible explanation for this phenomenon (in addition to the "cytokine storm" applicable to the 1918 h1n1 outbreak) is attributed to older adults having immunity due to a similar h1n1 outbreak in the 1970s [70] . this pandemic also resulted in some valuable data studying and analyzing the mental health aspects of the outbreak. it was among the first outbreaks where policy reports included mental health as an aspect of preparedness and mitigation policy efforts. this outbreak of h1n1 was notable for dissonance between the public sentiment about the outbreak and the public health steps recommended and undertaken by who and national health institutions. general public sentiment was that of alarm caused by who releases and warnings, but it quickly turned to discontent and mistrust when the initial grim outlook of the outbreak failed to materialize [71] . health agencies were accused of creating panic ("panicdemic") and peddling unproven vaccines to boost the pharmaceutical companies (in 2009, some extra $1,5 billion worth of h1n1 vaccines were purchased and administered in the usa) [72] . this outbreak illustrated how difficult it may be to gauge and manage public expectations and public sentiments in the effort to mobilize a response. it also demonstrated how distilling descriptions of the impact of a complex public health threat like a pandemic into a single term like "mild," "moderate," or "severe" can potentially be misleading and, ultimately, of little use in public health approach [73] . ebola virus, endemic to central and west africa, with fruit bats serving as a likely reservoir, appeared in an outbreak in a remote village in guinea in december 2013. spreading mostly within families, it reached sierra leone and liberia, where it managed to generate considerable outbreaks over the following months, with over 28,000 cases and over 11,000 fatalities. a very small number of cases were registered in nigeria and mali, but those outbreaks were quickly contained [74] . ebola outbreak, which happened to be the largest outbreak of ebola infection to date, gained global notoriety after a passenger from liberia fell ill and died in texas in september of 2014, infecting two nurses caring for him, and leading to a significant public concern over a possible ebola outbreak in the usa [75] . this led to a significant public health and military effort to address the outbreak and help contain it on site (operation united assistance) [76, 77] . zika virus was a little known, dormant virus found in rhesus monkeys in uganda. prior to 2014, the only known outbreak among humans was recorded in micronesia in 2007. the virus was then identified in brazil in 2015, after an outbreak of a mild illness causing a flat pinkish rash, bloodshot eyes, fever, joint pain and headaches, resembling dengue. it is a mosquitoborne disease (aedes aegypti), but it can be sexually transmitted. despite its mild course, which initially made it unremarkable form the public health perspective, infection with zika can cause guillain-barre syndrome in its wake in adults and, more tragically, cause severe microcephalia in unborn children of infected mothers (a risk of about 1%) [78] . in brazil, in 2015, for example, there were 2400 birth defects and 29 infant deaths due to suspected zika infection [79] . zika outbreak is an illustrative case of the context of global transmission; it was transferred from micronesia, across the pacific, to brazil, whence it continued to spread [78] . it is also a case of a modern media pandemic; it featured prominently in the social media. in early 2016, zika was being mentioned 50 times a minute in twitter posts. social media were used to disseminate information, to educate, or to communicate concerns [80] . its presence in social media, perhaps for the first time in history, allowed social researchers to study the public sentiment, also known as the emotional epidemiology (ofri), in real time [81] . while both public health institutions and the general public voiced their concern with the outbreak, scientists and officials sought to provide educational aspect, while concerned public was trying to have their emotional concerns addressed. it is indicative that 4 out of 5 posts on zika on social media were accurate; yet, those that were "trending" and gaining popularity were posts with inaccurate content (now colloquially referred to as the "fake news") [82] . this is a phenomenon that requires significant attention in preparing for future outbreaks because it may hold a key not only to preparedness, but also to execution of public health plans that may involve quarantine and immunization. since 2016, zika has continued to spread throughout south america, central america, the caribbean, and several states within the usa. it remains a significant public health concern, as there is no vaccine and the only reliable way to avoid the risk for the offspring is to avoid areas where zika was identified or to postpone pregnancy should travel to or living in affected areas be unavoidable [78] . disease x disease x is not, as of yet, an actual disease caused by a known agent, but a speculated source of the next pandemic that could have devastating effects on humanity. knowing the scope of deleterious effects a pandemic outbreak can have on humankind, in the wake of the ebola outbreak, the world health organization (who) decided to dedicate formidable resources to identifying, studying, and combating possible future outbreaks. it does so in the form of an r&d blueprint, though devising its global strategy and preparedness plan that allows the rapid activation of r&d activities during epidemics [83] . r&d blueprint maintains and updates a list of so-called identified priority diseases. this list is updated at regular intervals and, as of 2018, it includes diseases such as ebola and marburg virus diseases, lassa fever, middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome (sars), nipah and henipa virus diseases, zika, and others [84] . for each disease identified, an r&d roadmap is created, followed by target product profiles (i.e., immunizations, treatment, and regulatory framework). those efforts are important to help us combat a dangerous outbreak of any of the abovementioned diseases, but also to fend off disease x. since disease x is a hypothetical entity, brought by a yet unknown pathogen that could cause a serious international pandemic, the r&d blueprint explicitly seeks to enable cross-cutting r&d preparedness that is also relevant for both existing culprits and the unknown future "disease x" as much as possible. who utilizes this r&d blueprint vehicle to assemble and deploy a broad global coalition of experts who regularly contribute to the blueprint and who come from several medical, scientific, and regulatory backgrounds. its advisory group, at the time, does not include mental health specialists [85] . the black death: the greatest catastrophe ever the great leveler: violence and the history of inequality from the stone age to the twenty-first century. chapter 10: the black death mortality risk and survival in the aftermath of the medieval black death an epidemiologic analysis of the ten plagues of egypt the noble qur'an surah thucydides' description of the great plague the plague of athens: epidemiology and paleopathology the thucydides syndrome: a new hypothesis for the cause of the plague of athens the thucydides syndrome: ebola déjà vu? 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periods the black death 1346-1353: the complete history medieval europe: a short history black death. simon and schuster the black death the air of history (part ii) medicine in the middle ages mixed metaphors. the danse macabre in medieval and early modern europe the theme of death in italian art: the triumph of death daily life during the black death communities and crisis: bologna during the black death nostradamus: the new revelations. barnes & noble books images of plague and pestilence: iconography and iconology the origin of quarantine lessons from the history of quarantine, from plague to influenza a. emerging infectious diseases cdc: remembering the 1918 influenza pandemic molecular virology: was the 1918 flu avian in origin? plagues & wars: the 'spanish flu' pandemic as a lesson from history pandemic versus epidemic influenza mortality: a pattern of changing age distribution contagion and chaos expressionist portraits is the 1918 influenza pandemic over? long-term effects of in utero influenza exposure in the post-1940 u.s. population america's forgotten pandemic: the influenza of 1918 the spread, treatment, and prevention of hiv-1: evolution of a global pandemic estimates of global, regional, and national incidence, prevalence, and mortality of hiv, 1980-2015: the global burden of disease study 2015 academy of consultation-liaison psychiatry, hiv psychiatry bibliography meta-analysis of the relationship between hiv infection and risk for depressive disorders cognitive behavioural therapy for adherence and depression in patients with hiv: a three-arm randomised controlled trial the last major outbreak of smallpox (yugoslavia, 1972): the importance of historical reminders shining light on "dark winter evaluating public health responses to reintroduced smallpox via dynamic, socially structured, and spatially distributed metapopulation models extracting key information from historical data to quantify the transmission dynamics of smallpox responding to global infectious disease outbreaks: lessons from sars on the role of risk perception, communication and management summary of probable sars cases with onset of illness from 1 was sars a mental health catastrophe? gen hosp psychiatry geographic dependence, surveillance, and origins of the 2009 influenza a (h1n1) virus in new theory, swine flu started in asia, not mexico. the new york times estimated global mortality associated with the first 12 months of 2009 pandemic influenza a h1n1 virus circulation: a modelling study risk factors for hospitalisation and poor outcome with pandemic a/ h1n1 influenza: united kingdom first wave assessing the severity of the novel influenza a/ h1n1 pandemic doctors rake in billions battling h1n1 flu by dalia fahmy. abc news reflections on pandemic (h1n1) 2009 and the international response the emergence of ebola as a global health security threat: from 'lessons learned' to coordinated multilateral containment efforts overview, control strategies, and lessons learned in the cdc response to the 2014-2016 ebola epidemic ebola outbreak in west africa military ebola mission in liberia coming to an end zika: the origin and spread of a mosquito-borne virus the microcephaly epidemic and zika virus: building knowledge in epidemiology propagating and debunking conspiracy theories on twitter during the 2015-2016 zika virus outbreak the emotional epidemiology of h1n1 influenza vaccination spreading the (fake) news: exploring health messages on social media and the implications for health professionals using a case study who: r&d blueprint, about the r&d blueprint who: r&d blueprint, scientific advisory group members key: cord-016285-cwhmm3f6 authors: nan title: challenges to the european exception: what can s&t do? date: 2006 journal: a new deal for an effective european research policy doi: 10.1007/978-1-4020-5551-5_1 sha: doc_id: 16285 cord_uid: cwhmm3f6 nan a quick review of the available evidence shows, however, that, while great strides have been made over the past few decades towards the achievement of these goals, europe is facing significant challenges in most if not all of these areas. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. this is undermining what europeans are most proud of and turning europe into a negative exception at global level. the term "european exception" is most often used to refer to a european country not acting in accordance with what most other european countries are doing, whatever the field. sometimes, however, the vocabulary is also used to refer to how europe behaves differently from other advanced world economies. usually, reference to the european exception has a positive tone to it. europeans are proud of their commonly held values, their social model based on egalitarianism and solidarity, their high level of environmental awareness and protection and so on. however, europe appears to be the only advanced economy suffering from chronic low growth and high unemployment, and an unceasing lack of dynamism. its levels of poverty and of individual and regional income inequality are not that far removed from us levels. and this makes europeans feel anxious, and unsure of themselves, their future and further european integration. significant change has characterised the world economy over the past few decades. world trade has been liberalised as both formal and informal trade barriers have been reduced significantly, or disappeared altogether. capital roams the planet freely in search of the best investment opportunities as barriers to capital mobility have been eliminated. global communication and transportation networks have become denser and better integrated through a combination of technological and organisational innovation. the speed of technological change has accelerated while technologies are standardised more rapidly and use is made of modular production systems. as the combination of these factors has made it possible to locate the production of goods and services anywhere on the planet and still serve global markets, the global production system is in the process of being reconfigured. the new international division of labour not only provides both developing and developed countries with ample opportunities, it also has shady sides. on the one hand, low-, medium-and to an increasing extent high-technology manufacturing and services industries are under threat from delocalisation or so-called off-shoring and outsourcing, resulting in at least short-term disruption and unemployment. employment is also under threat from rapid process innovation leading to productivity increases. 2 on the other hand, rapid product innovation provides developed countries with opportunities to improve competitiveness and serve global markets by fleeing forward as it were. the race to upgrade the economy is never-ending, however, and innovation-based advantages are fleeting and unsustainable as rapid standardisation and modular production techniques quickly allow the production process to move partially or completely to developing countries. as reflected in its lacklustre economic growth performance, europe has not yet adapted to the rules of this new game. in the first half of the post-war period, the european economy grew as fast as the world economy ( fig. 1.1) . 3 in the second half of the post-war period, however, the decline in economic growth was more pronounced in europe than in the united states, japan and other oecd economies (figs 1.1 and 1.2) . in the last 15 years or so, europe has done worse than the united states, while japan has once again started to outperform europe, and the large bric (brazil, russia, india, china) economies and smaller east asian economies continue to grow rapidly. 4 the growth of output amounted to 1.3 per cent in the euro area in 2005, substantially lower than the 3.5 per cent in the united states and the 2.7 per cent in japan, and the 4.8 per cent at world level. output is projected to grow by a higher 2.0 per cent in the euro area in 2006, still economic growth in the euro area has been lagging that of the best performing oecd countries since the mid-1990s. it should be acknowledged, however, that some eu countries have performed rather well economically in the past decade. this group includes the member states formerly classified as cohesion countries (especially ireland), as well as finland, the netherlands and the uk. year cumulative growth gap fig. 1.2 . slow european economic growth in the second half of the post-war period compared to other industrialised countries (cumulative economic growth gap between the eu and the other industrialised countries (current prices and current ppps)) source: dg research data: oecd note: for both the eu-15 and the non-eu-15 oecd countries, 1974 gdp at current prices and current ppps (billions of dollars) was taken as 100. for all following years, gdp growth in percentages relative to the 1974 amount was calculated. then the series for the non-eu15 oecd countries (australia, canada, iceland, japan, korea, mexico, new zealand, norway, switzerland, turkey, us) was set to 100 and the difference with the series for the eu-15 calculated. significantly lower than the 3.4 per cent in the united states and the 2.8 per cent in japan, and the 4.9 per cent at world level. 5 whenever europe has been able to increase productivity in the past it has suffered in the field of employment, and vice versa, pointing to the existence of structural barriers to growth. 6 underlying europe's lacklustre economic growth performance is its weak competitive position. the most common definition of competitiveness refers to the overall capacity to improve standards of living in a sustainable way. 7 states during the 1950s and 1960s. but since the 1970s, european standards of living have not increased relative to the united states ( fig. 1.3) . 8 labour productivity is another common measure of competitiveness. though, except for a few countries, the productivity gap was never closed in the end, for most of the post-war period the eu somehow caught up on average with the united states. 9 this catch-up has now stopped and is even being reversed. since 1995, for the first time in three decades, growth in us labour productivity has outstripped that of the union (fig. 1.4) . 10 this eu productivity downturn is of a structural nature and mainly due to an outdated and inflexible industrial structure slow to adapt to the intensifying pressures of globalisation and rapid technological change. 11 deindustrialisation is often taken as a further sign of europe's deteriorating competitiveness. the fear is that slow labour productivity growth, high labour costs, 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 year gdp per capita (us=100) eu15 euro area fig. 1 and short and inflexible working hours drive entire industries to low-cost, hightech countries in eastern europe and asia. the evidence for deindustrialisation is not clear-cut. some analyses point out that industry still accounts for the same important share of gross domestic product in terms of volume as in the past, while the declining share in terms of value added and employment is due simply to decreasing prices because of productivity gains and exposure to competition higher than that for services. should it occur, the impact of deindustrialisation would indeed be worrying: the existence of many services depends on the presence of industry; industry pays better wages than services, even for low-skilled jobs; industry accounts for most innovations and technological revolutions; and industry has an important strategic role. 12 europe's feeble competitive position is also clear from its weak trade performance, especially that at the high-tech end. europe's most dynamic export products are generally not those one would closely associate with the knowledge-based economy. the top three products with the fastest growing market share are floor coverings, pork and poultry fat, and hemp. on the other hand, if one looks at products for which market share is in major decline (> 10 per cent loss in market share), the eu has many more (345 product groups) than the united states (65) or japan (90). what is more, in europe many technological products are among them (e.g. air launchers, turbines, insulating glazing, drugs containing alkaloids or hormones, telephones, photographic film). 13 high-tech manufacturing exports represent a much smaller proportion of total manufacturing exports in europe than in the united states or japan (in 2002, 19.7 per cent vs. 28.5 per cent and 26.5 per cent respectively). 14 europe's share of global high-tech manufacturing exports, though increasing, is lower than that of the united states (in 2002, 16.7 per cent vs. 19.5 per cent respectively). 15 and europe runs a structural deficit in high-tech manufacturing trade, whereas the united states and japan run surpluses. 16 the european employment input is significantly lower than that in the united states. first, though apparently catching-up, the european employment rate is still substantially lower than that of the united states ( fig. 1.5 ). in 2004, the eu-25 employment rate was 63.3 per cent and the eu-15 one 64.7 per cent, so 6 to 7 percentage points below the target under the lisbon agenda, compared to 71.2 per cent in the united states. 17 this is mainly due to the limited participation of women, the young, and the elderly in the labour force. at 55.7 per cent and .0 per cent, the female and older people's employment rates were about 4 and 9 percentage points below the lisbon targets for 2010. 18 second, europe also scores lower than the united states in terms of the number of hours worked annually per employee ( fig. 1.6 ). 19 for a long time, the low employment rate and number of hours worked annually per employee were explained with reference to the european emphasis on work-life balance. a growing number of authors draw attention to the existence of disincentives to work, however, the main one being the lack of employment opportunities. 20 this lack of employment opportunities is clear from the high unemployment rates. in 2004, about 19.4 million europeans were out of work. this equalled 9.0 per cent of the labour force, some 4 percentage points higher than the rates in the united states and japan ( fig. 1.7) . 21 the proportion of high-level jobs is also considerably lower in europe than in the united states. 22 though europe likes to pride itself on its superior social model, poverty rates are rather high, and regional inequality is substantial. in 2004, the at-risk-of-poverty 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 year eu-15 24 the gini coefficienta number between 0 and 1 used to express the degree of income inequality, where 0 corresponds to perfect income equality and 1 corresponds to perfect income inequality -was 0.30 in both the eu-15 and the eu-25 ( fig. 1.8) . 25 the share of children living in households with income below the poverty line ranges from 7 per cent in slovenia and 9 per cent in denmark to 30 per cent in slovakia. 26 28 the eu is also marked by substantial inequality in income levels. in 2002, gross domestic product (gdp) per capita was below 75 per cent of the eu-25 average in 63 out of 254 nuts 2 regions examined in the eu-25. 29 the highest 28 eurostat. 29 at the beginning of the 1970s, eurostat set up the 'nomenclature of statistical territorial units' (nuts) as a single, coherent system for dividing up the european union's territory in order to produce regional statistics for the community. nuts subdivides each member state into a whole number of regions at nuts 1 level. each of these is then subdivided into regions at nuts level 2, and these in turn into regions at nuts level 3. leaving aside regional gross domestic product per capita (inner london -united kingdom) was about 10 times the lowest one (lubelskie -poland). enlargement, for the european union, is at one and the same time a challenge and an achievement, a "raison d'être" and a "façon d'être". it is a continuation of the historical process that started over 50 years ago with the communities' inception, developed through several steps (in 1973, 1981, 1986, 1991, 1995) , and reached a high point -albeit not an end-point -with the enlargement of the european union to 10 countries of eastern and southern europe on 1 may 2004. preparation for that enlargement took several years and by the time they joined, the eu-10 had successfully transformed their economies from centrally planned to functioning free market ones. compliance with the copenhagen criteria for accession served as a powerful catalyst for change. this assessment is detailed in a recent stock-taking exercise in which the commission services have provided strong evidence and analyses indicating that the 2004 enlargement constitutes an economic success for the "old" and the "new" member states alike. 30 it has to be noted that enlargement has been a dynamic process rather than a discrete event and that its effects will become visible over time. figure 1 .9 shows that convergence and catching up in real income have been at work throughout the period since the late 1990s. per-capita incomes are now much closer to eu-15 levels than they were in 1997, the year in which enlargement prospects crystallized in the commission's agenda 2000. after the output collapse in the early years of transition, growth rates in the eu-10 have been higher than in the eu-15, but also more volatile. the key contributors to actual and potential economic growth in the eu-10 have been capital accumulation and technical progress (the so-called total factor productivity, tfp), while the contribution of labour has been mostly negative (that being a reflection of weak employment growth and, to a lesser extent, of an ongoing decline in hours worked per employee). in general, and consistent with the convergence hypothesis, member states with lower initial (1997) per capita income tended to grow faster in the intervening years. birth rates continue to be low in europe. 31 everywhere, the fertility rate is below the threshold needed to renew the population (around 2.1 children per woman), the local level (municipalities), the internal administrative structure of the member states is generally based on two of these three main regional levels. this existing national administrative structure may be, for example, at nuts 1 and nuts 3 levels (respectively the länder and kreise in germany, or at nuts 2 and nuts 3 (régions and départements in france, comunidades autónomas and provincias in spain). 30 of aids deaths was estimated at 3.1 million. 38 in europe, the number of newly reported hiv infections is increasing, while that of newly diagnosed aids cases is decreasing. in the 17 eu countries with data available for 1996 and 2003 for both hiv infections and aids cases, the number of newly reported hiv infections increased by almost 75 per cent (from 7641 to 13,257) while the number of newly diagnosed aids cases fell by over 55 per cent (from 4 085 to 1 772). 39 europe is also affected by other communicable diseases including sars and avian influenza. one of the most worrying challenges for europe, and indeed for the whole world, concerns the deterioration of the environment. european citizens overwhelmingly agree that the state of the environment influences their quality of life (72 per cent), that policy-makers should consider the environment to be just as important as economic and social policies (85 per cent), and that policy-makers should take into account environmental concerns when deciding policy in other areas such as the economy and employment. 40 "a high level of protection and improvement of the quality of the environment" is a european community objective (see above). europe has been implementing environmental action plans and pursuing sustainable development strategies at both national and european level for quite some time now. it plays a leading role in the fight against global warming. 41 and it occupies a strong position in the field of environmental technologies. yet, because of population growth; consumption patterns; market, policy and political failures; features of existing technologies; and world views and values, europe and the world at large are still far removed from a development trajectory that is truly sustainable, that is, which satisfies the current needs of society (growth, competitiveness, employment, etc.) without compromising the needs of future generations. 42 european citizens worry most about water pollution (of seas, rivers, lakes, underground sources, etc.) (47 per cent); man-made disasters (major oil spills, industrial accidents, etc.) (46 per cent); climate change (45 per cent); and air pollution (45 per cent). 43 the sixth environment action programme of the european community 2002-2012 (6 th eap) identifies four priority areas for urgent action: (1) climate change; (2) nature and biodiversity; (3) environment and health and quality of life; and (4) resources and waste. the environmental objectives of the eu sustainable development strategy include: (1) addressing climate change; (2) better management of natural resources; and (3) making transport more sustainable. a 2004 review of nine recent comprehensive analyses of global environmental problems (table 1 .1) showed near-unanimous agreement that the three problems posing the greatest threats to the global environment and continuing economic development include: (1) water quality and access; (2) climate change; and (3) loss of biodiversity. 44 climate change forecasts indicate that, if the level of emissions is not curbed, the temperature level will rise and risks such as water shortage, malaria and hunger will increase and affect millions of people by 2080 ( fig. 1.11 ). addressing such environmental problems is highly complex. one of the premises of sustainable development is that environmental problems interact with each other, as well as with economic and social issues. climate change affects agriculture, forestry, water availability, marine systems, terrestrial ecosystems, health and, last but not least, the economy. forests and oceans act as climate regulators but also harbour a wide diversity of species. decisively tackling the issue of biodiversity will require i.a. making forestry sustainable, addressing pollution, and dealing with climate change. pollution negatively affects health, from allergies and infertility to cancer and premature death. in the mid-1990s damage costs to the eu caused by air pollution originated in the eu (see table 1 .2) were calculated to be around 2 per cent of eu gdp (ranging from 0.3 to 3.2 per cent) and damages to eu and non eu countries caused by air pollution originated within the eu were estimated to be 2.6 per cent of eu gdp (with ranges between 0.4 and 6.9 per cent), with health damages accounting for the largest share. 45 an animal and human health problem like aviary flu also constitutes a threat to biodiversity. environmental degradation contributes to the increase recorded in the number of disasters and, in relation to this, to a heightened sense of vulnerability (see fig. 1 .13 in the last section of this chapter). disasters can be man-made or natural and include wildland fires, earthquakes, volcanic eruptions, landslides/debris flows, floods, extreme weather, tropical cyclones, sea and lake ice, coastal hazards including tsunamis, pollution events, and so on. during the period 1990-1999, disasters killed 500,000 people and caused 750 billion dollars of damage. throughout history, the relation between science and society has been marked by both continuity and change. 46 the continuity is situated in the tension between the c h a p t e r 1 philosophical and intellectual pursuit of and search for knowledge on the one hand, and the desire of researchers and their supporters to make scientific knowledge useful and apply it on the other hand. this tension was first recognised by the ancient greek philosophers, and has been reflected in recurring calls from philosophers and scientists throughout history, including today, for more "research for its own sake". within the context of this tension, the change has been located in what has constituted or better what has been considered useful knowledge in each age, in other words in "the changing social expectation of science": "what counts as useful knowledge differed from patron to patron and society to society, so that cosimo de medici and the united states department of energy looked for quite different 'products' to be created by their clients, but both traded support for the potential of utility". from century to century, societal expectations of s&t have not just changed. they have also increased. in the era of the ancient greek philosophers, societal expectations of s&t were rather low. s&t was a highly controlled activity carried out by a small elite group of people for philosophical or religious objectives. at present, however, it is considered a powerful tool for political, economic, and social change. in between, s&t helped exploit worldwide resources as trade empires and colonies expanded (18th century); helped expanding and consolidating trade empires and colonies, and turn their natural resources into wealth, or make up for the lack of trade empires and colonies (19th century); helped fight wars (first world war and second world war); and helped producing consumer goods, consumer medicines, exploring space, addressing environmental challenges, exploring the human genome, and so on (post-war period). it is no exaggeration to say that as a result today societal expectations of s&t have never been higher in industrial countries. in the united states, the carnegie commission on science, technology, and government listed in 1992 no less than 25 major societal goals to which s&t can contribute (table 1. 3). and a national academies report noted in 2005 that "the nation increasingly looks to the scientific and engineering communities for solutions to some of its most intractable problems, from chronic disease to missile defence, to transportation woes, to energy security, to ensuring clean air and clean water. expectations for s&t are perhaps higher than at any other time in our history and are placing unprecedented demands on leadership". 47 needs of society as they change over time, or in other words, to become a 'science and technology for society' ". 48 things are no different in europe. in 2000, the european commission remarked that "expectations of science and technology are getting higher and higher, and there are few problems facing european society where science and technology are not called upon, one way or another, to provide solutions". 49 out of the challenges europe is facing, and recommendations have been made on how to address them. time and again the same wide range of urgently to be addressed challenges is identified. the reports are also near-unanimous in the key role assigned to s&t in this respect, as will be seen in chapter 3. in other words, great expectations are held of s&t as regards the tackling of the multitude of challenges europe is facing. this will be developed in chapter 3 as part of the new policy context that enabled the genesis of the lisbon strategy as well as of the 7th framework programme. the role that s&t can play in addressing all these challenges is expected to be substantial. this section will show that s&t indeed has the potential to contribute to a range of economic, social and environmental challenges: it can improve economic performance, promote employment, improve public health, tackle demographic, cohesion and environmental challenges, and so on. modern mainstream economic theory -whether neoclassical, endogenous or evolutionary -has recognised for quite some time now that technological progress and innovation are the main engines of economic growth. according to baumol, innovation explains much of the extraordinary economic growth record under capitalism. the reason is that in important parts of the economy, competition is based on innovation rather than price. firms are therefore forced by market pressure to support innovative activity systematically and substantially. 50 according to romer, productivity growth is driven by innovation resulting in the creation of new though not necessarily improved product varieties. 51 and under the schumpeterian paradigm, growth results from "quality improving innovations that render old products obsolete, and hence involves the force that schumpeter called 'creative destruction' ". 52 even basic research generates several direct economic benefits. it is a source of useful new information; it creates new instrumentation and methodologies. those engaged in basic research develop skills which yield economic benefits when individuals move from basic research carrying codified and tacit knowledge. through participation in basic research, access is granted to networks of experts and information. those there is also empirical support for the contribution of s&t to economic performance (see tables and sources in annex). estimates of private returns to firms' own investment in r&d still produce varying figures, but there is an emerging consensus that gross returns between 20 and 30 per cent are common and plausible (table 1.4) . microeconomic studies confirm the existence of significant spillovers of knowledge from the firms that perform the r&d to other firms and industries. taking account of measured spillovers typically raises the estimated gross rate of return on business investment into the range of 30 to 40 per cent (tables 1.5-1.7) . macroeconomic studies, which by definition cover all sectors of the economy, also find significantly higher returns to r&d in oecd countries, with estimates ranging from 50 per cent to over 100 per cent. a recent austrian report found that the rise of corporate spending on r&d from 0.8 per cent to 1.1 per cent of gross domestic product in the second half of the 1990s produced a boost of three tenths of a per cent in growth. 54 both microeconomic and macroeconomic studies find that an important source of productivity growth in all oecd countries comes from the international diffusion of technology. a country's ability to absorb those foreign technologies is enhanced by investment in education and by investment in own r&d. the economic literature is not conclusive on the employment effects of innovation, since process innovation (the introduction of labour-saving technologies) is likely to have a negative effect on employment, assuming all other factors remain constant, while product innovation creates new markets and employment opportunities. 55 but empirical evidence suggests that technological change promotes employment. such evidence includes a recent study of the directorate-general employment which found that the rate of growth of total factor productivity (due to improvements in the efficiency of production or to pure technological progress) has a positive impact on the employment rate, with a one-year lag, and that both in the short-and long-term, countries with higher than average total factor productivity growth tend also to have higher than average growth in employment. 56 clear evidence exists that more computerised or r&d-intensive industries increased their demand for college-educated workers at a faster rate in the 1980s. such high-skilled workers also command higher wages, as the consensus is that the increase in the schooling wage premium and the rise in wage inequality are driven by technological change. 57 support also comes from the observation that all member states saw employment levels in the high technology sector rise between 1997 and 2002, leading to an increase of almost 2 million for the union as a whole, with employment in high-tech services accounting for 1.4 million of this total (fig. 1.12) . 58 through its contribution to product, process and service innovation, productivity growth, and the creation of more and higher paid jobs, research and innovation can also help meet the challenges of ageing and cohesion. higher employment rates and levels of productivity -to which s&t can contribute -would allow for maintaining or increasing living standards, and for the absorption of increasing medical and pension costs. doubling the growth of productivity over the next few decades would allow for maintaining current levels of industrial production and average per capita income with some 40 million elderly in the eu. 59 the best solution to poverty is investing in education. 60 for instance, in general the lower the illiteracy rate, the higher per capita income. 61 higher levels of educational attainment enhance the chance of finding work and enjoying a decent standard of living. however, education is not yet accessible for everyone and often only to those who can afford it. improving access to educations takes time and effort. education is, therefore, in its own right not powerful enough to solve the poverty problem. in the meantime, contributions to a solution to poverty can also be expected from science and technology. besides investing in education and developing skills, this means dedicating research programmes to find ways to fight inner-city poverty, to relieve the effects of urbanisation, to diminish the impacts of ever increasing mobility on our environment, and to improve the quality of life of the vulnerable groups in society, such as the handicapped and the ill, the elderly and the young. in developing countries this can take the form of helping to improve the productivity of natural and physical assets, for example, by protecting farmland against erosion and desertification, preserving an area's natural resources, building easy-tomaintain water storage facilities and de-salinisation installations, and strengthening farmers' diagnostic capabilities in relation to livestock diseases, to name a few. 62 that these advances have important impacts on farmers' income levels has been repeatedly demonstrated by the different targeted activities across the framework programmes. 63 science and technology can also make a large contribution to the improvement of public health. it can assist in prevention (e.g. through the development of vaccinations), it can play an important role in the quicker and more reliable diagnosis of diseases (e.g. through the further development of medical imaging), and it can find treatments for diseases or, in the absence of treatments, it can help finding ways to control them (e.g. hiv/aids retroviral drugs). s&t can also help to lessen the impact of disease. furthermore, s&t can help to find new ways to deliver treatment (e.g. ambulant rather than hospital treatment) and can provide better tools for health care system management. a good illustration of the way in which science and technology can make a positive contribution to public health is the article 169 edctp 64 initiative referred to in chapter 4. it is also useful to take a step back here. globalisation in this regards also means the globalisation of infection transmission. as travel of people (and goods) intensifies, communicable diseases constitute challenges which it is increasingly difficult to confine. interconnectedness is a defining feature of our modernity. as a case in point, healthcare systems are indeed organised as systems -which can lead to catastrophic failures such as the consequences of hiv-infected blood supplies that took a particular prominence in france but did in fact strike many countries. ours is a vulnerable society. while that vulnerability is most strikingly epitomized by ebola-type viruses, with diverse profiles of outbreaks, it is also revealed through 62 world bank, world development report 2000/2001. 63 the international s&t cooperation with third countries (inco) is one of those programmes which have been developed around the idea that poverty can be overcome by successfully developing human and institutional resources. 64 european and developing countries clinical trials partnership. the rise of nosocomial infections (i.e. ills originating in the very places which are devised to heal). these further illustrate the flipside -or paradoxical unanticipated consequences -of healthcare as interconnected systems. yet, while avian flu and sars together with the above examples represent the globalisation of infection transmission, they also point to the globalisation of the means to tackle public health challenges. the relative containment of avian flu and sars, and even more so the eradication of smallpox (the variola virus), constitute inspirational successes in that regard. there is no doubt that the solution to the environmental challenge has to come first and foremost from elsewhere than from new technological development. available technological best practices should first of all be disseminated as widely as possible. a change of mentality is also required leading to less consumption of more carefully selected resources and increased reuse and recycling within the limits of the current technological frontier. yet it does not seem unjustified to expect a contribution from new technological development. technology is already used in a variety of ways when it comes to the environment, and everywhere there is great scope for improvement. technology in the form of satellites is used to monitor the global environmental situation and change therein. technology in the form of super computers is used to develop climate models and make predictions. technological development has made industrial production less resource intensive. it has also reduced the energy consumption of machinery (e.g. cars). s&t has been successful at developing alternatives for harmful substances (e.g. within the context of fighting ozone depletion). technological development has increased the extent to which a larger variety of goods can be recycled. the production of green energy is wholly dependent on technological development. and s&t is needed to mitigate the impacts of environmental degradation. this need for a joint undertaking -combining existing technologies, technological innovations, as well as political innovations -is illustrated in fig. 1 .13 in the case of climate change (the fight to curb greenhouse gas emissions, that is). as the next chapter will further examine, s&t is not only an indispensable source for the evidence base on challenges such as environmental degradation, they are also taken to be one of the causes of such predicaments. one can undoubtedly point to the lack of societal controls on the use of s&t, to environmentally harmful production and consumption patterns, and to other types of failures in this regard. nonetheless, the outlook can change fundamentally if one can conceive of s&t as part of the solution rather than the problem. the "precautionary principle" is a useful notion to mark that double perspective. it can first be taken as stifling innovation in the name of environmental protection; but more interestingly, it can be understood as promoting innovations that take account of social and environmental difficulties, taking account of risks as well as benefits, taking account of less tractable, longer-term consequences. its emphasiseven with its origin in german environmental legislation in the 1970s -was as much on environmental protection as on gaining a competitive advantage through innovations on the backdrop of environmental regulation. indeed, although this remains a fiercely debated question, a recent survey of the literature 65 indicates that a transparent and non-discriminatory regulatory framework, coupled with high environmental standards, is an engine for innovation and business opportunities. this engine functions notably through the creation of lead markets. 66 the story of the catalytic converters provides a compelling example of such r&d-based win-win. a first step in that perspective consists in acknowledging the need to sever the link between economic growth and environmental degradation. the endeavour of a duly responsible polity -with a concern for the quality of life of present and future generations -is then to optimise the effects of its economic activity, that is to minimise adverse externalities without sacrificing part of its material well-being or endangering economic growth. 65 a second step consists not in ignoring the above "limits to growth" understanding, but in researching other links between development and sustainability. this move is at the heart of the role of s&t in relation to the environment -and is indeed at the heart of the lisbon strategy as underscored in the conclusions of the 2001 göteborg summit. the potential of technology to create synergies between environmental protection and economic growth was emphasised by the october 2003 european council. that well-established premise is taken to its most fruitful operational conclusions in the environmental technologies action plan. 67 more recently, the benefits of s&t for the economy and environment alike were further examined in the "towards a more sustainable eu" report for the dutch presidency and indeed in the kok report of november 2004. 68 in fact europe occupies a strong position in the field of environmental technologies. of course this also relates to the fragile but powerful synergies, introduced above, between environmental promotion/protection, s&t, and growth and competitiveness. these potential benefits can also be of great importance for developing countries. with appropriate technology transfer they can provide these countries with affordable solutions for reconciling their desire for strong economic growth with the need to do so without increasing the pressure on the local -or the globalenvironment. this north-south dimension highlights the sustainable development predicament as differentiated yet common. the question of sustainable development can be posed along two main lines: a question of adapting -or otherwise innovating -appropriate "clean" technologies, and a question of redefining needs and lifestyles. now it is interesting to re-consider the climate change issue in the light of the above remarks. the european union has taken a leading role in the international process to tackle global warming so as to promote environmentally responsible choices by all actors. the eu has ratified the kyoto protocol early on, joined by almost all of its international counterparts on this course -most recently russia. its successes are also the planet's successes. the eu is committed to meet its kyoto emissions reduction targets 69 and continues to show leadership on this issue. the role of s&t is set to become even more central in the post-kyoto (post-2012) regime, for which negotiations are starting now. the need for new and cleaner technologies as an indispensable means to tackle energy demands and co 2 emissions was the main message of the latest yearly report of the more widely, s&t plays an important part in the eu's capacity to shape -and implement -international agreements. by way of conclusion, it is worthy of note that the answers which science and technology can bring to environmental problems are increasingly judged with reference to the changes they bring in society. they demand choices of policies and governance, the impact of which on economic and social groups must be measured in terms of effectiveness and efficiency, the spread of costs and benefits, and social or regional equity. this is only possible if research also seeks to develop the knowledge-base and methodologies needed by such analyses. the ultimate answer? the ultimate challenge? as the previous discussion of the contribution of s&t to employment or environmental challenges has shown, it is not always clear-cut where problems start and where solutions end. or to put these tangled matters even more simply in this case: the role that s&t can play is manifold. and nowhere is this manifoldness better encapsulated than in the predicament of the "knowledge society". 71 here the challenges, the expectations, and indeed the role of s&t in eliciting and addressing them, are brought together in ways that it is most illuminating to examine. first, this section probes the mutual shaping of science and culture. second, it foregrounds some collateral features of the knowledge society, and in particular the vulnerability that accompanies its emergence. this will lead up, in chapter 2, to a discussion of our modernity -or modernities -as characterised by a distribution of goods but also of ills or risks, and of knowledge or claims thereon. indeed, in this subsequent chapter, the problematic and ambivalent relations between s&t and the public at large will be considered in the perspective of the weaknesses of european s&t. but firstly we must examine the crucial place of s&t within our knowledge society in the making. the mutual shaping of culture and s&t the examples in this chapter have already shown how profoundly our culture is marked by s&t developments. at the same time as s&t shapes our society, they are themselves produced, taken up, reconfigured, shaped by society. that is one (double) way in which culture is decidedly scientific culture, and thus in which s&t is at the heart of this nearly eponymic "knowledge society". but to allow all sections of society to benefit from those advances -as well as to take part in that shaping process -individuals need to be provided with the appropriate equipment, in terms of education, skills, awareness, and appreciation for the stakes in s&t endeavours. vital for a democratic society 71 in this day and age, such demands point towards another crucial sense for scientific culture, also exposing the acute need for it to be developed. actions to foster a thorough public grasp of what is science and how it contributes to society are thus sine qua non to a full-fledged democratic society. importantly, s&t developments accompany and affect lifestyle changes in societies. in this respect the taking up of mobile phones or gsm provides interesting illustrations. 72 the gsm has strikingly changed the way people communicate with their loved ones, organize their work and outings, and live everyday. as regards research, innovation, and competitiveness, the rise of the gsm standard provides an inspiring example of european leadership. 73 in effect, new information and communication technologies open up opportunities for new lifestyles and new ways of working. 74 remote working or online trading decouples economic activity from a particular geographic location (be it the office, capital cities or structurally favoured regions). moreover, such technologies can facilitate access to employment -and other forms of social inclusion/participation 75 -among sections of society (people with physical disabilities, the elderly) who may otherwise be excluded. key to achieving those benefits is ensuring that people are equipped with the necessary skills to get involved. much information society literature 76 also hypothesises that "ework" (remote working) may contribute to environmental sustainability as, in addition to other dematerialisations, travelling to work is reduced. on the other hand, transport technologies themselves -from the wheel through to the airplanecontinue to have a central role in society, for example in enabling communication. the quality of human life is made up of many more components than the ones already mentioned: greater access to knowledge, better nutrition and health services, more secure livelihoods, clean air to breathe, security against crime and physical violence, satisfying leisure hours, political and cultural freedoms and sense of participation in community activities. s&t can contribute to improvements and bring lasting solutions in each of these areas. for example, investment in research and new technologies to achieve sustainable transport solutions generates desirable impacts on the quality of life worldwide: less energy consumption; fewer air pollution; less respiratory diseases; lower noise levels; increased space and security for pedestrians and cyclists resulting in more friendly cities for children and older people; less congestion; fewer road accidents; and so on. besides, it is s&t which makes possible the novel lifestyles -and indeed the novel societydiscussed above. it may be that, in solving some age-old problems, s&t has created the possibility for new problems to emerge. yet even to address these new problems we can hardly do without s&t. but we can -and rightfully do -concern ourselves with the consequences of the solutions we devise. the vulnerable society and the knowledge society s&t has brought a mix of benefits and risks. in the modern world heightened wellbeing and security are accompanied by increased vulnerability and insecurity. this vulnerability can take many forms, from loneliness or travelling accidents to industrial disasters or the twisting of human rights in a totalitarian state. fig. 1 .14 provides an illustration of the rising challenge represented by disasters. here "disasters" include both technological and natural events. 77 the dramatic increase shown on the graph may be due not only to the consequences of concentrated urbanisation, climate change, and so on, but also to a heightened sense of vulnerability and risk, together with a better ability to measure disasters. hence the emerging knowledge society will have its problems too. besides, it will not depend solely on s&t but also on governance and on the citizens who will make up our society -and shape it. yet it is characterized by an increasingly pivotal role for s&t. the knowledge society requires a revolution in our understanding of knowledge: not only with regard to s&t researchers, but also concerning a democratisation or broadening of knowledge production. 78 this has profound implications for decision-making, for the lay-expert divide, for the handling of risks and uncertainties, and indeed for the relations between citizens and institutions of governance, as every individual should be recognized as -and given the means to be -a person of knowledge. europe finds itself in a peculiar situation in this regard, and the following chapter will unpack the paradoxical relations between s&t and its citizen. this chapter has explored in greater detail some important economic, social and environmental challenges europe is facing, the expectations held of s&t in addressing these challenges, and the role that s&t could potentially play. the 7th framework programme was designed against the background of europeans feeling anxious because the continent is experiencing a number of important economic, social and environmental challenges -or indeed against the background of a europe turning from a positive into a negative "exception" at global level. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. as will be further examined at the end of chapter 2 and in chapter 3, expectations of s&t have never been higher than they are now. such expectations held of s&t are partially justified. s&t can indeed play an important role in addressing societal economic, social and environmental challenges. s&t is the engine of economic growth and competitiveness. the employment effects of s&t are positive. s&t can play a major role in addressing the consequences of ageing, and the cohesion and public health challenges. s&t can play a key role in addressing environmental challenges. s&t is part and parcel of our lives, be they framed in a knowledge society or otherwise, and they are the linchpin of the latter's emergence. however, as will be seen in the next chapter, for s&t to be able to realise its potential, some serious s&t weaknesses will have to be addressed. united nations research institute for social development, information and communication technologies and social development in senegal: an overview/les technologies de l'information et de la communication groupe spécial mobile" hosted by the european conference of postal and telecommunications administrations, and its specifications where defined by the european telecommunications standards institute in the late 1980s. commercial operation began -and the world's first gsm phone call was made european foundation for the improvement of living and working conditions & prest european commission, dg jrc -institute for prospective technological studies impact of ict on sustainable development key: cord-308821-j4vylbhy authors: martin, r. title: the role of law in pandemic influenza preparedness in europe date: 2009-03-04 journal: public health doi: 10.1016/j.puhe.2009.01.002 sha: doc_id: 308821 cord_uid: j4vylbhy the european union (eu) is composed of 27 states with widely varying histories, economies, cultures, legal systems, medical systems and approaches to the balance between public good and private right. the individual nation states within europe are signatories to the international health regulations 2005, but the capacity of states to undertake measures to control communicable disease is constrained by their obligations to comply with eu law. some but not all states are signatories to the schengen agreement that provides further constraints on disease control measures. the porous nature of borders between eu states, and of their borders with other non-eu states, limits the extent to which states are able to protect their populations in a disease pandemic. this paper considers the role that public health laws can play in the control of pandemic disease in europe. the 27 states of the european union (eu) form a political and economic community with supranational and intergovernmental responsibilities, and constitute a single market that seeks to guarantee the freedom of movement of people, goods, services and capital between member states. the emergence or re-emergence of diseases such as severe acute respiratory syndrome (sars) and tuberculosis highlighted the need for eu-level health policy, and led to the community action programme 2003-2008 in the field of public health. this programme is now the cornerstone of community public health strategy, focusing on health information and on the community's capacity to react to health threats. in the context of disease control, the executive arm of the eu, the european commission (ec), has responsibility for the co-ordination of epidemiological surveillance of disease between member states and for regulating matters such as case definitions, disease notification and development of disease networks across europe. the ec is assisted by the european centre for disease control (ecdc), which issues protocols on matters of disease reporting and communication of disease information between states and to the ec. the ec and ecdc can only recommend appropriate disease control measures to states. neither is responsible for the management of disease protection and control in individual states. public health powers in relation to disease lie with national governments. it is member states, not the eu, which are signatories to the revised international health regulations (ihr) 2005, although the ihr recognize the role of 'regional economic integration organizations' such as the eu. a thus, if the world health organization (who) were to recommend under the ihr measures falling within eu legislation, such as restrictions on the movement of goods or the processing of personal data, b the eu would need to act collectively, at the initiative of the ec, as member states would be unable to take unilateral action. otherwise, ihr responsibilities lie with individual states. in 2007, a report on pandemic influenza preparedness in the eu 1 noted that substantial progress had been made in preparing for a possible pandemic influenza, but it remained the case that disease control operated at national level. despite encouragement from the eu towards harmonization of approaches, european national plans vary widely in the strategies they have adopted and the public health powers they propose for implementation of those strategies. harmonization of legislative responses to infectious diseases, based upon sound evidence, will be necessary if collaborative efforts in support of infectious disease control are to be effective. to assist in drawing together national responses to pandemic disease, the phlawflu project c was funded to develop public health law expertise across europe, 2 and to examine the legal underpinning of pandemic disease preparedness across the eu and five further european states. d this paper examines obstacles to european commonality of legal responses to communicable disease. there is no doubt that law is an important tool in containment of communicable and non-communicable disease. in the context of pandemic influenza, it is considered that social measures authorized by law will be at least as important as medical interventions. 3 evidence from the 1918 influenza pandemic suggests that compulsory home isolation and quarantine were not particularly effective disease control measures because of the difficulty in diagnosing mild cases. nor were such measures likely to be feasible beyond the initial cases. 4 however, compulsory interventions such as school closures, closure of public places and restriction of mass gatherings, along with disease surveillance and hygiene improvement, have proved effective both in influenza outbreaks and in the sars epidemic. 5 international and eu instruments require states to undertake such measures, many of which will require a legal underpinning. the requirement of compliance with the revised ihr and the globalization of disease information and exchange have prompted many states to revise their public health laws. other states, which had no public health legislation, have now enshrined public health laws in legislative form. these initiatives were long overdue. across europe, as elsewhere, national public health laws tended to be old, based on flawed science, and to predate contemporary understandings and protection of human rights. 6, 7 the allocation of responsibility for public health practice and the role of the state in regulating private behaviours have very different histories across europe. 8 not surprisingly, states have adopted very different positions on the issue of the extent to which constraints can be placed upon individuals for the public benefit. earlier research on european national public health laws in relation to tuberculosis 9 enabled the identification of four different 'families' of public health legislative models in europe. these were: authoritarian (the enforcement of a high number of compulsory control measures); moderate (the enforcement of predominantly compulsory control measures without recourse to prevention powers such as compulsory vaccination or population screening); preventive (where compulsory provisions were oriented towards preventive measures, including screening, medical examination and/or vaccination, rather than compulsory treatment or detention); and the laissez faire model, where few or no compulsory measures existed. a further complication to a comparison of national legal approaches to disease control is the range of different legal systems in europe. while the majority of european states have a civil law legal system based on the french or german systems, some states operate common law systems, e the former soviet states have vestiges of soviet law, and the legal systems of the scandinavian states recognize civil law overlain with some common law. whereas the definitive public health law of some states can be found in statutory form, other states also include the binding decisions of courts. some national legal systems recognize customary law, local edicts or administrative orders as having legal authority. it cannot be assumed that because a particular power does not lie within public health legislation, that power does not exist. determination of the full range of public health legal powers across european states is a technical and difficult task. following the eu working paper on community influenza pandemic preparedness and response planning in 2004, 10 european states have published national preparedness plans. as with the range of approaches to law, there is a wide range of approaches to pandemic preparedness planning across europe. coker and mounier-jack examined 21 european national plans against a who checklist and found considerable gaps and inconsistencies among preparedness plans, with implications for health in both individual states and for europe as a whole. the authors noted that 'the eu has a critical function in protecting its citizens from public health threats. the role of the eu will be essential to ensure improved sharing of knowledge on pandemic response among eu members, to support the effective provision of services, and to coordinate the response at a community level'. 11 few plans address the extent to which proposed interventions are authorized by their national laws. indeed, few state plans acknowledge the need for legal authorization for their proposed measures, and there is often a lack of clarity about the legality of measures. f while there is some commonality across european states in the measures considered appropriate in an epidemic, the formulation of those measures differs from state to state, reflecting the culture and social priorities of individual states. across europe, states have proposed disease reporting networks, social distancing powers, restriction on travel and trade, closure of premises and facilities, and measures regulating the provision of goods and services. however, the extent and scope of these powers vary widely. while most states contemplate powers of isolation and quarantine, some states also propose quarantining flight crews, and authorize compulsory vaccination, compulsory administration of prophylaxis, and compulsory medical treatment. most states authorize the closure of schools and leisure facilities in a pandemic, but some states would also close diplomatic and consular representation, restrict trade union activity or prohibit visitors to inpatients in hospitals. there is variation in the extent to which states will be prepared to requisition persons and property. many states have passed, or are in the process of passing, new legislation to support their preparedness planning. in england and wales, for example, the health and social care act 2008 has introduced into the public health act 1984 new powers of isolation outside a hospital, powers of quarantine, powers to require the wearing of protective equipment, powers to require people to attend counselling or disease risk training, and the power to require individuals to provide health information. it also provides for the application of compulsory power orders to groups of persons as well as to individuals, provides new border control measures and imposes new obligations to monitor health risk. states that had taken a liberal approach to intrusion on individual liberties for the benefit of the public health have, in the face of the threat of a pandemic, passed laws providing considerable public health powers. french public health law had previously c the phlawflu project has received funding from the eu in the framework of the public health programme. d croatia, turkey, iceland, liechtenstein and norway. e including the countries of the uk, ireland, malta and cyprus. f the spanish preparedness plan, for example, expresses concern regarding the legality of proposals for isolation, restriction of movement and the proposal to make compulsory the administration of antivirals to staff in contact with patients, noting that 'the legal services of the ministry of health will need to study the legal aspects relative to compulsory vaccination and isolation and the restriction of movement according to the constitutional act 3/1996 of 14 april of special public health measures in public health, articles 2 and 3'. focused on preventive measures and provided few compulsory powers for disease control. 9 the new french public health code now authorizes isolation and quarantine, obliges individuals to submit to temperature checks, and provides powers to close facilities such as schools, restrict use of public transport, requisition health personnel including students and retired persons, and regulate distribution of medicines. school buildings will be used as centres for vaccination and for accommodation of vulnerable persons. the new code withdraws employment rights such as the right not to work in a situation of danger. employees and public servants in france currently have the right to withdraw from their workplace if they reasonably believe that their work situation presents a grave and imminent danger to life and health, provided that they have alerted their employer to the danger and provided that their leaving does not create a new risk for others. under the new code, which only applies in the particular case of pandemic influenza, this right of withdrawal will not apply in circumstances where the employer has taken all foreseeable measures to reduce the risk of exposure to disease. the formulation of public health measures across europe reflects cultural values and priorities. french law, for example, proposes the possible closure of schools in an epidemic, but the new french public health code, recognizing the importance of education in france, provides very specific measures to protect the right to education of its children. the code acknowledges the need for school closures because children are more susceptible to the influenza virus than adults. however, the code requires that during a school closure, every effort must be made to continue educational provision via the internet, radio and television, and sets out detailed provisions on ways in which education might be continued throughout the pandemic. the difficulty of predicting what legal powers will be needed to exercise effective disease control has led some states to include in their public health legislation a power to make emergency regulations to provide powers that were not foreseen or which would not be appropriate outside an emergency. the health and social care act 2008 for england and wales, for example, proposes that where there is sufficient urgency, a legal instrument may be made without following normal parliamentary procedures. 12 the regulation will then cease to have effect after 28 days, unless it has been ratified by a resolution of each of the houses of parliament. the new french code allows that in the case of a grave threat calling for urgent measures, particularly in the case of an epidemic, the minister responsible for health can, by means of an arête, dictate in the interest of public health measures that are proportionate to the risk and appropriate to the time and place, in order to prevent or to limit the consequences of possible threats to the health of the population. in addition to emergency powers specifically addressed to pandemic disease, many european g and other h states have also introduced or updated separate emergency powers legislation to address unexpected threats, to authorize measures that would not normally be acceptable, or to provide powers as a last resort in the face of emergencies where existing legislation is insufficient. other states have constitutional provisions authorizing emergency powers. i it has until now been the case that for the purpose of legislation, emergencies have been conceptualized as aberrations, normally involving an aspect of violence such as war, rebellion or a violent natural disaster. european emergency powers have generally been limited to a 'state of siege' (france), armed rebellion (hungary), or industrial and natural disasters such as earthquakes or the forest fires in greece. they have not been considered a tool for disease control. in the uk, the civil contingencies act 2004 has replaced the 1920 emergency powers act j in relation to temporary special legislation to respond to serious emergencies. the emergency powers act had provided power to make emergency regulations, following a royal proclamation of a state of emergency, in case of an interference with the supply or distribution of food, water, fuel, light or the means of locomotion that deprived the community, or part of it, of the 'essentials of life'. the civil contingencies act expands the domain of emergency powers so that an emergency is widely defined to include 'an event or situation which threatens serious damage to human welfare', which could potentially include a public health threat such as a serious disease outbreak. while no regulations have been passed to date, there is clearly scope for a heavy-handed response in the event of a public health threat. the civil contingencies bill in its original form underwent prelegislative scrutiny by a joint committee which noted that the bill: ' in the wrong hands, [the bill] could be used to undermine or even remove legislation underpinning the british constitution and infringe human rights. our democracy and civil liberties could be in danger if the government does not take account of our recommended improvements'. 13 the bill was revised and the government agreed to remove a clause that would have prevented emergency regulations from being subject to judicial review with the consequence that the regulations could not be suspended or struck down by a court if they were challenged on human rights grounds. the committee recommended that certain acts of parliament of major constitutional significance should be exempted from a power to modify or disapply legislation, but this remains in the final legislation. the committee also proposed that those powers set out in part 2 of the bill should be subject to a 'sunset clause' and expire every 5 years from royal assent unless renewed by parliament. this was rejected by the government as inappropriate, because the bill contained enabling powers that were intended to deal with a problem that was 'not short-term'. this suggests that a new approach is being taken to the meaning of 'emergency'. under earlier emergency powers legislation, an emergency was determined by a royal proclamation, but under the civil contingencies act, a state of emergency is to be announced, without initial reference to parliament, by the secretary of state or a senior minister. public health emergency planning in the uk appears to acknowledge that the civil contingencies act will have a more general role in the control of disease, although how these plans relate to new powers under the public health act 1984 remains to be seen. a senior spokesperson from the english department of health told the author that the department does not intend to use emergency powers contained in the civil contingencies act for pandemic influenza. powers, contained in the health and social care act 2008 should provide all the necessary legal powers to contain and control disease. however, it is clear from government documents on pandemic planning that there is every expectation that civil contingencies act powers will be used should the need arise. 14, 15 the finnish national preparedness plan for pandemic influenza 16 recommended amending finland's 1991 emergency powers act so that a major epidemic can be classified as a state of emergency as defined in the act. previously, an emergency was defined to include an armed attack against finland, a serious violation of the territorial integrity of finland, a threat of war, a serious threat to the livelihood of the population or the economy by interrupted import of indispensable fuels and other energy, or a catastrophe. finland's communicable disease act of 2005 already contains quite intrusive powers including the power to administer compulsory mass vaccination by the defence forces, compulsory medical treatment, isolation from the workplace, and disease reporting that discloses personal information. the concern with use of emergency powers for disease control is that disease control ceases to be a matter of health protection, and becomes an issue of foreign and national security, with the risk of being hijacked by the agendas of security policy and politics. 17 ,l this has become even more pronounced with the merging of responses to naturally occurring infectious disease and bioterrorism within emergency powers legislation. the who and european commission have both established committees with responsibility for public health as a security issue. m it is questionable whether the suspension of separation of powers and potentially of civil rights and liberties is justified in the name of public health, and arguable that recognition of human rights is essential for dealing effectively with an epidemic. draconian quarantine measures can be counterproductive, and may even encourage people to avoid seeking medical treatment. emergency powers exercised for public health reasons treat citizens as the enemy, and reinforce the philosophy of original public health legislation which classified diseased persons as a public health nuisance to be removed and excluded from society for the benefit of the well. 18 hong kong, which has had recent experience of epidemic disease, considered but rejected expanding its emergency regulations ordinance to cover pandemic influenza, concluding that public health powers were sufficient and appropriate to disease control even during a pandemic. n hong kong has instead amended its quarantine and prevention of disease ordinance in the light of its sars experience. 19 emergency powers and human rights all council of europe member states are party to the european convention for the protection of human rights and fundamental freedoms, and any person whose convention rights have been violated by a state party can take a case to the european court of human rights. in the uk, the human rights act 1998 brings provisions of the convention into uk domestic law and enables human rights actions to be brought in a domestic court. rights with particular relevance to public health powers include article 2 (right to life), article 3 (an absolute right to freedom from torture and inhumane and degrading treatment), article 5 (a qualified right to liberty) and article 8 (a qualified right to private and family life). in enhorn v sweden, 20 a human immunodeficiency virus (hiv)-positive man detained by swedish public health authorities on public health grounds successfully challenged his detention on the grounds that it breached articles 5 and 8 of the convention. the european court of human rights held that any detention must comply with the principle of proportionality, there must be an absence of arbitrariness, detention must be a last resort measure, and any detention must have as its objective not only protection of the healthy but also care of the ill. 21 there has been little judicial challenge in british courts of the exercise of emergency powers. in relation to the english emergency powers act and the emergency powers (defence) act, the courts have played a minimal role, striking down only a handful of emergency measures as ultra vires, usually well after the emergency. more recently, in a case where the british parliament had sanctioned the indefinite detention of any person not a british citizen and certified as a 'suspected terrorist', and where the government had derogated from both the european convention and the international covenant on civil and political rights (iccpr) on the grounds that there was a 'public emergency', the house of lords rejected the government's assertion that the derogation was consistent with the european convention. although the majority of judges declined to question whether there was a public emergency on the grounds that the existence of such an emergency was largely a matter for the government to determine, they concluded that imprisonment of non-citizens alone was neither proportional, given the equal threat from citizens, nor necessary, and questioned the irrationality of singling out a minority (non-citizens) for special burdens, when members of the majority could present an equal risk. 22 lord hoffmann was prepared to consider the notion of an emergency and he found it to be a threat to the 'organised life of the community', which would include not merely a threat to the physical safety of the nation, but also to its fundamental values: 'the real threat to the life of the nation, in the sense of a people living in accordance with its traditional laws and political values, comes not from terrorism but from laws such as these.' 23 the decision suggests a judicial role in overseeing government powers in emergencies. the concept of a 'public emergency' is considered under article 15 of the european convention for the protection of human rights and fundamental freedoms as 'a situation of exceptional and imminent danger or crisis affecting the general public, as distinct from particular groups, and constituting a threat to the organised life of the community which composes the state in question.' o article 15 allows that states might derogate from some of their obligations under the convention 'in time of war or other public emergency threatening the life of the nation', but not from article 2 (right to life) or article 3 (prohibition of torture and inhuman or degrading treatment). the former european commission of human rights, which in 1961 defined a public emergency to consist of a 'threat to the organised life of the community', 24 was called upon to determine the criteria of a public emergency threatening the life of the nation in a case in which the greek government sought to justify derogation of rights on grounds of a public emergency. 25 the commission held that the emergency must be actual or imminent; it must affect the whole nation; the continuance of the organised life of the community must be threatened; and the crisis or danger must be exceptional, in that the normal exceptions permitted by the convention for the maintenance of public safety, health and order are inadequate. derogations may only last for as long as, and only be exercised to the extent required by, the demands of the circumstances. they must not limit the subject's rights of access to court protected in article 6 of the convention, nor the right of a remedy protected in article 13. in circumstances where a state wishes to exercise emergency powers which might contravene human rights, the state is required to make a formal derogation under article 15 of the european convention indicating the rights and the territory to which the derogation applies, 26 and to keep the secretary general of the council of europe informed of the measures taken, the justifications, and the cessation of operation of emergency powers. 27 similar requirements can be found in the iccpr. 28 if european states are to abide by their commitments under the convention, it seems that use of emergency powers will be subject to human rights examination. states will not then be able to exercise their powers in an arbitrary way, and will not be able to respond in a manner that is not proportional to the risk. despite these safeguards, the use of emergency powers legislation for serious ongoing disease outbreaks is questionable. an influenza epidemic could, on a worst case scenario, last for years, which would potentially allow the operation of emergency powers that derogate from human rights protections for a considerable period of time. there is a danger that laws made in the form of emergency regulations might, if in force for long enough, become embedded in the legal system and so constitute a permanent assault on liberties which had previously been achieved, as might be suggested of terrorism legislation in the uk. 29 emergency powers in the context of disease, based as they are on responses to war and catastrophes, tend to operate in such a way that persons affected with disease are characterized as the enemy. they propose that in public health emergencies, there must be a trade-off between the protection of civil rights and effective public health interventions. however, the ideals of democracy, individual rights, legitimacy, accountability and the rule of law suggest that even in times of acute danger, government should be limited in the activities that it can pursue and the powers that it can exercise. as gostin points out in the context of the us model state emergency health powers act, 30 this is not to say that individual rights should always trump public health, but that individual rights should never be infringed 'unnecessarily, arbitrarily or brutally'. 31 nevertheless, there has been significant criticism of the us legislation, and concern that measures proposed in the act are sufficiently dangerous as to 'undermine.constitutional values'. 32 while emergency powers might provide short-term solutions to serious threats, they could also do long-term harm to public trust in public health services, and encourage health behaviours which are counterproductive to the public health. in many countries, including the usa, 33 there are signs that public health and national security are increasingly conflated. the ihr are framed around the assumption that disease is a security issue. 34 however, the danger of subsuming disease control within foreign and national security is that the focus is on security rather than on health. wider national and international interests may not always coincide with public health. global public health may not always coincide with the security concerns of individual states, particularly more powerful states. mcinnes and lee note that policy responses to the sars epidemic elicited a 'garrison mentality' whereby strict border controls and control of movement of persons became central to disease containment, with consequences for the movement of persons, goods and services. 35 it has been widely argued that the promotion and protection of human rights is inextricably linked to the promotion and protection of public health, and that lack of respect for the rights and dignity of persons or groups of persons can increase their vulnerability to disease contagion. 36, 37 the importance of human rights to health has been acknowledged in the revised ihr article 3, which requires that the ihr be implemented with full respect for the dignity, human rights and fundamental freedoms of persons. as mann argues, '.the human rights framework is indispensable both for analyzing the central societal issues which must be confronted and for guiding the direction of societal transformation needed to promote and protect health.' 38 states have a significant number of non-medical tools at their disposal in a disease pandemic, and public health law reform has been undertaken with pandemic influenza in mind. public health legislation around the world now authorizes a wide range of social distancing powers and compulsory screening, examination and treatment measures. in addition, much public health legislation provides for the possibility of some limited emergency measures. nevertheless, some european states have proposed the use of emergency powers legislation to provide exceptional powers in the case of a pandemic; powers which will inevitably constrain the rights of individuals. the evidence base for the need for such exceptional powers has yet to be established, and in the absence of such evidence, there is concern that too heavy a hand will result in long-term harm to public trust in the exercise of population-based disease prevention strategies. early responses to public health threats as reflected in 19th century public health legislation were premised on building fortresses to protect the healthy (and generally wealthy) from those suffering from disease, rather than on care and protection of the population. public health legal powers tend to focus on containment and exclusion, representing 'the community response to social and economic pressures and the wide spread fear of death and disease' 39 rather than on positive public health outcomes. immigrant populations have long been targeted as carriers of disease, and in relation to diseases such as drug-resistant tuberculosis, increasing incidence in the western world is often attributed to persons entering from states with high tuberculosis rates. 40 much contemporary public health policy has rejected the 'fortress' approach to disease control in favour of seeing the public health mandate as imposing duties upon all members of a society or population, 18 or indeed duties of global health protection. the evidence base for border control as a public health, as distinct from a security, measure is limited, especially in a pandemic. 5 in relation to other diseases such as hiv and tuberculosis, border screening has proved to be unreliable and has shown little benefit for the health of the population. 41 compulsory border screening and refusal of entry to affected persons are contemplated by many states in their pandemic influenza preparedness plans, p and the revised ihr 2005 contemplate that who might recommend refusal of entry of suspect and affected persons and refusal of entry of unaffected persons to affected areas, 42 subject to the ethical consideration of respect, to the extent possible, for the individual right to freedom of movement. 43 article 19 of the ihr requires all signatory states to establish points of entry with surveillance and border control capacities. a consequence of having no internal eu borders is that the eu needs a strong common external border. under the 2004 eu free p for example, bulgaria, denmark, greece and latvia. movement directive, 44 member states may deny entry of eu citizens and their family members if they are considered to be a threat to public health, but only if this is proportionate and meets strict material and procedural safeguards. most eu member states q have signed the schengen convention, eliminating border controls between participating countries and creating an external frontier. the convention called for a common visa policy, harmonization of policies to deter illegal migration, and an automated schengen information system to coordinate actions in relation to individuals who had been denied entry. the 1997 amsterdam treaty incorporated the schengen convention into eu treaties, and set out a plan to integrate policies on visas, asylum, immigration and external border controls into community procedures and into the community legal framework. this has resulted in what is for all intents and purposes an eu external border, with much social and economic activity operating at regional rather than national level. however opt-out r and opt-in s possibilities make it difficult to define an administrative space that falls within the frontier, and there is no overarching political control. 45 rather, decisions are made by means of a complexity of intergovernmental and supranational institutions, and there remains considerable sovereign power in relation to many issues of border and public health relevance. the schengen agreement includes consent to share information about people, via the schengen information system. this means that a person cannot 'disappear' simply by moving from one participant country to another. a country is permitted by article 2.2 of the schengen agreement to reinstate border controls for a short period if it is deemed to be in the interest of national security. any schengen country can impose temporary or permanent border controls if it believes itself to be unprotected by other members. under this provision, portugal restricted border entry during the 2004 european football championship, as did france for the ceremonies marking the 60th anniversary of d-day, and again shortly after the london terrorism bombings of july 2005. with foot-and-mouth disease having been confirmed in france, the netherlands and britain, norway, in particular, put its border officers on high alert to prevent spread of the disease into the country. other nordic countries have also increased spot checks on entries into the region, irrespective of their new borderless status, in an attempt to contain foot-and-mouth disease. under the schengen borders code, third-country nationals may be refused entry if considered a threat to public health. one issue that arises from the lack of border controls within europe is the disparity in levels of disease preparedness across europe. in 2004, 10 new member states joined the eu, eight of which are former communist countries in central and eastern europe (slovenia, hungary, czech republic, poland, lithuania, latvia and estonia). these states are characterized by a history of underfunding of health and surveillance systems, unreliability of access to drugs, continuing increase in diseases such as drug-resistant tuberculosis and hiv/acquired immunodeficiency syndrome, and inadequate public health responses to disease. 46 since these states have entered into the eu, citizens can cross borders into other, better-resourced states. in the context of a pandemic, this could mean an influx of persons who are possible disease carriers from poor states with a frail public health system and with insufficient medicines, to other eu states, putting citizens at risk and draining health resources in those states. this creates difficult choices for host countries in terms of the assistance they offer. should they fail to offer healthcare services to mobile populations, these populations will put state population health at risk. should they offer healthcare services to mobile populations, this will strain resources and drain services from home populations. in their comparative study of european national preparedness plans, 11 mounier-jack and coker found that 15 eu states intended to take at least one measure to restrict travel to and from the state during a pandemic, and 13 of these states recommended border restrictions on entry and departure. one state proposed drafting new laws to give stronger border control powers. other states, however, conceded that by phase 6 of a pandemic, 47 while there might be political grounds for restrictions on travel, there would be little public health benefit. the possibility of border closure was an issue examined in exercise common ground, a pandemic influenza exercise for the european union, conducted by the uk's health protection agency over a 2-day period in november 2005. 48 this was the second of two eu exercises commissioned by the ec to evaluate the ability and capabilities of member states to respond to a health-related crisis, in this case an influenza pandemic. concern was expressed when switzerland indicated that it might consider the closure of its borders, given the location of drug manufacturers in switzerland. france's border closure proposals contained exceptions for pharmaceutical and vaccine materials and workers. the feasibility of instituting border controls within europe in a pandemic was then examined at an eu pandemic influenza workshop in august 2007. 49 it was concluded that while border closure might be a useful early containment strategy, at a pandemic stage, it would be impractical to enforce border controls within europe because of the porous nature of european borders and because of the need for cross-border traffic of goods. any prolonged border control would disrupt critical supply chains, and there was a risk that the consequent disruption of border controls within europe would result in greater harm than benefit. 50 screening at borders for diseases such as tuberculosis and hiv is common practice in many states, but has been much criticized on grounds of evidence and ethics. 41 a systematic review looking at the effectiveness of physical interventions such as screening in relation to respiratory viruses concluded that '(g)lobal and highly resource intensive measures such as screening at entry ports.lacked proper evaluation'. 51 there is also limited evidence regarding the efficacy of screening international passengers on departure or arrival in a flu pandemic, except possibly in the early phase. while control and screening measures may have worked in the days of slow travel, it is now the case that travel times are likely to be shorter than incubation periods, such that port screening will be ineffective in disease identification. nevertheless, the mounier-jack and coker study found that eight eu states proposed entry screening in their pandemic preparedness plans. 11 some european states indicated in exercise common ground that they intend to undertake border screening regardless of the evidence base, on the grounds that such measures provide reassurance to the public, and because the surveillance information might prove useful. the ihr 2005 authorize states to require information from travellers about their travels, and to undertake a non-invasive medical examination which is the least intrusive to achieve the public health objective. 52 entry may be refused where the traveller refuses to co-operate. 53 article 31 of the ihr provides that invasive medical examination, t vaccination or other prophylaxis shall not be required as a condition of entry except in limited circumstances, such as to determine whether a public health risk exists, or in relation to persons seeking temporary or permanent residence. in these circumstances, if a traveller refuses to comply, entry may be refused or be made subject to the least invasive procedure to achieve the public health objective. article 23 stipulates that such measures be undertaken within the confines of express informed consent and national and international safety guidelines, and article 32 requires that in implementing measures, travellers are to be treated with dignity and respect, and with recognition of gender, sociocultural, ethnic or religious concerns. within the eu, border measures are a matter of community competence that require state co-ordination. where eu member states intend to adopt border measures for the control of communicable diseases, they must inform and, where possible, consult other member states and the commission in advance. the exercise common ground report and the eu pandemic influenza workshop concluded that there was variability in the extent to which member states, european economic area states (including all eu countries plus iceland, norway and liechtenstein) and switzerland have included an international dimension in their pandemic influenza plans. rather, they have focused on national, domestic issues. it is necessary to consider an international dimension because: 'in a community like the eu, free of internal borders and with many common activities and free movement of people and goods, any countermeasures taken in one member state will be bound to affect at least some if not all, other member states'. 54 the reports noted that states also needed to address issues surrounding expatriates, travel restrictions, restriction of emigration, issues of contact persons and the potential for social disorder. there was a lack of clarity around community law on implementation of travel restrictions, and some confusion regarding the extent to which issues of freedom of mobility needed to be handled differently according to an individual's nationality. to be practical and costeffective, border measures would require policy coordination between countries of arrival and departure, and consensus between neighbouring states to avoid disruption. however, as mounier-jack and coker note, 11 few countries address the issue of collaboration with neighbouring states on matters of travel restrictions in their plans: ' there is clearly a need for countries within a european region to be informed and to inform others of their respective strategies in order to ensure that policies are consistent where necessary, or pose as few challenges as possible to public health protection where differences or inconsistencies exist. there may also be a need to ensure that european response mechanisms work together in harmony if public health interventions are to be similar in different countries'. national generic plans in europe have addressed issues of border control rather inadequately. questions have been raised about mobile populations and their implications for healthcare resources, but the issues remain unresolved. there appears to be political reluctance in the context of a united europe to invoke exemptions from internal market rules of free movement of goods and persons on grounds that neighbouring states are failing to address public health threats, and while there is concern about the consequent risk to populations, most states have taken the pragmatic view that any border control should take place at europe's external borders and not within europe. the variation in public health resources and in public health legal powers across eu states, in a context of free borders, is a concern for europe-wide pandemic disease strategies. it is not impossible that states with the strongest national public health powers, which permit, for example, compulsory vaccination or detention, will find some citizens moving states to avoid imposition of these powers. ideally, states within the eu will work together to achieve some commonality of pandemic disease policy and some commonality in their public health legal frameworks. much has been done to develop common policy approaches to preparation for an influenza pandemic across europe. however, article 152 of the european treaty, which states the eu objective of a high level of health protection and requires the european community to work with nation states to deal with health threats, does not allow for a policy of harmonization of state laws. the most that can be hoped for is some convergence of legal powers resulting from discussion and negotiation between states. the differing histories, politics, culture and legal systems of this group of highly divergent states does not bode well for agreement across europe on the appropriate legal response to disease threats. in an attempt to identify the extent to which there is variation in public health legal powers and the consequences of such variation for public health in europe, the phlawflu project is examining the role of national laws in the control of and protection against pandemic human influenza across europe. 2 the objective of the project is to provide an evolving critical study of national laws supporting and constraining defined issues of communicable disease control across europe, and to provide a resource to support public health law reform and public health policy making in europe. the project methodology includes workshops bringing together public health policy makers from 32 european states to examine legal responses to disease scenarios. it is to be hoped that some common legal responses emerge from these exercises, and given the absence of attention paid to public health laws in europe in recent years, that much can be learned by all states on ways in which to use law as a tool in pandemic disease control. meanwhile, europe is in a complex place in relation to its public health approach to pandemic disease. in times of economic strength and freedom from threats of war and disease, the commonality of eu states comes to the fore, and states are ready and willing to engage in joint enterprise. where states are at threat, however, they tend to turn inward on themselves, and political and cultural differences emerge. in times of threat, states which have traditionally been strong on public intervention in private rights are unwilling to accede to the approaches of more liberal states. traditionally, liberal states are reluctant to impose draconian measures, but at the same time may be unwilling to carry the public health burden of citizens from poorer states. the revised ihr have done much to focus public health law reform measures and to ensure some minimum commonality of content, but it is clear that some states, in accordance with their legal culture, are prepared to undertake more intrusive interventions than others. for all these concerns, it is clear that public health laws will be a mainstay of pandemic disease strategies, both in relation to the eu and in relation to nation states within europe. public health laws will be essential in providing powers to enable actions to be taken to control disease spread, but also to constrain states from taking actions that might reassure short-term security concerns but that have potentially harmful long-term public health consequences. of course, such issues are not unique to europe, but the nature of europe as a continent and as a legal entity creates particular complications for the ways in which law might best be used to create a coordinated european pandemic disease strategy. one unexpected benefit of the pandemic threat has been the renewed interest in exploring the role of law as a communicable disease tool, and in the examination of the range of public health legal approaches across europe. globally, a greater understanding of the role of public health law as a tool for managing and minimizing the spread of communicable disease will be a lasting and invaluable legacy of governance efforts in relation to pandemic influenza. none sought. none declared. european centre for disease prevention and control. technical report: pandemic influenza preparedness in the eu. status report as of autumn european public health law network website. available at: www.ephln.org social measures may control pandemic flu better than drugs and vaccine report on the influenza epidemic in nsw in 1919 world health organization writing group. nonpharmaceutical interventions for pandemic influenza, national and community measures the exercise of public health powers in an era of human rights: the particular problem of tuberculosis introduction. the importance of law for public health policy and practice public health powers in relation to tuberculosis in england and france: a comparison of approaches public health law and tuberculosis control in europe how prepared is europe for pandemic influenza? an analysis of national plans cabinet office and department of health. pandemic flu, a national framework for responding to an influenza pandemic. london: department of health pandemic flu, influenza pandemic contingency planning: operational guidance for health service planners. london: department of health ministry of social affairs and health. finnish national preparedness plan for pandemic influenza; proposal of the working group on national pandemic preparedness. helsinki: ministry of social affairs and health uk international priorities: a strategy for the fco. cmnd 6052. london: hmso the limits of law in the protection of public health and the role of public health ethics quarantine and prevention of disease ordinance the exercise of public health powers in cases of infectious disease: human rights implications a v secretary of state for the home department a v secretary of state for the home department greek case, 12 yb 1, opinion of the commission russian federation. ecthr judgment of 24 european commission for democracy through law (venice commission) the interface between public emergency powers and international law the law of exception: a typology of emergency powers drafted by the centre for law and the public's health at georgetown and johns hopkins universities the model state emergency health powers act bioterrorism, public health and civil liberties public-private health law: multiple directions in public health global public health security health, security and foreign policy public health strategies for pandemic influenza: ethics and the law health and human rights: a reader human rights and the new public health human mobility and population health increasing drug resistant tuberculosis in the uk compulsory screening of immigrants for tuberculosis and hiv world health organization. ethical considerations in developing a public health response to pandemic influenza directive 2004/58/ec of the european parliament and of the council of 29 mapping schengenland: denaturalizing the border health-care system frailties and public health control of communicable disease on the european union's new eastern border world health organization pandemic phases exercise common ground: a pandemic influenza exercise of the european union department of health and cabinet office. pandemic influenza -sharing of evidence and response policies across the eu. london: department of health workshops 11 and 12 facilitated by dr miguel betancourt cravioto and dr daniel reynders physical interventions to interrupt or reduce the spread of respiratory diseases: a systematic review specifications attached to the invitation to tender document, sanco/c3/ 2004/05, quoted in health protection agency, exercise common ground, a pandemic influenza exercise for the european union, final report. london: health protection agency none declared. key: cord-018240-trbge505 authors: gaubert, philippe title: fate of the mongooses and the genet (carnivora) in mediterranean europe: none native, all invasive? date: 2015-09-21 journal: problematic wildlife doi: 10.1007/978-3-319-22246-2_14 sha: doc_id: 18240 cord_uid: trbge505 the mediterranean basin (mb), connected by cultural exchanges since prehistoric times, provides an outstanding framework to study species introductions, notably in mammals. carnivores are among the most successful mammalian invaders. as such, a number of middle-sized representatives (“mesocarnivores”) such as the domestic cat and mongooses have been pinpointed for their deleterious impact on the native fauna. in the mb, three species of mongooses (herpestidae) and one genet (viverridae) are or have recently been recorded and none of them has been considered native: the indian grey mongoose herpestes edwardsii, the small indian mongoose h. auropunctatus, the egyptian mongoose h. ichneumon, and the common genet genetta genetta. in order to clarify the history of introduction and status of the mongooses and genet in europe, i review various bodies of evidence including (1) their natural history and relationships with humans in their native ranges, (2) their history of introduction in europe, (3) the enlightenments—and sometimes contradictions—brought by recent genetic analyses on their dispersal histories, and (4) their range dynamics and ecological interactions with the european fauna. the species of herpestids and viverrids present in europe fall into three categories: (1) introduced and spreading (g. genetta, h. auropunctatus), (2) introduced and extinct (h. edwardsii), and (3) natural disperser and spreading (h. ichneumon). in view of the reviewed evidence, there is weak support for a deleterious impact of the mongooses and genet on the european fauna (except possibly on the herpetofauna of small adriatic islands in the case of h. auropunctatus), notably in comparison with genuine invasive species such as the black rat and the domestic cat. rather than inefficient control programs such as those targeting h. ichneumon in portugal and h. auropunctatus in croatia, we suggest that a greater attention is focused on the restoration of large carnivores (the natural regulators of mesocarnivore populations), mesocarnivore communities and natural habitats, to contribute to a more sustainable way of “managing” the mongooses and genet in europe. introductions are considered as a component of the mediterranean bio-cultural heritage (gippoliti and amori 2006 ) . human-mediated introductions since the end of the würmian glaciations (14-12 kyr ago) have deeply impacted current patterns of biodiversity in the mb (vigne et al. 2009 ). these led to dramatic levels of endemic extinction, at the same time counterbalanced by the establishment of various allochthonous taxa (masseti 2009 ). the intensity of introductions signifi cantly increased from the fi rst millennium bc , following massive human migrations from eastern to western borders of the mediterranean sea that opened several dozens of potential routes to the humanmediated dispersal of species across the mb (ciolek 2011 ) . historical introductions had motives mostly related to agricultural practices (domestication, pest control) but also to more "esthetic" and political considerations, including entertainment, cultural exchanges and pet trade (hughes 2003 ; morales et al. 1995 ) . more recent introductions (twentieth to twenty-fi rst centuries) of mammals still originated from such motives (e.g., delibes 1977 ) . thus, the long history of introductions in the mb has resulted in serial faunal turnovers involving local extinctions of endemic fauna and serial establishments of introduced species, with new "invaders" regularly entering the native fauna (cuttelod et al. 2008 ) . assessing the impact of such introductions on the mediterranean fauna is politically and economically crucial, but has proven a diffi cult task that may deserve a "case-by-case" (i.e., taxonomically and/or geographically) approach . by focusing on a group of afro-asian small carnivores present in southern europe, we intend to provide an exhaustive reassessment of their status that shall clarify their ecological impact in the mb. carnivores are among the most successful mammalian invaders, with species such as the domestic cat ( felis silvestris catus ) and dog ( canis lupus familiaris ), the american mink ( neovison vison ), and the small indian mongoose ( herpestes auropunctatus ; see below) each established in more than 30 countries or islands around the world (clout and russell 2007 ) . middle-sized representatives (" mesocarnivores ") such as those above-mentioned have been pinpointed for their deleterious impacts on the native communities of carnivores and their preys (bonesi and palazon 2007 ) , notably in the context of endemic fauna (medina et al. 2011 ). in the mb, mustelids (martens, weasels, badgers) seem to have been the earliest carnivores transported on islands (masseti 1995 ) . this pattern is congruent with the earliest molecular estimate of transportation of weasels ca. 10 kya (lebarbenchon et al. 2010 ) . however, given their natural, circum-mediterranean distribution at the pleistocene period , it is unclear whether all the mustelids present on mediterranean islands were introduced or natural dispersers (masseti 1995 ) . a contrario , the establishment of another lineage of small carnivores including mongooses ( herpestidae ) and genets ( viverridae ) in europe has traditionally been considered as more recent. four species of herpestids and viverrids are or have recently been recorded from mediterranean europe and none of them has been considered native: the indian grey mongoose herpestes edwardsii , the small indian mongoose h. auropunctatus , the egyptian mongoose h. ichneumon , and the common genet genetta genetta (long 2003 ) . those species are medium-sized predators naturally distributed in the tropical and subtropical zones of the old world. they were supposedly introduced in europe at various historical times, from the middle age to the twentieth century. because such small carnivores actively predate on species that can have a deleterious role in agriculture (e.g., rodents) or be directly harmful to humans (e.g., snakes), and also because they are commensal and can be kept as pets, they were good candidates to be spread through mediterranean's trading and political networks. 1 although the introductions of the indian grey and small indian mongooses in europe are quite well documented, the introduction history of the egyptian mongoose and the common genet has remained highly speculative. importantly, it is unclear whether those four carnivores have or had deleterious impacts on the native european fauna, and how their niches/ranges in the mb are characterized. despite such lack of empirical data, local control operations-notably targeting mongooses in portugal and croatia-have been attempted with various levels of "success" (hays and conant 2007 ; barun et al. 2011 ; beja et al. 2009 ). in order to clarify their history of introduction and their status within the european fauna , i will (1) briefl y review the natural history of the afro-asian herpestids and viverrids present in the mb and their relationships with humans in their native ranges, (2) review their history of introduction, and for the lesser known species the speculations that have surrounded the factors promoting their possible introduction in europe, (3) detail the recent enlightenments-and sometimes contradictions-brought by genetic analyses (mostly phylogeography) as to the dispersal histories of those small carnivores, and (4) summarize their range dynamics and ecological interactions with the european fauna. in view of the reviewed evidence, i will then conclude on the expected "invasiveness" of those species in europe and will eventually open a prospective on the strategies that could be adopted to improve our understanding of small carnivores' establishments in the mb. the indian grey mongoose occurs in the indian subcontinent and at the eastern fringe of the middle east ( fig. 14 .1 ). it seems preferentially commensal with humans as it is often recorded near human settlements in central india where it frequently scavenges on carrion. the species is most common in disturbed areas, in dry secondary forests and thorn forests. it is generally diurnal, goes solitary or by mating pair and mainly feeds on small mammals, insects and reptiles (santiapillai et al. 2000 ; choudhury et al. 2013 ) . litter size is 2-4 and there are 2-3 litters a year (gilchrist et al. 2009 ). the small indian mongoose ranges from the eastern fringe of the middle east to the indian subcontinent and southern china (veron et al. 2007 ; gilchrist et al. 2009 ) (fig. 1 4 . 2 ). the species is found in a variety of open habitats and tolerates a large degree of habitat conversion (notably in its introduced range). it seems quite resistant to persecution and is still recorded from intensely hunted and cultivated areas (wozencraft et al. 2008 ). it goes solitary or by pair and feeds during both day and night on a wide range of items including arthropods, small mammals, birds, reptiles, frogs and crustaceans. mean litter size is 2 (range = 1-5) and there are 2-3 litters a year (gilchrist et al. 2009 ). because they are natural predators of snakes , mongooses can be very popular animals in asia, in contrast with them being viewed as pests in most parts of their introduced ranges. it is, in fact, mainly for this reason (snake killing, but also rodentkilling) that asian mongooses have been introduced in various parts of the world (hays and conant 2007 ) . archaeological evidence from harappan sites (western indian subcontinent; fourth to fi rst millennia bc ) supports the idea that mongooses frequented human habitations, possibly as semidomesticated animals (lodrick 1982 ) . the " brahmin and the mongoose " is a famous folktale from india that is another token of the good consideration that the mongoose benefi ts there. it describes the impulsive killing of a loyal mongoose that had protected a baby from snakes, and thus is a warning against hasty actions (emeneau 1940 ) . in india, the mongoose is also associated to opulence and generally represents the god of wealth in the buddhist iconography (lodrick 1982 ) . small indian mongooses were possibly introduced during the second or fi rst millennium bc in eastern arabia and bahrain (uerpmann 1995 ) and were found buried in the temple of saar (dobney and jaques 1994 ) where they were probably linked to religious rituals. as of today, the small indian and the indian grey mongooses are frequently captured and sold as pets, notably in india and nepal. in central india, people consider the two species of mongooses to be sacred (wozencraft et al. 2008; choudhury et al. 2013) . another use is made by the jogi tribes in pakistan, whom capture the small indian mongoose for stage fi ghts with cobras (gilchrist et al. 2009 ). the egyptian mongoose is widely distributed in northern and sub-saharan africa and the coastal near east, avoiding deserts, high rainfall forest areas and the southern african steppe ( fig. 1 4 .3 ) . it primarily occurs in habitats having dense understory vegetation, but is also frequent in cultivated zones. the species is generally solitary, although pairs and families of 4-6 individuals can be observed. it is mostly diurnal and has an opportunistic, omnivorous diet including small mammals, birds, small red arrows indicate introductions on several adriatic islands arthropods, amphibians, reptiles, fi sh, gastropods, carrion, fungi, fruit and other plant material. mean litter size is estimated to be 3.3 (range = 1-4), and there is usually a single litter per year (palomares 2013 ) . ichneumon is derived from the ancient greek for "tracker," possibly originating from the mongoose's supposed ability to track crocodile dens and feed on their eggs. in addition to this ancient belief related to the sacred crocodiles, its capacity of preying on snakes made the egyptian mongoose played an important part in the bestiary of the pharaonic egypt. representations of the species can be found on the walls of tombs and temples in thebes and saqqara as early as the period of the old kingdom (2800-2150 bc ). the egyptian mongoose was associated to several deities including atum, re and horus. it was also sacred to mafdet, the goddess providing protection from snakebite, and mummifi ed egyptian mongooses were discovered inside bronze statues of the lion-headed goddess uto. a legend relates the defeat of the thunder snake apophis by the mongoose as the surrogate of the god letopolis, refl ecting again the representation of the species as a benefi cial snakekiller. in ancient egypt and later in the arabic culture (as late as nineth century ad ), the egyptian mongoose was believed to alter its size between day and night, becoming very small at night (as a shrew or a mouse) and being able to kill snakes by suddenly increasing its size if captured (stuart 1988 ) . depictions of mongooses hold by their tail or on a leash suggest that the species was tamed in ancient egypt, possibly as a household pet, biocontrol agent, or hunting animal. egyptian mongooses were kept in temples as votive offerings until the greco-roman times. however, they seem not to have been domesticated or bred in captivity (osborn and osbornova 1998 ) . the status of the species is said to have moved from benefi cial to pest once the domestic fowl, on which it can prey, was introduced in egypt (osborn and osbornova ). more likely, the arising of the domestic cat as the preferred household pet and biocontrol agent against rodents all around the mb together with the spread of monotheist religions should have brought forward the discredit on the egyptian mongoose. there is, to date, no concrete evidence for the domestication or taming of h. ichneumon by post-roman north african cultures, although the discovery of a tibia from punic sardinia ca. fi fth to fourth century bc shows that episodic, historical translocations of the species might have occurred as early as the carthaginian period (campanella and wilkens 2004 ) . the common genet has a wide distribution in northern and sub-saharan africa and is also present in southern peninsular arabia ( fig. 1 4 .4 ) . it avoids deserts, rainforests, dense woodlands and woodland-moist savannah mosaics, and is mostly found in open savannahs, oak forests and bushy areas with woody or rocky shelters. the species has a predisposition to live in the vicinity of human settlements . it is solitary and nocturnal, and is a generalist feeder consuming small mammals, arthropods, birds, eggs, reptiles, amphibians, fi sh, fruits, mushrooms and garbage. mean litter size is 2-2.6 (range = 1-4), and there seems to be a single litter per year (delibes and gaubert 2013 ) . remains of common genets associated to hunting sites were found in the late pleistocene of northern africa (ouchaou and amani 2002 ) . although possible associations between common genets and humans have been the subject of numerous speculations, the archaeological and historical evidence is scarce. the species was pictured in swamp scenes climbing papyrus stems -often in association with the egyptian mongoose-on the walls of tombs and temples of ancient egypt (ca. 3000-2200 bc ). the common genet was seldom represented in later periods (i.e., the xviiith dynasty: 1600-1300 bc ). no mummies of the species have ever the upper left inset shows the potential range of the species (in red ) in southwestern europe (gaubert et al. 2008 ; delibes and gaubert 2013 ) : 1 , portugal; 2 , spain, 3 , france; 4 , ibiza isl.; 5 , mallorca + cabrera isl been found in egypt. the assertions of a large number of authors as to the use of the species as a tamed " pre-cat " in egypt and later in northern africa are not based on any concrete evidence (see osborn and osbornova 1998 ) . there has been some confusion around which species of mongooses were introduced worldwide. the supposed introductions of the indian grey and the egyptian mongooses in various parts of the world (malaysia, japan, mauritius, antilles isl., madagascar) are most probably confusions with other (asian) mongooses, including h. auropunctatus (gilchrist et al. 2009 ; choudhury et al. 2013) . the history of introduction of the small indian mongoose in italy is relatively well documented. probably in 1952, the owner of a hotel in san felice circeo (central italy) released a few mongooses-acquired from the giardino zoologico di roma-in her park with the aim of removing adders. those animals escaped during the second half of the 1950s, and a population established into nearby areas of the circeo national park . at the end of the 1970s, mongooses reached their maximum range, which covered ca. 15 km 2 from the whole circeo promontory to most of the protected area south of molella bay (carpaneto 1990 ; angelici 2003 ) . the collection of a specimen of h. edwardsii from capalbio (tuscany), ca. 200 km northward of circeo, shows that at least two events of introduction occurred in italy at ca. 10 years of interval, probably from the same captive stock. the reasons for this second introduction remain unknown. however, a letter from 1966 written by the director of the capalbio hunting estate quoted a negative advice provided by the laboratorio di zoologia applicata alla caccia (future istituto superiore per la protezione e la ricerca ambientale) about the introduction of mongooses to control populations of adders, reinforcing the idea that using these animals to control venomous snakes was rather widespread at that time. the indian grey mongoose is now considered extinct in italy (angelici 2003 ) , a unique fate among the herpestids and viverrids introduced in europe (see below). the small indian mongoose is considered as one of the world's 100 worst invasive species. it was introduced to many islands in the pacifi c and indian oceans and the caribbean sea, mostly in the late nineteenth and early twentieth centuries, to control rats and poisonous snakes in sugar cane fi elds (lowe et al. 2000 ) . the introduction of h. auropunctatus in europe is well documented. seven males and four females purchased in india were released in 1910 on the island of mljet (current croatia), formerly known as the " island of snakes ." at that time, the austro-hungarian authorities had decided to introduce wild mongooses in order to exterminate the horned viper vipera ammodytes from the island. given the rapid decrease in the number of snakes and the growing numbers of mongooses on mljet isl., the species was soon introduced on nearby islands (korcula, peljesac, brac) between 1921 and 1927. afterwards, several attempts of introduction-with various levels of success-were planned onto a series of adriatic islands but also in the mainland of former yugoslavia (currently bosnia-herzegovina and macedonia) until the 1970s (tvrtkovic and krystufek 1990 ; krystufek and tvrtkovic 1992 ) . interestingly, the historical record kept track of a transportation of ca. 100 mongooses from mljet isl. to venezuela around 1926, thus suggesting that part of the small indian mongooses introduced in the caribbean isl. originated from europe (tresic pavicic 1936 ) . conversely, the scenario of introduction of the egyptian mongoose in europe is highly speculative. the absence of paleontological records in southwestern iberiathe european range of the species-and the existence of archaeological remains dated from the arab occupation led some authors to postulate an introduction of the egyptian mongoose associated to migrant berber farmers between the eighth and thirteenth centuries ad (riquelme-cantal et al. 2008 ; detry et al. 2011 ). however, this scenario is somewhat contradicted by the discovery of an egyptian mongoose remain in a carthaginian site from the fi fth to fourth centuries bc in sardinia (campanella and wilkens 2004 ) , evidencing the historical transportation of the species by an earlier civilization. besides, it has long been said that there is no evidence for the domestication or taming of h. ichneumon by north african people during historical times (geoffroy saint-hilaire 1813 ). as a matter of fact, traces of manipulation or taming as could be the case with tooth abrasion, presence of associated artifacts or intentional disposal practices, have never been observed on any of the archaeological remains found in europe. the scenario of introduction of the common genet in southwestern europe (the species is present from southern iberia to southwestern france and in several balearic islands) is highly speculative and calls to earlier periods than the arab conquest. the greek historian herodotus (fi fth century bc ) mentioned a " weasel from tartessos " (southwestern iberia) similar to the one found in libya, which has been identifi ed as a common genet (amigues 1999 ) . this led authors to suggest an early introduction of the species through the political network between the greek colonies and the kingdom of tartessos. according to posidonius (fi rst century bc ), this "weasel" was used in southern iberia as a bio-control agent against rabbit proliferation (amigues 1999 ) . the common genet was also mentioned in a faunistic list from the gallic site of ambrussum (southern france) as associated with domestic furniture from the third century bc (columeau 1979 ) . however, the remains of the animal have been lost. despite such possibilities for anterior introductions, the common genet has traditionally been associated to the arab conquerors of europe. a legend relates that after the defeat of moor armies near poitiers, france (732 ad ), the king's majordomo charles martel found in the loot of the defeated armies such a great quantity of furs-but also living animals-belonging to the common genet that he decided to create the "ordre de la genette" (favyn 1620 ) . although this order of chivalry is a total myth, this narrative long stood as the main evidence supporting the introduction of the species through arab invasions. such hypothesis was further supported by the fact that there is no fossil record of the species in europe and the only known archaeological remain dates back to the almohads-an arab dynasty-in portugal, at the thirteenth century ad (morales 1994 ) . the material representing the extinct indian grey mongooses in italy is very scarce. only four specimens are known to be preserved in collections: three fl at skins from the early 1960s are kept at the ispra museum (ozzano dell'emilia, italy) and one mounted specimen from the 1970s is exhibited at the museum visitors' centre of sabaudia at circeo np (angelici 2003 ) . those represent the two distinct sites where the species was introduced, including circeo np and capalbio (tuscany), ca. 200 km north of the former. to date, a single genetic analysis based on mitochondrial dna (mtdna) and including the four remaining specimens of the mongooses introduced in italy has been conducted. it clearly confi rmed the indian grey mongoose as the species having been introduced in italy during the twentieth century and traced the introduced pool's origin to pakistan or india, which is the core distribution of the species in its native range. the mtdna diversity of italian mongooses was null, thus suggesting a very limited number of founders (gaubert and zenatello 2009 ) . it is likely that the low number of preserved italian individuals will significantly limit the contribution of future genetic studies on the assessment of the species' introduction in europe. the introduction history of the small indian mongoose has been assessed in more details. genetics-and notably, rapidly evolving markers such as microsatelliteshas shown its utility in tracing the introductions of the small indian mongoose worldwide and allowed to discover new paths of transportations (thulin et al. 2006 ; watari et al. 2011 ). it has also provided insights into the demographic characteristics of introduced populations and potential admixture with h. edwardsii in the species' native range that may be used to better delineate the dynamics of the introduced populations (thulin et al. 2006 ) . despite this, no detailed genetic study has so far been conducted on the small indian mongooses introduced in europe. to date, only a study on the systematic status of the small indian mongoose and the javan mongoose h. javanicus confi rmed that the former was the species introduced in croatia ( veron et al. 2007 ). thus, further genetic investigations will have to be undertaken to characterize in detail the introduction patterns of the small indian mongoose in the balkans. the dispersal history of the egyptian mongoose has been assessed by a mitochondrial analysis based on ca. 90 samples from africa, the middle east and europe (gaubert et al. 2011 ) . the results of this study radically contradicted the established idea that the egyptian mongoose was introduced in europe. instead, gaubert et al. ( 2011 ) proposed a natural crossing of the mediterranean sea by h. ichneumon via the strait of gibraltar during the middle pleistocene, long before the earliest (paleolithic) human exchanges between north africa and europe. the strong genetic differentiation between european and north african haplogroups, the signifi cant level of genetic diversity found in europe, and the important phenotypic differences between european and north african mongooses all pointed to a scenario of long-term in situ evolution of european populations. these molecular results supported the hypothesis that natural dispersal across the strait of gibraltar was possible for nonfl ying vertebrates during the pleistocene cyclical lowering of sea levels. the swimming abilities of the egyptian mongoose make plausible a sweepstake migration using a partially emerged shoal such as the archipelago of cape spartel (where the mythic city of atlantis was possibly located) that is now 56 to 200 m below sea level (collina-girard 2001 ) . the long-term stability of mongooses' effective population size in europe was supported by various genetic indices and the remarkable correspondence between the limits of the proposed ice age refugium in southwestern iberia (hewitt 1996 ) and the distribution of suitable ecological conditions for the species (specifi cally, low rainfall and warm temperatures; borralho et al. 1996 ) . niche modelling approaches have since supplied independent evidence for the long-term stability (climatic niche conservatism) of the egyptian mongoose in southwestern iberia (papeş et al. 2015 ) . the introduction scenario of the common genet in europe has been assessed by the genetic analysis of ca. 180 individuals from the native and introduced species' ranges, using mtdna gaubert et al. 2011 ) and more recently, microsatellite markers . the combined evidence supported multiple introductions from north africa into europe, including the balearic isl. (with three distinct introduction events on ibiza, mallorca and later cabrera), southwestern iberia (corresponding to the tartessian kingdom's zone of infl uence), and possibly northeastern spain and southwestern france (secondary introduction from iberia for the latter). those studies suggest that the common genet was intentionally introduced in southern iberia at a time (<300 bc) antedating the arab invasion, possibly via phoenicians' commercial routes. subsequent introduction in france, longterm genetic drift, and admixture between the iberian and french pools likely shaped the species' genetic variation currently observed in continental europe. the mtdna-based demographic scenario of multiple, historical introductions of common genets in europe followed by sudden population expansion is characteristic of populations at disequilibrium gaubert et al. 2011 ) . such scenario was supported by niche modelling analysis through the detection of a climatic niche shift in the northern european range of the species (papeş et al. 2015 ) . altogether, these results suggest that an exceptional combination of factors including multiple introductions, local admixture, and ecological adaptation promoted the successful spread of the common genet in continental europe. the number of indian grey mongooses in italy abruptly decreased from the early 1980s, and the species was considered extinct by 1984. a survey conducted in summer 1984 failed to recover any evidence for the presence of the mongoose (biondi 1985 ) . although poorly documented, it is probable that the extinction process of h. edwardsii in italy might have taken place quickly after the species reached its maximum range between 1978 and 1980 (carpaneto 1990 ) , possibly due to harsh winters. mongooses were seen wandering in villages close to the circeo promontory, apparently searching for food and shelter . the species showed a tame, diurnal behavior, consuming tourists' leftovers and accepting direct feeding from humans. its sudden extinction in italy fi ts with crashes observed in populations with very restricted ranges within the 25 years following their time of introduction (duncan and forsyth 2006 ) . because the mitochondrial diversity among italian individuals was null, it is reasonable to conclude that a combination of deleterious factors including low genetic diversity, restricted range, and non-adaptation to western palearctic winter conditions was likely responsible for the extinction of the species in italy (gaubert and zenatello 2009 ) . documentation of interspecifi c competition with native carnivores is scarce, although a dominance of the indian grey mongoose over polecats mustela putorius was suggested during the years of mongooses' maximal expansion. during the brief establishment of the indian grey mongoose in circeo np, no impact on the density of black rats rattus rattus was observed (carpaneto 1990 ). the small indian mongoose successfully established and spread in europe, with the notable exception of the island of brac where it went extinct for unknown reasons. the two introduction sites on the continent (peljesac peninsula, bosnia-herzegovina and mostar, macedonia) are supposed to be the sources of the populations having spread ca. 150 km southwards into montenegro. at present, the european range of the species includes the thick mediterranean vegetation of the adriatic coast, from skrda isl. and the neretva river in the north to albania in the south (barun et al. 2010 ; ćirović et al. 2011 ) . given the favorable (higher) mean annual temperatures in southern europe, the further spread of the species' range should be expected towards southern albania and greece (ćirović et al. 2011 ). on european islands, the small indian mongoose can show drastic annual fl uctuations of population densities . because the species' range in europe is characterized by temperatures well below its previously known isothermal limit (10 °c), episodic cold winters could be the cause of such large density fl uctuations (tvrtkovic and krystufek 1990 ). in comparison with h. edwardsii , the small indian mongoose shows a series of characteristics that may promote invasive success: (1) effi cient physiological mechanisms for dealing with hot and moderately cold environments; (2) aggressive behavior against direct competitors/predators such as domestic cats; and (3) wide range of deleterious pathogens, including rabies (gaubert and zenatello 2009 ) . the success of the small indian mongoose as a biocontrol agent is questionable because the species is a generalist predator preying on other species than rodents and snakes (hinton and dunn 1967 ) . reductions or extinctions of populations of birds, reptiles, and amphibians caused by h. auropunctatus have been reported on islands worldwide, although there is controversy over whether the small indian mongoose has genuinely been the main culprit (lewis et al. 2011 ; hays and conant 2007 ) . a secondary aspect of the deleterious impact of the species resides in its role of main reservoir for viruses (e.g., rabies) and parasites (e.g., weil's disease) impacting wildlife and humans in several parts of the caribbean (hatcher et al. 2012 ; everard and everard 1992 ) . this latter point remains undocumented in europe. in croatia , the species is accused of having a deleterious impact on wild fowl, poultry and several cultivars, and so is subject to extermination campaigns led by hunting federations (tvrtkovic and krystufek 1990 ) . it has also been speculated that the species could have " catastrophic consequences " on the balkan continental herpetofauna (ćirović et al. 2011 ). however, a study conducted on korcula isl. evidenced a low consumption of reptiles and amphibians by the small indian mongoose, and in comparison a high consumption of small mammals, birds, arthropods and plants (cavallini and serafi ni 1995 ) . the minor representation of the herpetofauna in the mongoose's diet is actually a general trend throughout its introduced range ( table 1 in hays and conant 2007 ) . on the other hand, it was observed that reptiles and amphibians were generally rare or absent from the islands occupied by the species whereas they were common on the mongoose-free island of brac (barun et al. 2010 ) . unfortunately, predation of the native herpetofauna by other invasive species such as the black rat and the domestic cat has not been evaluated. the egyptian mongoose must have occurred in the papyrus swamps of the nile valley at the time of ancient egypt. the reasons for its extinction are unknown, but were probably linked to its artifi cial maintenance as a semi-domestic animal or to the progressive disappearance of such habitat (osborn and osbornova 1998 ) . in europe, suitability models predicted the expansion of the species in southern and central spain in areas with a high rabbit abundance, thus foreseeing the existence of large regions of potential confl ict with hunting interests (recio and virgos 2010 ) . climatic niche modelling outputs were less conservative and predicted most of the iberian peninsula as potentially suitable for the egyptian mongoose (papeş et al. 2015 ) . because there is no signifi cant change in the composition of the carnivore community at the northern fringe of the european range of the species (wilson & mittermeier, 2009 ) , interspecifi c competition cannot be considered a limiting factor. in addition, release from biotic/historical constraints, including h abitat disruption and climate warming , could lead to local or temporary range expansion of the egyptian mongoose, as refl ected by its recent spread into northern portugal related to rural depopulation (barros 2009 ). whether this current trend can be assimilated to a colonization front and whether the recent records of the species in northwestern spain (balmori and carbonell 2012 ) refl ect a genuine increase of northern dispersals will have to be evaluated. in northwestern portugal, mongooses prey mostly upon mammals (especially lagomorphs) but also on reptiles and arthropods, with males preferentially consuming mammals ). in case of competition with other carnivores, the egyptian mongoose may modify its realized niche by having more diurnal activities (santos et al. 2007 ) and can shift its microhabitat use (e.g., by preferentially using thicker scrubland) to prevent deadly encounters with dominant species such as the iberian lynx lynx pardinus (viota et al. 2012 ) . so far, the role of h. ichneumon in carrying zoonotic diseases seems very limited. in europe, rabies spillover infection from red foxes ( vulpes vulpes ) was not detected (müller et al. 2015 ) . in portugal, a high prevalence of parvovirus dna was detected in mongooses (58 %), potentially carrying a risk to susceptible populations at the wildlife-domestic interface and to threatened species of sympatric carnivores (duarte et al. 2013 ) . the common genet was probably present in the papyrus swamps of the nile valley further north from its current range, as suggested by remains found in the south galala plateau cave, egypt, and illustrations on papyrus and in stone reliefs from the nile valley (osborn and osbornova 1998 ) . the reasons for its extinction are unknown, but were probably similar to those of the egyptian mongoose (i.e. artifi cial maintenance by humans or progressive disappearance of the habitat). in europe, the species has recently crossed its traditional range barriers of the rhône (southeastern france) and loire (northwestern france) rivers (gaubert et al. 2008 ; léger and ruette 2010 ) . climatic niche modelling predicted a large portion of europe as suitable for the species, italy being the best candidate for a near future colonization via the liguria-southern piedmont corridor (papeş et al. 2015 ) . the common genet is an opportunistic carnivore that may expand its trophic niche on the mediterranean islands (ibiza and cabrera) where it is the sole mesopredator (virgós et al. 1999 ) . conversely, marked trophic differentiation occurs on another island (mallorca) where the species coexists with the pine marten martes martes (clevenger 1995 ) . in continental europe, niche overlap among the common genet, the egyptian mongoose, and other carnivores is generally high, but subtle and dynamic (i.e., seasonal) adjustments in foraging behavior and in the use of microhabitats and main prey items seem to balance the coexistence of such small carnivores' communities (zabala et al. 2009 ; lopez-martin 2006 ; carvalho and gomes 2004 ; melero et al. 2008 ; santos-reis et al. 2005 ; monterroso et al. 2014 ; zapata et al. 2007 ). the common genet eats signifi cantly more fruits than the egyptian mongoose and shows little overlap (in terms of fruit diversity) with the other mediterranean carnivores . interestingly, the invasive american mink seems to have a deleterious impact on the abundance of the common genet in northeastern spain because of high niche overlap (melero et al. 2012 ) . similarly to the egyptian mongoose, the common genet avoids suitable habitats where densities of iberian lynxes are high, suggesting a " mesopredator release " when larger carnivores competing for food and interspecies-killing disappear (palomares and caro 1999 ) . the role of g. genetta in carrying zoonotic diseases is unproven. asian viverrids such as the masked palm civet paguma larvata were identifi ed as the source of sars cases with mild symptom in 2004 in china (shi and hu 2008 ) , but so far, no similar coronaviruses were detected in the common genet. on the other hand, in portugal and southwestern france, the species suffers from a high prevalence of a host-adapted canine parvovirus ). the species of herpestids and viverrids present in europe fall into three categories: (1) introduced and spreading ( g. genetta , h. auropunctatus ), (2) introduced and extinct ( h. edwardsii ), and (3) natural disperser and spreading ( h. ichneumon ). usually, species introduced within the last century are considered deleterious ("invasive") by nature , whereas species having naturally dispersed or introduced during historical times (i.e., before 1500 ad ) have been considered as "naturalized." thus, in our case, only the introduction of the small indian mongoose in the balkans has been envisaged in an invasive framework. from the above-mentioned amount of evidence, there is weak support for a deleterious impact of herpestids and viverrids on the european fauna (except possibly on the herpetofauna of small mediterranean islands in the case of the small indian mongoose), notably in comparison with genuine invasive species such as the black rat and the domestic cat. in fact, the small indian mongoose is only 11th on the list of alien species affecting native species in europe, far behind the american mink, the domestic cat, the domestic goat, the european hedgehog erinaceus europaeus , and rats (genovesi et al. 2012 ) . coexistence among native european carnivores seems to occur through a dynamic adjustment of their niches, and there is no body of evidence to refute the fact that the mongooses and genet have fi tted this framework without disrupting the equilibrium of carnivores' communities. my conclusions should have some impact on the way mongooses and genets are considered and managed in european countries. indeed, the episodic, local control operations of those carnivores-notably of mongooses in portugal and croatiahave been shown to be expensive, ineffi cient, and/or potentially deleterious for the rest of the carnivores' communities, while favoring the pullulating of the species on which they prey (e.g., rabbits) (hays and conant 2007 ; barun et al. 2011 ; beja et al. 2009 ). eradication successes of mongooses seem somehow limited to small islands up to 1.15 km 2 (barun et al. 2011 ) , whereas extirpation from larger islands or areas might require enormous means not affordable by most governments (see abe et al. 2006 ; fukasawa et al. 2013 for an example on another species of mongoose in japan). predator control is a contentious issue that is becoming under the scrutiny of the general public, with sectors of the society expressing ethical and biological arguments against the killing of predators (barun et al. 2011 ) . instead, we suggest that the attention of governments should be focused on restoration programs including (1) large carnivores that are natural regulators of mesocarnivore populations (palomares and caro 1999 ) , (2) small carnivores' communities, and (3) their natural habitats, which all may be a safe buffer to the deleterious impacts potentially related to introduced small carnivores ( letnic et al. 2009 ; mcdonald et al. 2007 ) . we urge ecologists to conduct long-term surveys on the population dynamics and trophic overlap of the small indian mongoose with sympatric carnivores and invasive species in europe, in order to provide scientifi cally based guidelines on the attitude to adopt for the management of the species (notably on adriatic islands). future studies should also be directed on the benefi cial aspects of herpestids and viverrids on european ecosystems, including their role as seed dispersers and as regulators of potential pest species such as native and invasive rodents and insects. the potential colonization fronts of the mongooses and genet in europe provide a tremendous framework for studying the dynamics of mesopredators at disequilibrium with their environment. yet, there is a crucial need for comparative studies in areas such as northwestern iberia ( h. ichneumon ), northwestern and southeastern france ( g. genetta ), and the balkans ( h. auropunctatus ) to better understand the processes behind the spread of herpestids and viverrids in europe. eventually, a global perspective on the natural history of those small carnivores in their native ranges (including reproduction strategies, interspecifi c competition with other 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mongoose herpestes auropunctatus on kyushu island herpestes javanicus testing for niche segregation between two abundant carnivores using presence-only data analysis of trophic structure of two carnivore assemblages by means of guild identifi cation domestication and early agriculture in the mediterranean basin: origins, diffusion, and impact key: cord-029201-hkq7wti5 authors: haukkala, hiski title: nonpolar europe? examining the causes and drivers behind the decline of ordering agents in europe date: 2020-07-15 journal: int polit doi: 10.1057/s41311-020-00257-1 sha: doc_id: 29201 cord_uid: hkq7wti5 is europe headed towards nonpolarity? what would that entail for the future stability and security of the continent? taking its cue from ir debates about the effects of polarity on international order, the article develops conceptual tools and an analytical narrative concerning europe during the post-cold war era. it refines the concept of a great power by suggesting the notion of ‘ordering agents’ and ponders whether europe is in danger of drifting towards a period of nonpolarity with no power being able to shoulder the responsibility of ordering and providing good stewardship over europe. for the past five centuries, europe has been the veritable centre of the world. at first the europeans developed the modern conceptions of statehood and international politics and then actively projected these innovations through the application of a 'standard of civilisation' well beyond the continent's boundaries (bull and watson 1984) . in the process, an increasingly global international system was formed, and it has been one where the europeans have continued to enjoy a pride of place. the europeans have also been one of the main sources as well as beneficiaries of western international order. since the end of the cold war, it has rested on us primacy, but it is a wider western phenomenon that has resulted in a liberal and rulebased world order (ikenberry 2018) . in europe, it has been manifest in a concentric hegemonic order where the us global primacy and regionally preponderant security role through nato have been complemented by the european union (eu) that has assumed the position of a regional normative hegemon in its own right ( 2008) with a view of ordering the continent along essentially unipolar lines by envisaging a europe of concentric circles revolving around 'brussels' (aalto 2006; diez and whitman 2002) . in europe, the usa and the eu have formed a 'matryoshka hegemony' (deyermond 2009 ) of sorts that has sought to, and largely succeeded in ordering the continent in a largely unified, or at least complementary manner. for many, these developments have been welcome and benign. unarguably europe has never been as stable and secure as it has been for the past three decades. yet there are growing signs that this era is coming to an end. on the global level, the usa has entered a period of retrenchment with tensions increasing with the rapidly rising china (allison 2017) . under president donald trump, it has also largely abdicated its global leadership role and the liberal rule-based international order is under an immense and growing strain (sørensen 2019) . china together with russia and other smaller regional powers is challenging the current international order on the global level while staking their claims for regional spheres of influence. this is visible also in europe where russia has for some time been making the case for a more equitable bipolar setting. this process of contestation culminated in the ukraine conflict in 2014 that has resulted in a low-simmering conflict between the west and russia. taking its cue from international relations (ir) debates about the effects of polarity (the number of great powers) on the evolution of international order (for a chronological lineage, see waltz 1979; kegley and raymond 1994; mearsheimer 2001; brooks and wohlforth 2008; monteiro 2014) , this article poses the question whether europe is experiencing not only a period of 'normal' geopolitical contestation, but could it in fact be in a transition towards a state of affairs where it will become void of great powers capable of effectively ordering the continent, let alone the wider world. in a word, is europe headed towards a period of nonpolarity? and if so, what would it entail for the future of cooperation, stability and even security on the continent? the article makes three main contributions. firstly, it links european studies with ir debates concerning polarity and the ongoing change in the structure of international politics. it situates itself in the so-called third wave of hegemony studies (ikenberry and nexon 2019) , but concentrates on examining the unravelling of western hegemony in europe. secondly, it seeks to conceptually expand our understanding of great powerhood by introducing the notion of 'ordering agents'. the article seeks to add nuance to the extant literature that has largely simply assumed that great powers are always also capable of generating order. instead, the article draws attention to a whole gamut of prerequisites for successful ordering role in contemporary international politics. moreover, it is argued that these requirements are particularly salient in europe that is undoubtedly the most highly institutionalised region in the world (diez and whitman 2002) . thirdly, the article presents an analytical narrative concerning the developments in europe during the post-cold war era. it does so in two stages: firstly recounting the story of western attempts at hegemonic ordering of europe and russia's growing contestation of it, and then moving on to analysing the main causes and drivers behind potential nonpolarity in europe. the argument will be developed in four stages. firstly, the concepts of (non) polarity and great powerhood are introduced and refined with a view of introducing the concept of 'ordering agents'. secondly, the roles that the usa, the european union and russia have played in ordering europe during the post-cold war era are analysed. thirdly, the causes, drivers and consequences of nonpolarity in europe are discussed. finally, the article concludes by pondering the question whether europe indeed is headed towards a period of nonpolarity and what that could entail for the future of the continent. it ends with a policy relevant point by warning about the possible unintended consequences of current contestation and institutional atrophy in europe. the article suggests that the current trajectory is not in the best interest of any party and engages in some normative argumentation by contending that in the twenty-first century a great power worthy of the name should be held to a higher standard in terms of providing building blocks for stability and order on both the regional and global levels than is currently the case. often order is the norm in everyday life. this is the case in our domestic societies where the monopoly on the legitimate use of violence enjoyed by the states ensures a hierarchical and, at least most of the time, also orderly conduct of our national politics. the anarchical international system does not lend to a clear-cut hierarchy along the domestic lines, but it is not entirely without order, either, that for the purposes of this article is defined as (sub-)systemwide structures and practices-institutions, norms, values and principles-that govern and regulate the conduct of international politics. in international politics, order stems mainly from two sources (see young 1989: 88-89 from which the following is taken). it may emerge spontaneously generated by the 'hidden hand' of international anarchy. oran young has called these self-generated orders, the classic example of which is the principle of balance of power that has at times been rather successful in moderating interstate conflict (little 2014 ). yet for the purposes of this article, and indeed the increasingly interdependent and global international system in which we find ourselves, this is too rudimentary and in effect shallow conception of order. therefore, the other, and arguably more important, avenue for generating order is that of premeditated design. in young's terminology, these imposed or negotiated orders require intentional agency on the part of key actor(s) that take the lead, or act in concert, in generating, upholding and, at times, modifying and even undoing orders. there is nothing automatic in this latter type of order generation, as it takes effort and the use of power to achieve. in the final analysis, it requires not only great power but great power(s) to generate and uphold an international order. but being a great power is not in itself enough, as one must also be both able to conduct the ordering role and willing to carry the associated burden. therefore, it is suggested in this article that order-generating great powers are a particular subset of the category that should be called ordering agents that are defined here as a great power that has the capacity, ability and willingness to establish, uphold and project (sub-)systemwide ordering structures and practices-institutions, norms, values and principles-and, as a consequence, to have intended/desired ordering effects. the essential building blocks of a successful ordering agent are summarised in table 1. let us begin with capacity. this refers to power that is perhaps the most essential concept in the study of international politics (baldwin 2002: 177) . it is also one of the most contested ones. this is not the occasion to try to settle these debates; suffice it to say, that a multifaceted conception of power is called for. the key question here pertains to the quantity and quality of power as well as its varying effects when employed in ordering the international. according to waltz (1993: 50) , great powers require a whole spectrum of attributes: size of population and territory, resource endowment, economic capability, military strength, political stability and competence. traditionally the master variable has been military power, which in an anarchic setting is the ultimate arbiter of conflicts between states. yet it is possible to overstate its relevance, especially in our global and interdependent world (nye 2011) . other forms of power, ranging from economic to 'soft' and normative, play an increasingly important role (baldwin 1989; nye 2004; manners 2002) . it is also noteworthy that military power does not ensure reliable control over outcomes across the board of relevant issues in contemporary international politics: states can employ strategies that offset military power differentials and they can have meaningful geopolitical effects despite not being fully credible peer competitors. indeed, an actor may have the power to affect the behaviour of others through disruptive forms of power-power to avoid nonpreferred outcomes or simply acting as a spoilerwithout necessarily being fully able to coerce others into adopting a stance preferred by the actor. also, if military power is the hammer, not every issue of consequence in contemporary international politics is a nail. on the contrary, there are plenty and perhaps even increasingly issues in the world today that cannot be solved, nor necessarily even contained with the use of military power. the question of climate change as well as other systemic risks, such as pandemics, is a case in point (goldin and mariathasan 2016) . the same applies to the disruptive forms of power, as they do not generate collective capacity for problem-solving and governance. therefore, identifying the existence of great power capacity in the abstract is only the first step in the analysis. without the ability to channel, or translate, that capacity into actual influence they remain only resources, void of actual ordering effects (see also sørensen 2019: 59). analysing power differentials is imperative, yet it does not tell us anything about the quality of interaction and the nature of consequent contestation and ordering between the great powers. the exercise of power is always an empirical issue: it is an outcome of interaction and it cannot be deducted from power differentials alone, regardless of how significant they may be (arreguin-toft 2001) . to gain a more nuanced view of the processes at play, one can turn to the english school and the seminal work of hedley bull. he was one of the first theorists who argued that an order is not merely a pattern that grows out of mechanical interaction between like units, but it is an intentional and in the final analysis also inherently social process where the key actors take the lead in generating and upholding a particular conception of order that rests on a set of shared values, norms and institutions (bull 1995) . for bull, it was indeed the existence of shared institutions, such as balance of power and international law, that formed the basis of what he called table 1 key characteristics of a successful ordering agent in international politics material capability competence, ability to act political willingness to act in an ordering role ideational/ideological foundation for organising principles external appeal/legitimacy of ideas, norms and values promoted 'international society'. but for him the common institutions represented something shared and universal. halliday (1994: 101) has pointed out how bull's international society is 'communitarian', implying a group with shared values. he also did not address the question of change, but adopted a rather conservative stance, advocating relative perpetuity in the constitution of the international society (see friedner parrat 2017). in bull's reading, norms, values and institutions were static and, by and large, seen at the same time as both prerequisites for and in their operation beneficial to the existence of an international society. the point is not that bull was entirely off the mark, however. international order always serves the interests of the wider international society, but does so unevenly. it is important to bear in mind anna leander's (2006: 371) insightful words that an order is never neutral: it always works to the advantage of some and to the (at least potential) disadvantage of others, inviting us to ask whose international order we are talking about (see also williams 2006: 24) . in this interpretation, an international order does not only serve certain useful functions for the society at large, but it also reflects the interests and ideas of certain key players of that society. therefore, an international order is never neutral, nor is it necessarily an entirely voluntary exercise on the part of all its members: a certain amount of co-optation and coercion, at times perhaps even domination is to be expected. the stance taken here is that when it comes to the question of order in international politics, norms, practices and institutions should be viewed as sites of contestation and struggle: in the final analysis, it is their content that reflects both the power and the ideas of those who are able to affect change in them (wiener 2014 ; see also ikenberry and nexon 2019; wivel and paul 2019). in this reading, a choice between power and ideas is a false dichotomy: it is not either ideas or power but both that will be required to make sense of any given international order (sørensen 2008) . although at times a single actor-or a group of actors acting in concert-may be powerful enough to dictate the rules of the game on others, brute strength alone is usually not enough to recalibrate international order. all these point towards the role of intentional agency. order does not change by itself, but it is changed by wilful actors who are able to affect that change. nor does an order sustain itself on its own, but it requires agents that seek to uphold it. this refers to the third variable in our definition, namely the willingness to act as an ordering agent and to carry the associated burden. here, ikenberry's (2001) treatment of international order as a process where the leading state(s) has sought to lock other states into a certain set of institutionalised practices is a useful starting point. in addition, order has always entailed a viable domestic model and the projection of its essential elements beyond borders to generate that very order. this is the case in two different respects. firstly, a viable domestic model is a prerequisite for effective agency: you can only function as an ordering agent internationally if you first function to a satisfactory degree internally. secondly, the reconstitution of an international order must also rely on legitimacy: of the actors involved and the normative foundation promoted (cf. hoffmann 1990: 19-20; philpott 2001: 355-356) . in the words of georg sørensen (2019: 57), 'a stable and legitimate order is founded on a fit among a power base…, a common collective image of order expressed in values and norms, and an appropriate set of institutions'. the last conceptual issue that needs to be discussed in this context deals with the relationship between great power politics and polarity, i.e. the number of great powers in any given international system (waltz 1979: 72) . power is obviously the key consideration in deciphering the number of great power poles: to count as one, their relative capabilities must be roughly commensurate across all domains with the most powerful state in the world. according to kegley and raymond (1994: 75) in a bi-/multipolar system, great powers must be near, but not necessarily absolute equals. the number of poles has varied historically, but in general multipolarity-the existence of more than two poles in the system-has been the norm (see kegley and raymond 1994) . indeed, the post-world war ii eras stand out in a sense that they witnessed, first, a period of intense rivalry between two superpowers locked into a bipolar setting during the cold war, followed by the period of unipolarity with the usa enjoying unrivalled primacy and hegemony during the post-cold war era (monteiro 2014; brooks and wohlforth 2008) . see table 2 for a summary of great powers in europe during the modern era. table 2 shows how although polarity has varied historically, the issue of nonpolarity has not arisen during the modern era. at first sight, the whole notion of nonpolarity might seem odd: surely we are not anticipating the wholesale collapse of the state-centric international system and the disappearance of great powers with it. 1 to better understand how nonpolarity in the european context might be possible and perhaps even likely, we must examine the question of polarity in light of our definition of ordering agents. in its established usage, the relationship between great powers and polarity is almost tautological-great powers are poles and vice versa. but for the present purposes this is not analytically very useful. instead, the article contends that polarity in its traditional reading is a bird's-eye view of international politics based on resources and potential, whereas a more useful analytical lens would take into account the other aspects of agency, namely the ability and willingness to act as an ordering agent in the sense defined above. this entails that to count as a pole, the agent in question must be in possession of a host of attributes: a material power base, ideational foundation and perceived external legitimacy to begin with, but also a political variable concerning the essential competence to act as an ordering agent in international politics and willingness to carry the associated burdens. in light of this discussion, we may define nonpolarity as the lack of great powers that are capable, able and willing to act as ordering agents in a given international system or its sub-system. the term nonpolarity was introduced by richard n. haass who in his article written for foreign affairs over a decade ago defined it loosely as an 'international system… characterised by [too] numerous centres with meaningful (haass 2008 ; see also bremmer 2012 who spoke about a 'g-0 world'). yet the use of the term in this article differs from haass's conception in two respects. first, it is regional in scope, drawing attention to europe instead of overall global politics. second, it does not assume that power has drifted away to or been diffused by a host of nonstate actors to a degree that would account for nonpolarity. on the contrary, the article argues that the potential period of nonpolarity stems from changes that are taking place within the key actors at play: their indigenous capacity and willingness to act as ordering agents are atrophying. in addition, nonpolarity is also an outcome generated by the current interaction and growing contestation between the main contenders for an ordering role. in short, nonpolarity is a situation where great powers are either incapable or unwilling, either alone or in concert, to apply power to successfully create or uphold an international order in europe. the dissolution of the soviet union and the end of the cold war division opened (geo)political space in europe. the rigid bipolar confrontation gave way to a much more fluid setting where fresh opportunities and challenges rapidly mushroomed. this called for new policies on the part of both the usa and the emerging eu. for the usa, the four main objectives were: (1) managing the transition to a new post-cold war order in a peaceful and orderly fashion; (2) facilitating the emergence of russia as a successor state of the soviet union as a responsible and constructive player, including the development of cooperative threat reduction with russia to deal with the toxic assets left behind by the soviet union; (3) ensuring the primacy of nato-and by extension also the usa-in european security, and downplaying the eu's potential to emerge as a fully independent security actor; while (4) using that very eu as a proxy to organise political and economic integration and consequent transition in the emerging wider europe. (for a discussion concerning the key tenets of us policy, see goldgeier and mcfaul 2003; talbott 2002; stent 2014.) the usa took the lead in ordering the post-cold war setting along liberal lines, first in europe and then increasingly also globally (mearsheimer 2019) . for quarter of a century, the usa was able to secure an unrivalled position at the top of international hierarchy. it was also successful in stabilising the conflicts in europe during the 1990s while locking most of the continent into its preferred security structure through the expansion of nato (mastanduno 1997) . even if russia made some dissatisfied noises at the time, there was an expectation that it, too, could be successfully placated by offering moscow some privileged forms of partnership with the west and the usa in particular (asmus 2002) . the eu's rise to prominence dovetailed these developments. in the early 1990s, it started to express ambitions and develop capacities for indigenous views about international affairs and to develop them into policies and actions on the world stage. the adoption of the common foreign and security policy (cfsp) in the maastricht treaty of 1991 was of particular significance, as it created fresh instruments for external action and institutionalised a cooperative culture that over time have resulted in impressive, although perhaps needlessly cumbersome, finesse and complexity in today's eu (see keukeleire and delreux 2014) . in the process, the eu was effectively thrust into assuming a leading role in responding to the economic effects of the dissolving soviet empire. the objectives of the nascent 'european foreign policy' and those of the usa were largely compatible and even complementary to each other. one way to characterise the role the two played in ordering europe is to think of 'matryoshka hegemony' where the us global primacy and regionally preponderant security role through nato set the broad liberal framework within which the eu took the lead in ordering the european continent through the expansion and outward projection of its policies, norms and values (haukkala 2008) . consequently, the usa and the eu, working in tandem, met practically all the requirements for a successful ordering agent in europe: they enjoyed unrivalled material preponderance while portraying both competence and political willingness to act as ordering agents. they also promoted a coherent set of idea(l)s and did so during a period when their leading role enjoyed a great deal of external legitimacy, reflected in the long queues of accession candidates in front of both nato's and the eu's doors. having established this, one should exercise some caution in assigning too much strategic intentionality on the part of the west. both nato's and the eu's eventual sprung nach osten were more reactions and responses to events and demands beyond the west's control or initial appetite rather than preconceived programmes to order or subjugate the whole continent to their will (see asmus 2002; smith 1999; hill 2018) . the hegemonic underpinnings of their ordering role were arrived at in a piecemeal, almost haphazard manner. this gives the western unipolar hegemony over europe a paradoxical quality. to a degree, this also explains why it fizzled out so quickly in the face of growing russian resistance. for quite some time, russia remained an outlier to the western attempts at ordering europe. it was not fully in nor fully out, while it was trying to figure out its own national interests and international identity. in the process, russia has developed an increasingly strained relationship with both the usa and the eu and adopted a highly belligerent approach towards the concentric order they have been propagating. for the russians, the crux of the issue was that it lacked a voice and a role that would have been commensurate with its own self-image as a great power. one way to interpret the events during the last quarter century in europe is to view it as a process of increasing frictions and tensions between the western nato/eu-centric attempts at ordering the continent and russia's growing frustration and even hostility towards its inability to secure a place for itself that would have allowed it a voice and a veto (marten 2017) . in the words of hill (2018) , in the eyes of moscow the european architecture has left 'no place for russia'. related to this is the wider russian complaint concerning the role the usa has played globally. the us post-cold war primacy in general and the way washington responded to the 9/11 terrorist strikes in 2001 accentuated the russian impression of a rampant usa bent on dominating the world unilaterally. in vladimir putin's resentful words, uttered already in 2007, the usa had 'overstepped its national borders in every way' (putin 2007) . positioning itself as a counterforce to a reckless and domineering washington became the leitmotif of putin's rhetoric and russian foreign policy well before the dramatic events in ukraine. although not felt as keenly at the time, the eu enlargement also created its own frictions between russia and the west. in particular, the question of a 'common/ shared neighbourhood' created in the aftermath of the 'big bang' eastern enlargement of 2004 proved to be a source of tensions. ukraine's 2004 orange revolution-which took both the west and russia equally by surprise-changed moscow's tack concerning the eu's role in the region. moscow's previous benign neglect subsided, as it began to view the eu's growing role and the western orientation of the cis countries with increasing suspicion (gretskiy et al. 2014) . although it was not appreciated at the time, the orange revolution was the starting gun for the preparation of operations and practices witnessed first in georgia in 2008 and then in crimea and eastern ukraine since 2014 (franke 2015) . over time russia's grudging acquiescence to western liberal hegemony morphed into outright opposition. yet the current conflict between russia and the west was far from inevitable. on the contrary, in early 2000s both parties were still looking for ways to make the relationship work. (for accounts that testify to this effect, see forsberg and haukkala 2016; stent 2014.) these repeated attempts at 'resets' and other fresh beginnings were marred by the underlying and largely irreconcilable tension where the western unipolarity, however, well intended, ran counter to the growing russian calls for a more equitable and essentially bipolar setting in europe. by the end of 2000s, russia started to take much more assertive steps to promote its preferred vision of order beyond its borders. in the first instance, this took the form of the eurasian economic community (eurasec) that soon became the eurasian economic union (eaeu) through which russia started to invest in a more institutionalised bipolar setting in europe, with moscow as the leading power in the other half of the continent with the expectation of attracting the majority, if not all, of the post-soviet states under russia's leadership (see dragneva and wolczuk 2013) . although the eaeu did gain some initial momentum, as exemplified by the expansion of its members from the original three to current five, the fact that russia felt compelled to resort to open blackmail and coercion to attract new members to the eaeu speaks volumes about the power of attraction of the new regional bloc. the conflict in ukraine was the culmination of these unhappy trends (haukkala 2016) . with its actions, russia made abundantly clear that it views eastern europe as its primary sphere of interests (trenin 2009 ) that both the eu and nato must respect and that it is willing to use all the means at its disposal to enforce this policy. russia also signalled its readiness to pay a high price in terms of economic hardship and international, although mainly western, opprobrium for doing so (menon and rumer 2015; wilson 2014) . the reasons for this are myriad, but the main point worth stressing is that the near-existential nature of russian interests in and over eastern europe creates an asymmetry that is unfavourable to the west: no matter how hard it pushes its version of order on the east, moscow is always willing to push back a little harder-and accept the eventual price for doing so. in other words, russia has been stable, able and ruthless enough to act as a spoiler in europe, but, apart from the eaeu that contains severe internal tensions and contradictions, as exemplified by the catastrophic outcome of trying to co-opt ukraine to join the organisation in 2013-14 testified, it is not competent, capable or even willing to act as an ordering agent in europe. on the contrary, the dramatic escalation in ukraine in 2014 has been followed by a pattern where russia has proved ruthless in the application of power to challenge and to a degree overturn the current order on the regional level. admittedly, compared with the west russia is lacking in many of the key attributes of power. its population is stagnating and its economy is weak and almost entirely reliant on the sale of hydrocarbons on increasingly turbulent world markets. yet what it may suffer in the aggregate, it amply makes up in the skill and will to employ the wherewithal at its disposal (see baldwin 1979: 163) . when this is factored in, russia's record of accomplishment, and indeed short-to midterm potential, looks more promising. russia has also shown great acumen in projecting military means to achieve political ends beyond its borders both in its immediate vicinity in ukraine and even beyond as the events in syria have shown. this continued contestation is also a factor that feeds into the potential emergence of nonpolarity in europe, discussed next. to a degree, the above narrative is compatible with traditional forms of ordering in international politics. it is possible that the process we are currently witnessing is merely 'normal' turbulence associated with a period of intense contestation that will be followed by the creation of a new or at least amended order in europe (gilpin 1981 ). yet in recent years a myriad of factors and developments have warranted asking the question whether the notion of nonpolarity is in fact more applicable. by examining the factors outlined in the definition of an above ordering agent, we can see how the main contenders in europe portray varying drivers for the rapid decline in the current order and augur the possible emergence of nonpolarity on the continent. to begin with, one must note how the unified, even if concentric, western hegemony in europe is rapidly unravelling. both the usa and the european union portray much less cohesion and ability to act in tandem as successful ordering agents than previously. under trump, the transatlantic partnership has experienced growing strains, even signs of serious erosion. (the process is documented in brookings 2020.) the trump administration views the eu and its institutions with hostility and its european allies with growing suspicion. over time, the europeans, too, have started to lose faith in their partnership with the americans. the relations between the eu and the usa have atrophied with no meaningful dialogue or interaction currently taking place between brussels and washington. consequently, the ability of the two to coordinate their activities and channel their respective energies in the same direction has been lost. as a result, it is difficult to talk about western hegemony in europe anymore. what is more, the whole idea of a unified 'west' is increasingly being questioned on both shores of the atlantic (kimmage 2020; tcherneva 2018) . this is a development that affects the european order negatively and has a major impact on the evolution of relations on the global level as well. if the two former hegemons have found it hard to work together, the same applies to their roles individually in europe. in the us case, the issue is not the wholesale atrophy in the capacity to act as an ordering agent. no one is suggesting that in terms of overall capacity or competence the usa is completely lacking or that it lacks economic or military power. but what it increasingly is lacking, is the ability, through the erosion of perceived legitimacy and the lack of essential willingness to uphold the current order globally and in europe. this is due to the political variable that stems from the current period of soul-searching revolving around the perceived need to recalibrate the us global role and posture in light of the new era of 'great power competition' that is seen as being in the offing. the trump presidency has accentuated and aggravated these trends, but he is not the root cause behind them. kagan (2018) might be right in arguing that trump has struck a stake through the heart of the liberal world order, but the problem is not just him. the us role would be changing in any case. in the short term, a lot will depend on the presidential elections in november 2020. but even if trump is unseated, it will most probably affect mainly the mood and atmospherics in transatlantic relations. that can be significant, but will not undo nor necessarily even repair the damage that stems from deep-seated structural factors and tensions between the usa and the eu (polyakova and haddad 2019) . turning to the eu, we find it increasingly isolated, alone and adrift, essentially clinging to the vestiges of its preferred order globally and regionally without the necessary means to project or protect that very order. the fact that the eu does not seriously register as a military power would seem to exclude from the list of possible poles, yet it would be erroneous to discount it as an ordering agent. economically the eu is still in a very strong position, even if the problems of governing the european common currency cast a shadow on its prospects. in addition, waltz's (2000: 31) verdict concerning the europeans two decades ago seems to hold: the eu still lacks the organisational ability and the collective political will to translate its sizable power potential into credible international actorness. moreover, there are mounting signs that the eu is no longer acknowledged as a key player in global affairs, if indeed it ever was. on the contrary, european perspectives are increasingly sidelined in global politics. increasingly, the eu is not the actor, but the stage upon which others act. the eu's inability to project order, or at least stymie growing instability, is most visible around its own borders. the european neighbourhood policy (enp) that was meant to result in a 'ring of friends' around the eu effectively collapsed in the ukraine conflict. the aftermath of the so-called arab spring resulted in the tragic civil war in syria and completed the current outcome that the economist dubbed a 'ring of fire' around the union (haukkala 2017) . none of this to argue that these developments are primarily the eu's fault-but to act as a successful ordering agent, one needs to be able to project stability and not just protest instability around you. internally the eu's situation is equally precarious. during the last decade, it has repeatedly succumbed into crises that have sapped its energies and legitimacy even in the eyes of its own citizens (wivel and waever 2018) . at times, it seems as if the europeans are facing growing problems in keeping even their own eu house in order, as exemplified by brexit and the growing internal fissures concerning economic governance and the rule of law in europe (krastev 2017; zielonka 2018) . it should, however, be pointed out that we are not talking about the potential collapse of the eu itself. yet there exists serious doubt whether and to what extent the eu can keep up its role as an ordering agent even among its own ranks, let alone aspire to a successful ordering role externally. the final contender, russia, demonstrates very few or perhaps not at all signs of playing a constructive ordering role in europe for the moment. on the contrary, it does not even aim to generate order elsewhere than at home and seems busy wielding a geopolitical wrecking ball to hasten the demise of the current order. considering our definition for an ordering agent, russia has fallen short during post-cold war era, and even before, as exemplified by the collapse of the soviet union and its empire. currently it does not have the economic power base to act as an ordering agent nor does it offer any coherent alternative to the order it is criticising. currently moscow's actions do not add up to a positive agenda nor does it seem to aspire to one. consequently, the external appeal and legitimacy of russia's agenda in europe is very limited. taken together, none of these attributes translate into a capacity to act as an ordering agent in the european setting. this discussion is tentatively summarised in table 3 : tentatively, because to assess these findings with full confidence would obviously require more rigorous analysis. that said, it is nevertheless hoped that the thesis has enough prima facie plausibility so that it merits to be taken seriously and is subjected to more rigorous research and analysis in the future. europe has entered a period of relative decline and its role and heft in global politics is rapidly shrinking. there are deep structural forces at play, and the diminution in europe's importance is inevitable. at the same time, these developments are compounded by the fact that the very order undergirding europe's own security and stability is deteriorating. this article argues that this not only is due to normal geopolitical contestation, but is a sign that europe is in danger of losing ordering agents, i.e. great powers capable, able and willing to create or sustain order on the continent. the main driver behind these developments is the changing us power and role in europe. under trump, washington has lost its appetite to act as the bulwark of stability in europe. this has resulted in the ongoing collapse of the 'matryoshka hegemony', the previously complementary concentric us and eu ordering roles in europe. to make matters worse, the eu is not up to the task on its own and, it seems, the final contender for the ordering role in europe, russia, is not even interested in it. in addition, the internal trajectories within both the eu and russia point towards decreasing capacity for successful ordering agency. therefore, it is time to put forward the question whether the conflict between the west and russia is contributing to the relative decline of europe in world politics at large, and whether the unintended consequence of this contestation could be hastening the arrival of a period of nonpolarity in europe, with no power being able nor necessarily even willing to shoulder the responsibility of ordering and providing good stewardship in and over europe. we have no historical track record of nonpolarity in the modern era, yet we can surmise about its possible effects based on conceptual and empirical understandings weak of international politics. it is argued that a period of nonpolarity would pose serious problems, for two reasons. firstly, europe is living in an era of high and constantly rising interaction capacity that creates both demands and challenges in terms of coordination and cooperation (buzan 1993, 331) . trade and other flows, both legal and illicit, as well as the increasingly important cyber space all require governance and joint management. secondly, we are living in an era of high complex interdependence (keohane and nye 1977) that also includes mounting risks and challenges, some of them potentially catastrophic, even on a global scale (ord 2020) . handling these issues requires order and ordering agents. order is the prerequisite for governance without which the risks inherent in our current world become very difficult, practically impossible to control or contain. the haphazard and uneven response to the covid-19 coronavirus pandemic is a case in point. these are global trends, but it is argued that in europe these issues are even more pertinent because for the last three decades, and more, europe has generated its own web of densely institutionalised forms of cooperation, rules and regulations that require capable ordering agents for their continued existence. russia might find some of these entanglements too close for comfort, but, it is argued, they, along with the us military overlay, have been instrumental in keeping the peace on the continent. a way to read the current situation is to envisage it as a dialectical process where the western thesis has now been fully countered by the russian antithesis. the synthesis remains still to be seen-but it is not an easy one to locate or arrive at due to the essential incommensurability of current positions. indeed, the crux of the potential for nonpolarity in europe is the fact that currently no one can impose an order anymore, while the sides are deeply divided and unable to agree on a new one. one avenue forward might be a return to some form of a balance of power in europe. yet the discrepancies between the various forms of power are probably too large to allow for that. moreover, the internal dynamics within the main potential ordering agents are such that the situation is unlikely to remain stable enough to allow for a sustainable recalibration of the european setting. on the contrary, a safer prognosis seems to be the continued and perhaps even expanding turbulence in europe. over time, the lack of good stewardship over europe will result in further erosion of norms and institutions, generating growing friction and potential for conflict. this means missed economic opportunities and increasing inability to work successfully together to tackle wider problems facing europe and the world. more worryingly, the hard-won gains of the past 80 years are at risk of being undone. an open conflict between russia and the west cannot be excluded. this should be a cause for concern and rallying call for more responsible policies and politics. the emergence of a nonpolar europe cannot or should not be in anyone's interest. what is more, in the twenty-first century a great power worthy of the name should be held to a higher standard in terms of providing building blocks for stability and order on both the regional and global levels than is currently the case. this is not a new idea: as brown (2004) has argued, great powers, simply due to the virtue of their size and importance, have always been held to a higher standard than other powers. in the final analysis, the advent of possible nonpolarity in europe depends on political choices by the main protagonists. indeed, this article is not a prognosis that nonpolarity in europe is inevitable. three questions in particular stand out that will affect the future developments: (1) the evolution of the us role globally and in europe; (2) the eu's ability to overcome its current crises and to develop more robust forms of international actorness; and (3) the future of russia's conflict with the west as well as the evolution of its appetite to seek more constructive roles and openings in europe. nonpolar europe can still be avoided by political choices and responsible policies by the main actors that foster the return of capable, credible and committed ordering agents in europe. european union and the making of a wider northern europe destined for war: can america and china escape thucydides's trap? how the weak wins wars? a theory of asymmetric conflict opening nato's door. how the alliance remade itself for a new era power analysis and world politics: new trends versus old tendencies paradoxes of power power and international relations every nation for itself: what happens when no one 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american foreign policy after europe. philadephia paradigms as a hindrance to understanding world politics the balance of power in international relations: metaphors, myths and models normative power europe: a contradiction in terms reconsidering nato expansion: a counterfactual analysis of russia and the west in the 1990s preserving the unipolar moment: realist theories and u.s. grand strategy after the cold war the tragedy of great power politics bound to fail the rise and fall of the liberal international order conflict in ukraine. unwinding of the post-cold war order theory of unipolar politics public affairs. nye, j.s. 2011. the future of power the precipice: existential risk and the future of humanity sovereignty: an introduction and brief history speech and the following discussion at the munich conference on security policy the making of eu foreign policy: the case of eastern europe the case for combining material forces and ideas in the study of ir pyrrhic victory: a world of liberal institutions, teeming with tensions the limits of partnership. u.s.-russian relations in the twenty-first century the russia hand. a memoir of presidential diplomacy the end of the concept of 'the west'? ecfr commentary russia's spheres of interests, not influence the emerging structure of international politics a theory of contestation order and society ukraine crisis: what it mean for the west 2019. international institutions and power politics: bridging the divide the power of peaceful change: the crisis of the european union and the rebalancing of europe's regional order international cooperation: building regimes for natural resource and the environment counter-revolution: liberal europe in retreat publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest the author asserts no conflict of interest with this article. key: cord-022176-hprwqi4n authors: löscher, thomas; prüfer-krämer, luise title: emerging and re-emerging infectious diseases date: 2009-07-28 journal: modern infectious disease epidemiology doi: 10.1007/978-0-387-93835-6_3 sha: doc_id: 22176 cord_uid: hprwqi4n emerging infectious diseases (eids) are characterized by a new or an increased occurrence within the last few decades. they include the following categories emerging diagnosis of infectious diseases: old diseases that are newly classified as infectious diseases because of the discovery of a responsible infectious agent. europe including great britain as well as in india, china, and japan. emerging vector-borne disease events concentrated in densely populated subtropical and tropical regions mostly in india, indonesia, china, sub-saharan africa, and central america (see figs. 3.3, 3.4 , and 3.5). the identification of new infectious agents in old diseases with unknown etiology is still the basis in many epidemiological studies. such newly detected bacteria and viruses in the last few decades are listed in table 3 .1. since the detection of helicobacter pylori in 1983, this infection has been identified as the causative agent in 90% of b-gastritis cases. the risk of duodenal ulcer is increased by 4-25-fold in patients with helicobacter-associated gastritis. who declared h. pylori as a carcinogen of first order because of its potential to enhance the risk of stomach carcinoma and malt lymphoma in long-term infection. in highprevalence regions for h. pylori, the frequency of stomach carcinoma is significantly higher compared to low-endemic areas (correa et al. 1990 ). the identification of h. pylori facilitates curative treatment of most associated diseases in individuals. but the most important epidemiological effect on associated diseases is attributed to increased hygienic standards in industrialized countries with a substantial reduction of h. pylori prevalences in younger age cohorts. transmission of h. pylori occurs mainly in childhood. in western developed countries the overall prevalence is around 30%, higher in older age groups due to a cohort effect, and this increases with low socioeconomic status (rothenbacher et al. 1989 ). in countries with low hygienic standards the prevalences are still high in younger age groups and reach 90% in developing countries. in developed countries, migrant subpopulations from less-developed regions show significantly higher prevalences in comparison to the nonmigrant population (mégraud 1993 ). since the early 20th century, a characteristic expanding skin lesion, erythema migrans (em), and an arthritis associated with previous tick bites were known. borrelia for many decades. increased outdoor activities facilitated contacts between humans and ticks in the 1970s and the 1980s and increased transmission of borrelia to humans at the northeastern coast of north america, leading to the discovery of borrelia burgdorferi in 1981 by willy burgdorfer. three different stages of the disease that describe the stage of infection and the involvement of different organ systems are known: stage 1, early localized infection; stage 2, early but disseminated infection; and stage 3, late stage with persistent infection. lyme disease is endemic at the east coast and in minnesota in the united states, in eastern and central europe, and russia. seroprevalence rates that reflect about 50% of nonclinical infections vary between 2 and 18% in the general population in germany (hassler et al. 1992; weiland et al. 1992) . in high-risk groups like forest workers in germany the prevalences reach 25-29% (robert koch institute 2001a). in ticks (ixodes) the prevalences are between 2 and 30% depending on the geographical area and the testing method used [immunofluorescence test, ift and polymerase chain reaction (pcr)]. in most studies the main risk factors of infection are age (children: 4-9 years, adults 35-60 years), outdoor activities, skin contacts with bushes and grass, and the presence of ticks in domestic animals (robert koch institute 2001b) . the probability of infection (seroconversion) after a tick bite in germany is 3-6% and the probability of a clinical disease is 0.3-1.4%. the probability that the bite of an infectious tick leads to infection in the host is 20-30%. this depends on the time duration that the tick is feeding on the human body. since the detection of the etiologic infectious agent and the subsequent development of laboratory diagnostic tests in the 1980s, the number of reported cases of lyme disease has increased from 0 to 16,000 per year, indicating that it is an "emerging diagnosis." the reported numbers vary depending on the reproduction of the hosting rodents for ticks as well as the contacts between humans and nature (spach et al. 1993) . ticks may live for several years and their survival, reproduction rate, and activity are directly affected by changes in seasonal climate through induced changes in vegetation zones and biodiversity, hence causing local alterations of the tick's habitat and in the occurrence of animals that are carriers of different pathogens (like small rodents). several studies in europe have shown that in recent decades the tick ixodes ricinus, transmitting lyme borreliosis and tick-borne encephalitis (tbe), has spread into higher latitudes (e.g., sweden) and altitudes (e.g., czech republic, austria), and has become more abundant in many places. such variations have been shown to be associated with recent variations in climate. as a result, new risk areas of both diseases have recently been reported from the czech republic. climate change in europe seems likely to facilitate the spread of lyme borreliosis and tbe into higher latitudes and altitudes, and to contribute to extended and more intense transmission seasons. currently, the most effective adaptive strategies available are tbe vaccination of risk populations and preventive information to the general public (danielova et al. 2004; lindgren et al. 2006; materna et al. 2005 ). an effective vaccine was licensed for b. burgdorferi in 1999. in europe, where different variants of borrelia are present (mostly b. afzelii and b. garinii), this vaccine is not protective. trivalent vaccines for europe are in clinical trials. in recent years, norovirus infections are increasingly recognized as the cause of large outbreaks of diarrheal diseases in the general population, school classes, nursing homes, hospitals, and cruise ships in western countries with peaks in colder seasons (winter epidemics) (centers of disease control 2006; verhoef et al. 2008; robert koch institute 2008a) . this is a typical example for emerging diagnosis due to increasing availability of routine pcr testing for these viruses in stool samples. noroviruses (family caliciviridae) are a group of related, single-stranded rna viruses first described in an outbreak of gastroenteritis in a school at norwalk, ohio, in 1968. five genogroups are known. immunity seems to be strain specific and lasts only for limited periods, so individuals are likely to get the infection repeatedly throughout their life. it is estimated that noroviruses are the cause of about 50% of all food-borne outbreaks of gastroenteritis. for several years there has been an ongoing epidemic in several european countries due to drift variants of a new genotype (gg ii.4jamboree) previously unknown to this nonimmune population (robert koch institute 2008a). as a result of an analysis of 232 outbreaks in the united states between 1997 and 2000, direct contamination of food by a food handler was the most common cause (57%), person-to-person transmission was less prevalent (16%), and even less frequently waterborne transmission could be proved (3%) (centers for disease control 2006). vomiting is a frequent symptom of norovirus enteritis and may result in infectious droplets or aerosols causing airborne or contact transmission. this may explain the difficulty to stop outbreaks in hospitals, nursing homes, and similar settings despite precautions to prevent fecal-oral transmission. also on cruise ships, person-to-person transmission is most likely in those closed settings, and drinking tap water is a risk factor as well (verhoef et al. 2008 ). searching for an agent which causes large outbreaks of enterically transmitted non-a hepatitis in asia and other parts of the world, the hepatitis e virus (hev) was first described in 1983 and cloned and sequenced in 1990 (reyes et al. 1990 ). meanwhile, hev has been shown to be a zoonotic virus circulating in pigs and other animals. it is implicated in about 50% of sporadic cases of acute hepatitis in developing countries and associated with a high case fatality rate in the third trimester of pregnancy (10-25%). hev is a major cause of large epidemics in asia, and to a lesser extent in africa and latin america, typically promoted through postmonsoon flooding with contamination of drinking water by human and animal feces. recent data show hev also to circulate in european countries and to be associated with severe and fatal disease not only during pregnancy but also in the elderly and in patients with chronic liver conditions. in patients with solid organ transplants, hev may even cause chronic hepatitis and liver cirrhosis (kamar et al. 2008) . a recombinant hev vaccine candidate has demonstrated a high protection rate of approximately 95% during clinical trials in nepal (shrestha et al. 2007 ). for 30 years, specific human papillomaviruses have been linked to certain human cancers and have been identified as causative agents of malignant proliferations. in the 1980s the detection of papillomavirus dna from cervical carcinoma biopsies were published, showing that hpv types 16 and 18 are the most frequent (dürst et al. 1983; boshart et al. 1984) . the relation of hpv infections and cancer is further discussed in chapter 23. definition: only infections that are newly discovered in humans are listed in this chapter: hiv, new variant of creutzfeldt-jakob disease (vcjd), hemorrhagic uremic syndrome (hus) caused by enterohemorrhagic escherichia coli, viral hemorrhagic fevers like hanta, lassa, ebola, and marburg fever, nipah virus encephalitis, monkeypox, human ehrlichiosis, severe acute respiratory syndrome (coronavirus infection, sars), and avian influenza (h5n1) (see fig. 3 .1 and table 3 .2). these infections mostly have their origin in zoonotic wildlife (e.g., avian influenza, monkeypox, hantavirus, nipah virus, and filoviruses) or livestock (e.g., vcjd). factors promoting the spread of these infections in humans are contacts with wildlife, mass food production of animal origin, and globalization (migration, transportation of goods and vectors) (see fig. 3 .2). in addition, new strains or variants of well-known pathogens have emerged showing increased or altered virulence such as clostridium difficile ribotype 027 or staphylococcus aureus strains expressing the panton-valentine leukocidin (see also chapter 22). the epidemiology of hiv is treated in chapter 18 and that of avian influenza and new influenza h1n1 in chapter 16. in the year 1995, 3 years after the peak of the bse epidemic in the united kingdom, with an annual incidence rate in cows of 6.636 per million bovines aged over 24 months, the first mortalities in humans with a new variant of creutzfeldt-jakob disease were observed in the united kingdom. until 2007, smaller incidence rates of bse cases had been reported by 21 other european countries in indigenous bovines and up to more than 43,000 per million in 2004 in ireland. from 1999, bse started to increase in switzerland and portugal, from 2004 in spain and in recent years has spread to eastern european countries (organisation mondiale de la santé animale 2008). the infectious agent is a self-replicating protein, a "prion." the source of infection for cows is infectious animal flour. the transmission to humans occurs through oral intake of cow products, most likely undercooked meat and nerval tissues as well as transplants of cornea, dura mater, contaminated surgical instruments, or the treatment with hypophyseal hormones extracted from animal tissues. after a statuary ban on the feeding of protein derived from ruminants to any ruminant and the export ban of all cow products from england, the epidemic of bse in cows and the occurrence of human infections decreased in the united kingdom since 2004. by june 2008 the total number of deaths in definite/probable cases of vcjd in the united kingdom was 163 (the national creutzfeldt-jakob disease surveillance unit 2008). only a few numbers of vcjd were reported from other european countries and the united states (who 2008). nipah virus encephalitis was first observed in 1997/98 in malaysia. the disease was transmitted by pigs to laborers in slaughterhouses and showed a lethality of 40%. the infectious agent was detected in 1999 (chua et al. 2000; lam and chua 2002) . since then, several outbreaks of nipah virus infections have been observed in asian countries: singapore in 1999, india 2001 , and bangladesh since 2003 (who 2004a harit et al. 2006) . the virus has been isolated repeatedly from various species of fruit bats, which seem to be the natural reservoir (yob et al. 2001 ). west nile is a mosquito-borne flavivirus that was first isolated from a woman with a febrile illness in uganda in 1937. from the 1950s, west nile fever endemicity and epidemics started being reported from africa and the middle east. severe neurological symptoms were thought to be rare. more recent epidemics in northern africa, eastern europe, and russia suggested a higher prevalence of meningoencephalitis with case fatality rates of 4-13%. in 1999, west nile virus was identified as the cause of an epidemic of encephalitis at the east coast of the united states (nash et al. 1999) . a seroepidemiological household-based survey showed that the first outbreak consisted of about 8,000 infections of which about 1,700 developed fever and less than 1% experienced neurological disease ). since then, epidemics occur during summer months in north america each year, with an estimated 35,000 febrile illnesses and over 1,200 encephalitis or meningitis cases in the united states in 2007 (centers for disease control 2008). age above 50 years is the main risk factor for developing severe disease. the virus is transmitted mainly by culex mosquitoes, but also by sandflies, ceratopogonids, and ticks, with birds as reservoir hosts and incidental hosts such as cats, dogs, and horses. efforts are made to reduce the transmitting mosquito population and to prevent mosquito bites through personal protection as well as to prevent transmission through blood donations by screening (centers of disease control 2008). the first case of sars occurred in guangdong (china) in november of 2002, leading to an outbreak with 7082 cases in china and hong kong (8096 cases worldwide) until july 2003. the case fatality rate was 9.6%. a new coronavirus (sars-cov) was identified as the causative agent (drosten et al. 2003) , being transmitted first by infected semidomesticated animals such as the palm civet and subsequently from human to human. some cases were exported to other countries, causing smaller outbreaks there, canada being the most affected country outside asia with 251 cases, before control of transmission was effective. eight thousand and ninety-six cases were reported worldwide, until july 2003, then further transmission stopped (besides one more case of laboratory transmission in 2004), indicating an efficient international cooperation in disease control (who 2004b) . recently, sars-cov has been found in horseshoe bats, which seem to be the natural reservoir of the virus. about 150,000-200,000 cases of hemorrhagic fever with renal syndrome (hfrs) caused by hantaviruses are reported annually worldwide, with more than half in china, many from russia and korea, and numerous cases from japan, finland, sweden, bulgaria, greece, hungary, france, and the balkan with different death rates depending on the responsible virus, ranging from 0.1% in puumala to 5-10% in hantaan infections (schmaljohn and hjelle 1997) . hantaviruses are transmitted from rodent to rodent through body fluids and excreta. only occasionally do humans get infected. different types of hantaviruses are circulating in europe and the eastern hemisphere, predominantly puumala virus, dobrava virus, and tula virus, adapted to different mouse species. depending on the virus type the case fatality rate is between 1 and 50%. as an example, the annual rate of reported cases in germany was about 100 cases per year from 2001 onward. this started to change in 2005 with 448 reported cases and rose dramatically to 1687 cases in 2007. that year, hantavirus infections were among the five most reported viral infections in germany. reasons for the rise in human infections were an increase in the hosting rodent population due to a very mild winter 2006/2007 and an early start of warm temperatures in spring which led to favorable nutritional situations for the mice influencing their population dynamics. in addition, favorable climatic conditions enhanced the outdoor behaviors of humans facilitating transmission in rural areas (robert koch institute 2008b; hofmann et al. 2008) . since 1993, a previously unknown group of hantaviruses (sin nombre, new york, black creek canal, bayou-in the united states and canada; andes, in south america) emerged in the americas as a cause of hantavirus pulmonary syndrome (hps), an acute respiratory disease with high case fatality rates (approx. 35%), causing a new, significant public health concern. a total of 465 cases had been reported until march 2007 in 32 states, most of them in the western part of the united states (centers for disease control 2007). lassa virus was detected for the first time in 1969 during an outbreak affecting nurses in a missionary hospital in lassa, nigeria. however, the disease had previously been described in the 1950s. lassa virus is enzootic in a common peridomestic rodent in west africa, the multimammate rat mastomys natalensis, which is chronically infected and sheds the virus in urine and saliva. human infection through direct or indirect contact with rats or their excretions is rather common in some west african countries and estimates from seroepidemiological and clinical studies suggest that there are several hundred thousand cases annually. however, only a minority of infections seems to progress to severe hemorrhagic disease with a case fatality rate of 5-30% in hospitalized cases. the virus can be transmitted by close person-to-person contact and nosocomial spread has been observed under poor hygienic conditions. marburg and ebola viruses, which were first detected during outbreaks in 1967 and 1975, respectively, have so far been observed only during several limited outbreaks and a few isolated cases in certain countries of sub-saharan africa. however, very high case fatality rates (25-90%), the occurrence of outbreaks that were difficult to control in resource-poor settings, and the obscure origin of these viruses have attracted considerable public interest worldwide. recently, evidence was found for both marburg and ebola viruses to occur in certain species of bats that probably constitute the natural reservoir of these filoviruses (towner et al. 2007 ). although the disease burden of these viral hemorrhagic fevers is low, they gained considerable international attention due to -their high case fatality rates, -the risk of person-to-person transmission, -several imported cases to industrialized countries, and -fears of abuse of these agents for bioterrorism. as a consequence, considerable resources have been invested, even in nonendemic countries, in the setting up of task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing. this highly virulent strain of c. difficile expresses both cytotoxins a and b and, in addition, the binary toxin cdt, an adp-ribosyltransferase. due to a deletion in the regulatory tcdc gene, the synthesis rates of toxin a and b are increased by 16-and 23-fold, respectively. this strain was detected in 2000 for the first time in pittsburgh, usa. since then it has spread to canada, and in 2003 it reached europe causing multiple outbreaks in hospitals and nursing homes (warny et al. 2005) . c. difficile 027-associated colitis has shown high case fatality rates (10-22%) and an increased relapse rate. containment of outbreaks in hospitals and other institutions necessitates isolation of patients or cohorts and strict hygienic measures. during recent decades, a large variety of well known infectious diseases has shown regional or global re-emergence with considerable public health relevance (table 3. 3). globally, tuberculosis is probably the most important re-emerging infectious disease. in developing countries, tb infection still is extremely common and, in the wake of the hiv pandemic, the percentage of those developing overt disease has increased dramatically. worldwide, tb is the most common opportunistic infection in patients with aids. the significance of tb and hiv/tb coinfection is reviewed in chapters 16 and 18. the re-emergence of some infectious diseases is closely related to the lack or the breakdown of basic infrastructures as seen in periurban slums and in refugee camps in developing countries, or as a consequence of war, breakdown of the civil society, or natural or man-made disasters. cholera is a formidable example for both re-emergence and epidemic spread under those conditions. another important group of re-emerging infectious diseases is caused by various vector-borne infections, such as malaria, dengue fever, and yellow fever. these major vector-borne diseases are treated in more detail in chapter 21. in addition, there are a variety of re-emerging infections transmitted by arthropod vectors such as various arboviral diseases and some protozoal diseases other than malaria (i.e., leishmaniasis, human african trypanosomiasis). the reasons for the emergence of several vector-borne diseases are rather variable and may range from climatic factors (e.g., global warming, rainfall), lack or breakdown of control, to changes in agriculture and farming and in human behavior (e.g., outdoor activities). these factors are usually quite specific for each of these diseases and largely depend on the specific ecology of the agent, its vectors, and reservoirs. cholera, an acute diarrheal infection transmitted by fecally contaminated water and food, had been endemic for centuries in the ganges and brahmaputra deltas in the 19th century before it started to spread to the rest of the world. since 1817, six pandemics caused by the classical biotype of vibrio cholerae were recorded that killed millions of people across europe, africa, and the americas. it has been a major driving force for the improvement of sanitation and safe water supply. the seventh pandemic was caused by the el tor biotype, first isolated from pilgrims at the el tor quarantine station in sinai in 1906. it started in 1961 in south asia, reached africa in 1971, and is still ongoing. after more than hundred years, cholera spread to the americas in 1991, and beginning in peru, a large epidemic hit numerous latin american countries with 1.4 million cases and more than 10,000 fatalities reported within 6 years. out of the 139 serogroups of v. cholerae, only o1 and o139 can cause epidemics. the serogroup o139, first identified in bangladesh in 1992, possesses the same virulence factors as o1 and creates a similar clinical picture. currently, the presence of o139 has been detected only in southeast and east asia, but it is still unclear whether v. cholerae o139 will extend to other regions. since 2005, the re-emergence of cholera has been noted in parallel with the everincreasing size of vulnerable populations living in unsanitary conditions. cholera remains a global threat to public health and one of the key indicators of social development. while the disease is no longer an issue in countries where minimum hygiene standards are met, it remains a threat in almost every developing country. the number of cholera cases reported to the who during 2006 rose dramatically, reaching the level of the late 1990s. a total of 236,896 cases were notified from 52 countries, including 6,311 deaths, an overall increase of 79% compared with the number of cases reported in 2005. this increased number of cases is the result of several major outbreaks that occurred in countries where cases had not been reported for several years such as sudan and angola. it is estimated that only a small proportion of cases -less than 10% -are reported. the true burden of disease is therefore grossly underestimated. the absence or the shortage of safe water and sufficient sanitation combined with a generally poor environmental status are the main causes of spread of the disease. typical at-risk areas include periurban slums where basic infrastructure is not available, as well as camps for internally displaced people or refugees where minimum requirements of clean water and sanitation are not met. however, it is important to stress that the belief that cholera epidemics are caused by dead bodies after disasters, whether natural or manmade, is false. on the other hand, the consequences of a disaster-such as disruption of water and sanitation systems or massive displacement of population to inadequate and overcrowded camps-will increase the risk of transmission. chikungunya virus, an arbovirus belonging to the alphavirus group, is transmitted by various mosquitoes. the virus was first isolated in tanzania in 1952 and since then has caused smaller epidemics in sub-saharan africa and parts of asia with low public health impact. in 2005, the largest epidemic ever recorded started in east africa, spread to réunion and some other islands of the indian ocean, and then spread further to asia, with more than 1.5 million cases in india alone so far. characteristics of the disease are high fever and a debilitating polyarthritis, mainly of the small joints that can persist for months in some patients. now, for the first time, severe and fatal cases have been observed that may be due to certain mutations of the epidemic strain (parola et al. 2006) . the asian tiger mosquito aedes albopictus has proved to be an extremely effective vector in recent epidemics causing high transmission rates in big cities and leading to epidemics with high public health impact. this southeast asian mosquito species has been shipped by transport of used tires and plants harboring water contaminated with larvae to other continents and, since 1990, ae. albopictus has successfully spread in italy and other parts of southern europe. in august 2007, an outbreak of chikungunya fever occurred in northern italy with more than 200 confirmed cases. the index case was a visitor from india who fell ill while visiting relatives in one of the villages and further transmission was facilitated by an abundant mosquito population during that time, as a consequence of seasonal synchronicity (rezza et al. 2007 ). ross river virus (rrv) is another arbovirus of the alphavirus group that causes an acute disease with or without fever and/or rash. most patients experience arthritis or arthralgia primarily affecting the wrist, knee, ankle, and small joints of the extremities (epidemic polyarthritis). about one-quarter of patients have rheumatic symptoms that persist for up to a year. the disease can cause incapacity and inability to work for months. it is the most common arboviral disease in australia with an average of almost 5,000 notified cases per year. rrv is transmitted by various mosquito species and circulates in a primary mosquito-mammal cycle involving kangaroos, wallabies, bats, and rodents. a human-mosquito cycle may be present in explosive outbreaks which occur irregularly during the summer months in australia and parts of oceania. heavy rainfalls as well as increasing travel and outdoor activities are considered as important factors contributing to the emergence of rrv epidemics. this flavivirus is transmitted by certain culex mosquitoes and is a leading cause of viral encephalitis in asia with 30,000-50,000 clinical cases reported annually. it occurs from the islands of the western pacific in the east to the pakistani border in the west, and from korea in the north to papua new guinea in the south. only 1 in 50-200 infections will lead to encephalitis, which is, however, often severe with fatality rates of 5-30% and with a high incidence of neurological sequelae. despite the availability of effective vaccines, je causes large epidemics and has spread to new areas during recent decades (e.g., india, sri lanka, pakistan, torres strait islands, and isolated cases in northern australia). je is particularly common in areas where flooded rice fields attract water fowl and other birds as the natural reservoir and provide abundant breeding sites for mosquitoes such as culex tritaeniorhynchus, which transmit the virus to humans. pigs act as important amplifying hosts, and therefore je distribution is very significantly linked to irrigated rice production combined with pig rearing. because of the critical role of pigs, je presence in muslim countries is low. crimean-congo virus is a bunyavirus causing an acute febrile disease often with extensive hepatitis resulting in jaundice in some cases. about one-quarter of patients present hemorrhages that can be severe. fatality rates of 7.5-50% have been reported in hospitalized patients. cchf is transmitted by hyalomma ticks to a wide range of domestic and wild animals including birds. human infection is acquired by tick bites or crushing infected ticks, and also by contact with blood or tissue from infected animals that usually do not become ill but do develop viremia. in addition, nosocomial transmission is possible and is usually related to extensive blood exposure or needle sticks. human cases have been reported from more than 30 countries in africa, asia, southeastern europe, and the middle east. in recent years, an increase in the number of cases during tick seasons has been observed in several countries such as russia, south africa, kosovo, and greece. in turkey, where before 2002 no human cchf cases had been observed, a total of 2,508 confirmed cases, including 133 deaths, were reported between 2002 and june 2008. the emergence of cchf has been associated with factors such as climatic features (temperature, humidity, etc.), changes of vector population, geographical conditions, flora, wildlife, and the animal husbandry sector. rvf is a mosquito-borne bunyavirus infection occurring in many parts of sub-saharan africa. it infects primarily sheep, cattle, and goats, and is maintained in nature by transovarial transmission in floodwater aedes mosquitoes. it has been shown that infected eggs remain dormant in the dambos (i.e., depressions) of east africa and hatch after heavy rains and initiate mosquito-livestock-mosquito transmission giving rise to large epizootics. remote sensing via satellite can predict the likelihood of rvf transmission by detecting both the ecological changes associated with heavy rainfall and the depressions from which the floodwater mosquitoes emerge. transmission to humans is also possible from direct and aerosol exposure to blood and amniotic fluids of livestock. most human infections manifest themselves as uncomplicated febrile illness, but severe hemorrhagic disease, encephalitis, or retinal vasculitis is possible. in 1977, rvf has been transported, probably by infected camels to egypt, where it caused major epidemics with several hundred thousand infections of humans. it has been suggested that introduction of rvf may be a risk to other potentially receptive areas such as parts of asia and the americas. floods occurring during the el niño phenomenon of 1997 in east africa subsequently gave rise to large epidemics and further spread to the arabian peninsula. most recent epidemics occurred in 2006 and 2007 following heavy rainfalls in kenya, somalia, and sudan, causing several hundred deaths. besides mosquito control, epidemics are best prevented by vaccination of livestock. leishmaniasis, a protozoal transmitted by sandflies, has shown a sharp increase in the number of recorded cases and spread to new endemic regions over the last decade. presently, 88 countries are affected with an estimated 12 million cases worldwide. there are about 1.5 million new cases of cutaneous and mucocutaneous leishmaniasis, a nonfatal but debilitating disease with 90% of cases occurring in afghanistan, brazil, bolivia, iran, peru, saudi arabia, and syria. the incidence of visceral leishmaniasis (vl), a disease with a high fatality rate when untreated, is estimated at around 500,000 per year. the situation is further aggravated by emerging drug resistance (table 3 .4) and the deadly synergy of vl/hiv coinfection. epidemics usually affect the poorest part of the population and have occurred recently in bangladesh, brazil, india, nepal, and sudan. for many years, the public health impact of the leishmaniases has been grossly underestimated. they seriously hamper socioeconomic progress and epidemics have significantly delayed the implementation of numerous development programs. the spread of leishmaniasis is associated with factors favoring the vector such as deforestation, building of dams, new irrigation schemes, and climate changes, but also with urbanization, migration of nonimmune people to endemic areas, poverty, malnutrition, and the breakdown of public health. antimicrobial resistance of epidemiological relevance has emerged as a major problem in the treatment of many infectious diseases (table 3 .4). resistance is no longer a problem that predominantly affects the chemotherapy of bacterial infections. it became increasingly important in parasitic and fungal diseases, and despite the short history of antiviral chemotherapy, it already plays a prominent role in the treatment of hiv infection and other viral diseases. resistance is also a problem in some of the emerging infections and will further complicate their treatment and control. resistance of bacterial pathogens has become a common feature in nosocomial infections, especially in the icu and in surgical wards. currently, the number one problem in most hospitals is s. aureus resistant to methicillin (mrsa, see chapter 22). however, common problems of resistance also extend to other major bacterial pathogens such as enterococci, various gram-negative enteric bacilli, and pseudomonas species. resistance has developed not only to standard antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, macrolides, or quinolones) but also to second-line antibiotics including carbapenems, glycopeptides, and newer quinolones. however, there is considerable geographic variation. in 2006, the european antimicrobial resistance surveillance system (earss), a network of national surveillance systems, reported vancomycin-resistant rates among enterococci ranging from none in iceland, norway, romania, bulgaria, denmark, and hungary to 42% of enterococcus faecium strains in greece (earss 2006) . a surveillance study conducted in the united states hospitals from 1995 to 2002 showed that 9% of nosocomial bloodstream infections were caused by enterococci and that 2% of e. faecalis isolates and 60% of e. faecium isolates were vancomycin resistant (wisplinghof et al. 2004) . rates and spectrum of antibacterial resistance of e. coli and other gram-negative enteric bacilli may differ considerably from one hospital to the other. in some important pathogens of hospital-related infections such as klebsiella, enterobacter, and pseudomonas species, resistance to almost all available antimicrobials has been observed. this may complicate the choice of an effective initial chemotherapy considerably. therefore, each hospital has to monitor the epidemiological situation of resistance regularly, at least for the most important bacteria causing nosocomial infections, such as staphylococci, enterococci, gram-negative enteric bacilli, and pseudomonas. even in community-acquired infections, there has been a considerable increase in resistance problems. at present, approximately 15% of pneumococcal isolates in the united states are resistant to penicillin, and 20% exhibit intermediate resistance. the rate of resistance is lower in countries that, by tradition, are conservative in their antibiotic use (e.g., netherlands, germany) and higher in countries where use is more liberal (e.g., france). in hong kong and korea, resistance rates approach 80%. in addition, about one-quarter of all pneumococcal isolates in the united states are resistant to macrolides. this rate is even higher in strains highly resistant to penicillin, and increasingly there is multiresistance against other antibiotics such as cephalosporins. the prevalence of meningococci with reduced susceptibility to penicillin has been increasing, and high-level resistance has been reported in some countries (e.g., spain, united kingdom). although high-dose penicillin is effective in infections with strains of intermediate resistance, most national and international guidelines recommend broad-spectrum cephalosporins such as ceftriaxone as first-line drugs. however, in most developing countries, penicillin and chloramphenicol are the only affordable drugs. in recent years, certain strains of community-acquired s. aureus with resistance to methicillin (cmrsa) have been observed which produce a toxin (panton-valentine leukocidin) that is cytolytic to pmns, macrophages, and monocytes, and which are an emerging cause of community-acquired cases and outbreaks of necrotic lesions involving the skin or the mucosa, and in some patients also of necrotic hemorrhagic pneumonia with a high case fatality (vandenesch et al. 2003) . development of resistance is mainly determined by two factors: -the genetic potential of a certain pathogen, i.e., mobile elements such as plasmids, transposons, or bacteriophages, genes coding for resistance, and mutation rate. -the selection pressure caused by the therapeutic or the para-therapeutic application of antimicrobial drugs. in the hospital these factors are supported by -microbial strains that are highly adapted to this environment (e.g., rapid colonization of patients, resistance to disinfectants), -an increasing percentage of patients who are highly susceptible to infections due to old age, multimorbidity, immunosuppression, extended surgery, and invasive procedures, and -the frequent use of broad-spectrum antibiotics or combinations of antimicrobial drugs. another source of resistant bacteria has been identified in mass animal production and the use of antimicrobials as growth promoters (e.g., the glycopeptide avoparcin, the streptogramin virginiamycin) or as mass treatment in the therapy or the prevention of infections. the inadequate use of antimicrobial drugs is also an important factor responsible for the development of resistance in community-acquired infections. this is especially true in developing countries where only a limited spectrum of antibiotics is available, where shortage of drugs often leads to treatment that is underdosed or too short, and where uncontrolled sale and use of antibiotics is commonplace. as a consequence, resistance of gonococci is extremely frequent in southeast asia, and resistance of salmonella typhi, shigella, and campylobacter to standard antibiotics is common. some of the still effective second-line antibiotics have to be given parenterally or are not available because they are too costly. a typical example of the consequences of insufficient chemotherapy due to lack of compliance and/or unavailability of drugs is the alarming increase in multiresistance and extreme resistance in tb (see chapter 16). resistance is also a problem in parasitic diseases such as malaria (see chapter 21), leishmaniasis, or african trypanosomiasis. plasmodium falciparum developed resistance against all major antimalarial drugs as soon as they were used on a broad scale. resistance had contributed significantly to the increase in malaria-associated morbidity and mortality observed in many endemic areas (wongsichranalai et al. 2002) . a recent report on failures of the new artemisinin combination treatment for p. falciparum malaria at the thai-cambodian border supports fears of the development of resistance to this most promising class of drug at present (dondrop et al. 2009 ). resistance against antiviral drugs has developed almost from the beginning of antiviral chemotherapy (table 3 .4). in the treatment of hiv infection, the risk of development of resistance has been drastically reduced by the combination of several drugs with different mechanisms of action (see chapter 18). however, drug resistance remains the achilles' heel of the highly active antiretroviral therapy (haart) and may be at a considerable risk of expanding haart to the developing world. today, we have to realize that as we develop antimicrobial drugs, microbes will develop strategies of counterattack. antimicrobial resistance occurs at an alarming rate among all classes of pathogens. even in rich countries it causes real clinical problems in managing infections that were easily treatable just a few years ago. in life-threatening infections such as sepsis, nosocomial infections, or falciparum malaria, there is a substantial risk that the initial chemotherapy might not be effective. in addition, the delay caused by inadequate treatment might favor transmission to other people and support the spread of resistant pathogens (e.g., multiresistant tb). last but not the least, surveillance and control and the necessity to use expensive second-line drugs or combinations of antimicrobials are enormous cost factors. for developing countries this is a major limitation in the treatment and control of infections caused by resistant agents. so, in many ways, emerging resistance contributes to the emergence of infectious diseases. despite the availability of effective strategies for treatment and prevention, infectious diseases have remained a major cause of morbidity and mortality worldwide. however, the problems associated with infections are due to considerable changes. in industrialized countries the mortality caused by infectious diseases has decreased tremendously during more than 100 years. however, during recent years, both mortality and morbidity associated with infections are increasing again. ironically, this is closely associated with the advances in medicine which have contributed to profound changes in the spectrum of both patients and their infections. advanced age, underlying conditions, and an altered immune response are common features in the seriously infected hospital patient today. immunosuppressive therapy is frequently used to treat neoplastic and inflammatory diseases or to prevent the rejection of transplants. some infections, most notably hiv/aids, cause immunosuppression by itself. in the compromised patient, infections are generally more severe or may be caused by opportunistic pathogens that will not harm the immunocompetent host. antimicrobial treatment is often less effective in these patients and tends to be further complicated by antimicrobial resistance which may manifest itself or develop at a higher frequency in the immunocompromised patient. an increasing percentage of infections are hospital acquired or otherwise health care associated. it is estimated that nosocomial infections affect 1.7 million patients and contribute to approximately 100,000 deaths in us hospitals annually (klevens et al. 2007 ). considering the rising number of elderly and immunocompromised patients, a further increase in severe infections can be predicted. in developing countries, the significance of infectious diseases has remained high for ages and despite the advances in medicine. until now, infections are by far the leading cause of both disability-adjusted life years and life years lost. the reasons are obvious and mostly related to poverty and lack of development causing poor and unhealthy living conditions, inadequate health systems, and lack of resources for prevention and treatment. this is, of course, just an integral part of the general socioeconomic problems of developing countries. however, poor health conditions per se are an important obstacle to development, and infections such as hiv/aids in sub-saharan africa can be a major cause of lack of development, increasing poverty, and political instability. generally, the situation of many developing countries has not improved during the last two decades, and the gap between the first and the third world has increased. however, most of the mortality and morbidity associated with infectious diseases is avoidable. as laid down in the millennium goals, a major task of the world community will be to counteract the imbalance between the industrialized and the developing countries and to find strategies to ensure participation in the progress of modern medicine for all. developing countries also carry the main burden of diseases caused by newly emerging and re-emerging infections (table 3. 2 and 3.3) . however, the consequences of economical and political crises on emerging infectious diseases are obvious in industrialized countries also-such as the return of diphtheria or the increase in tb and multiresistant tb after the breakdown of the former soviet union. today, all countries worldwide are affected by emerging infections as well as by emerging antimicrobial resistance. in the age of globalization, travel and transport of people, animals, and goods of all kinds have increased tremendously. as a consequence, infectious agents may travel over long distances and at high speed. this is clearly evident with influenza pandemics or outbreaks such as the sars epidemic or with imported cases of viral hemorrhagic fever transmissible from person to person. the spread of antimicrobial resistance or the re-emergence of tb seems to be less spectacular, but the consequences may be at least as important in the long run. management and control of emerging and re-emerging infectious diseases can be very different from disease to disease and has to allow for all relevant factors of the populations at risk and of the specific disease including the ecology of the agent, its vectors, and reservoirs. however, some basic principles apply to all situations: -surveillance -information and communication -preemptive planning and preparedness -provision and implementation of • adequate treatment • adequate control and prevention -international cooperation active and passive surveillance systems with rapid reporting and analysis of data are essential for the early detection of outbreaks, changes in epidemiology, and other events of public health concern (see chapters 8 and 9). however, many resourcepoor countries do not have functional surveillance systems. in addition, reporting of infectious diseases may be neglected or delayed because of fears of stigma, international sanctions including trade and travel restrictions, or interference with tourism. classical examples are plague and cholera, but also recent examples such as the bse/vcjd crisis in the united kingdom or sars originating from china showed undue delays between first occurrence of cases and information to the public. although, in outbreaks of new and unknown diseases it may be difficult, or even impossible, to predict or assess the magnitude of the problem and the potential consequences, timely and adequate information and communication is not only obligatory, according to international regulations, but also the best strategy to avoid rumors, misbeliefs, panic, or disregard. in recent years, many countries have installed national plans of action for important epidemiological scenarios and outbreaks such as pandemic influenza, bioterrorism, import of viral hemorrhagic fevers transmissible from person to person, sars, and comparable diseases or outbreaks. all member states of the world health assembly that have so far not been able to install functional surveillance and/or pre-emptive planning are obliged to do so within a maximum of 5 years after their ratification of the new international health regulations (who 2005) . preparedness not only means surveillance and planning but also has to include the provision of facilities to adequately treat and, if necessary, to isolate patients with infectious diseases of public health importance and relevant epidemic potential and/or at risk of transmission to other persons including health-care workers. task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing have been set up in several countries. however, all health facilities of a certain level such as general hospitals should be prepared by their organization and structure to treat patients with infections of public health relevance such as multiresistant tb under appropriate isolation and barrier nursing conditions. this also applies to hospitals in resource-poor countries. adequate training of health-care workers and strict management have been effective to control outbreaks of highly contagious infections within rural african hospitals lacking sophisticated technical equipments (cdc 1998) . strategies for control and prevention may be quite different for various emerging infections. effective vaccinations are available only for some infections and are usually lacking for newly emerging infections (table 3 .5). for the majority of emerging infections, control and prevention have to rely on information, education and exposure prophylaxis, interruption of transmission by vector control and control of reservoir hosts (e.g., rodents), and case finding with early diagnosis and treatment. for diseases and outbreaks caused by infections of public health relevance that are transmissible from person to person, containment procedures including isolation and treatment of patients under condition of barrier nursing as well as tracking and surveillance of contacts are warranted by national and international health regulations. here, international cooperation is essential to successfully contain outbreaks and epidemics such as the sars epidemic in 2003. despite dramatic progress in their treatment and prevention, infectious diseases are still of enormous global significance with tremendous economic and political implications. emerging and re-emerging infectious diseases as well as emerging antimicrobial resistance are major challenges to all countries worldwide. for the management of current and future problems, it will be most important to counteract the imbalance between the industrialized world, new economies, and developing countries, and to adequately and timely react to new threats on a global scale. a new type of papillomavirus dna, its presence in genital cancer and in cell lines derived from genital cancer world health organization: infection control for viral haemorrhagic fevers in the african health care setting nipah virus: a recently emergent deadly paramyxovirus helicobacter and gastric carcinoma. serum antibody prevalence in populations with contrasting cancer risks effects of climate change on the incidence of tick-borne encephalitis in the czech republic in the past two decades artemisinin resistance in plasmodium falciparum malaria identification of a novel coronavirus in patients with severe acute respiratory syndrome a papillomavirus dann from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions susceptibility results for e. faecium isolates lyme-borreliose in einem europäischen endemiegebiet: antikörperprävalenz und klinisches spektrum hantavirus outbreak global trends in emerging infectious diseases hepatitis e virus and chronic hepatitis in organtransplant recipients estimating health care-associated infections and deaths in u.s. hospitals nipah virus encephalitis outbreak in malaysia lyme borreliosis in europe: influences of climate and climate change, epidemiology, ecology and adaptation measures. who regional office for europe altitudinal distribution limit of the tick ixodes ricinus shifted considerably towards higher altitudes in central europe: results of three years monitoring in the krkonose mts epidemiology of helicobacter pylori infection 1999: results of a household-based seroepidemiological survey outbreak of west nile virus infection novel chikungunya virus variant in travelers returning from indian ocean islands isolation of a cdna from the virus responsible for enterically transmitted non-a, non-b hepatitis infection with chikungunya virus in italy: an outbreak in a temperate region waldarbeiter-studie berlin-brandenburg 2000 zu zeckenübertragenen und andere zoonosen risikofaktoren für lyme-borreliose: ergebnisse einer studie in einem brandenburger landkreis übertrifft die infektionszahlen der vorjahre zahl der hantavirus-erkrankungen erreichte 2007 in deutschland einen neuen höchststand prevalence and determinants of helicobacter pylori infection in preschool children: a population-based study from germany hantaviruses: a global disease problem safety and efficacy of a recombinant hepatitis e vaccine tick-borne diseases in the united states the national creutzfeld-jakob disease surveillance unit (ncjdsu) marburg virus infection detected in a common african bat community-acquired methicillin-resistant staphylococcus aureus carrying panton-valentine leukocidin genes: worldwide emergence multiple exposures during a norovirus outbreak on a river-cruise sailing through europe toxin production by an emerging strain of clostridium difficile associated with outbreaks of severe disease in north america and europe prevalence of borrelia burgdorferi antibodies in hamburg blood donors nipah virus outbreaks in bangladesh revision of the international health regulations nosocomial bloodstream infections in us hospitals: analysis of 24 179 cases from a prospective nationwide surveillance study large outbreak of norovirus: the baker who should have known better epidemiology of drugresistant malaria nipah virus infection in bats (order chiroptera) in peninsular malaysia key: cord-025724-ea09nbkh authors: mitzner, veera title: conclusion and further thoughts date: 2020-05-30 journal: european union research policy doi: 10.1007/978-3-030-41395-8_10 sha: doc_id: 25724 cord_uid: ea09nbkh the conclusion chapter not only summarizes the main results of the research conducted for this book but also connects the events and discussions between the 1960s and 1980s to later political developments. it shows striking ideational and institutional continuity and reveals a substantial character of european integration: by relying on powerful political framings and discourses, as well as on sturdy institutions, the european community/union was able to move into areas that were not sanctioned by the treaties. the chapter further argues that to stay relevant, the eu research policy must be capable of breaking with the past and dramatically expand its mission to embrace the social and environmental challenges of the twenty-first century. in fact, with the existential threat of climate change and other global challenges, and the urgent need for socio-technological transformation at scale, opportunities and imperatives for european level activity in research might be greater than ever. separation of europe from the technologically more advanced united states, the european political and economic elites appeared open to arguments for unifying european resources in science and innovation. with the postwar market liberalization, rapid technological change, and the gradual shift of production to the newly industrialized countries, the case for joint european research effort seemed plausible. maria nedeva and linda wedlin have divided the development of european union research policy in two main phases: "science in europe" and "european science." according to these two scholars, the first phase, "science in europe," which roughly covers the time period analyzed in this book, was characterized by the principle of subsidiarity-an idea that european-level action would only be appropriate if action at a national level was insufficient; focus on increasing collaboration amongst researchers from different european countries; and concerns of the technology gap, which nedeva and wedlin call the "european paradox," as europe as a world leader of science seemed to lag behind in the industrial and economic exploitation of scientific ideas. furthermore, "science in europe" witnessed three distinct waves: the establishment of large, transnational facilities, such as european organization for nuclear research (cern), euratom, european molecular biology organization (embo), and european molecular biology laboratory (embl); the creation of "diffuse" organizations, such as european cooperation in science and technology (cost) and the european science foundation (esf), including all fields of research and providing platforms for cross-national cooperation rather than supporting science at european level; and finally the creation of the ec/eu framework program for research, bringing the scattered research programs under one administrative umbrella. for nedeva and wedlin, "science in europe" was a period "during which a partial and fragmented science and research system was developed." it complemented rather than challenged national science, research, and innovation arrangement; it had a limited impact on universities, research institutes, and national funding agencies and landscapes; and it "didn't in a rule, include explicitly european-level research performing organizations." 1 this book doesn't challenge nedeva's and wedlin's analysis. for a long time, the ec/eu research policy had a partial character-the first initiatives were not designed to directly challenge activity in national settings. the proponents of european level activities in the field, while often ambitious and visionary, were aware of the political realities. even the "european paradox" argument is solid, although the debate had its ebbs and flows and occurred in different variations depending on the context and advocates. fears of european technological retard did push initiatives forward, at different degrees of success, giving them rationale and a sense of urgency. also, european level research facilities were still few and far in between, and decisions in brussels barely influenced the daily operations of universities and research institutes in the ec member states. however, with a closer historical analysis, we also see an emerging policy that was constantly challenged, contested, and vetted by a number of groups, and in particular those who would mostly have been affected by it. and this is the vital "more to the story" that nedeva's and wedlin's and others' accounts do not fully tell. this book also unveils the bigger ambitions of policy-makers and dreamers by fletching out the protracted struggles for initiatives that either never quite made it to the fruition or were realized as truncated versions, to the disappointment of many. it sheds light to the already forgotten and fluid policy spaces where the feasible and unfeasible were defined, and where future pathways were sometimes painfully determined. crucially, these spaces were shaped by broader political, social, and economic circumstances within and beyond europe, and the prevalence and strength of specific ideational shifts and conditions, such as the fading of the naïve enthusiasm about science that had characterized the immediate postwar period; increasing uneasiness about growth policies and calls for better accountability of economic and scientific activity; new limitations imposed by economic austerity; persisting distrust in european level bureaucracy among academics and national policy-makers; and ongoing political battles in other policy areas within the ec context. yet one distinct thread runs through all these events and debates: a basic agreement on the beneficial role of research and research policy in achieving greater growth and competitiveness, and the need to create joint political mechanisms to that end. how this would eventually be achieved remained open for contestation. besides being a story of continuity and struggle, this book also is an account of the vulnerability of a political idea that survived, grew big, and eventually transformed european research. it was just as strong as its proponents, which at the beginning were not many. although the commission made sure that science policy experts would be involved in the elaboration of the various schemes from the start, these experts often represented governments and national science funding bodies rather than the broader science community. the lack of active participation of scientists and their advocates, as well as of industry and the wider public in the early discussion on the topic, is striking; until the 1980s, most proposals were developed in technocratic milieus with little public attention. the backing of pro-european associations such as union des industries de la communauté européenne (unice), the european parliament, and some individuals from national research institutions and administrations remained too weak and fragmented to put significant pressure on key decision-makers. this is the tragedy of the early ec/eu research policy. politicians in the ec member states, whose main concern was often winning the support of the electorate, tended to focus on issues with more immediate political benefit. it was not the case that the citizens in the community member countries had opposed the idea of the europeanization of scientific and technological activities: in the community's surveys of public opinion, research has consistently been at the top of the list of policies that people think should not be managed exclusively at a national level. 2 research was, nevertheless, not the kind of "high politics" that would be surrounded by glamour and drama and that would have reached the headlines. it remained distant to the lives of ordinary citizens who barely knew of the commissions initiatives. 3 it is also exactly this technical, abstract, complex, and distant nature of this policy domain that at least in part explains the persisting gap between rhetoric and reality in european research policy from the mid-1960s to the mid-1980s. for national politicians, expressing catchy phrases and stirring rhetoric about science and its many promises for the future, could be politically advantageous but also relatively safe: sacrifices in this sector rarely had a direct impact on the lives of voters, and therefore, they seldom provoked significant public protests. the late 1960s' protests at the ispra euratom joint research centre stand out as a notable exception, as multiple employees were threatened to lose their jobs as a result of decisions made in brussels. but in most cases, lip service in research policy came at a low political price. in the absence of a systematic backing of scientists or their representatives, the commission alone was too weak to induce the national governments to truly commit to developing a community research policy. moreover, commission's strategy was not always consistent: important tensions prevailed between the dgs, while each commissioner in charge of research pursued a slightly different policy. the existence of dg research, under various names since 1967, however, became a central structure for guaranteeing institutional and ideational continuity. the dg constituted a center where bureaucrats and experts, sharing some important ideas and interests, could further elaborate schemes for new community activity. this finding supports katia seidel's research on dgs iv (agriculture) and vi (competition), which shows that the administrative cultures developed in those dgs and the subsequent socialization of officials into these cultures, "helped to bring about policies in relevant areas, and then to keep them on track." 4 through the discussions initiated by dg research and others, the ec gradually formed an arena for "europeanization" 5 in research where socialization of different experts and political actors could take place. intra-european connections were reinforced, and similarities increased, while "europe" was given new contents and contours. at the same time, it would be misleading to argue that all contacts within the realm of the research policy debate would automatically have led to greater cohesion. these exchanges also exposed to governments and experts the diverse character of european research systems and made them aware of the difficulty in creating a strongly integrated common policy. yet they prepared the ground for subsequent initiatives that would take off with a more favorable political momentum. in the early 1980s, the various plans and scattered activities of the previous twenty years finally evolved into something that could be said to have an important scope and political and economic significance. the first step into this new direction was the launch of sizeable technological programs, the pioneer being european strategic program on research in information technology (esprit), an initiative that was intended to develop a european strategic scheme based on collaboration between major european companies, small-and medium-sized firms, universities, and research institutes. the project was successful: of the proposals received in response to the first call, less than 25 percent could be funded. not surprisingly, after 1985, esprit became the model for successive community programs, such as research in advanced communications in europe (race) and basic research in industrial technologies (brite). 6 the expansion of these activities led to the creation of the first framework program for research (1984) (1985) (1986) (1987) in 1984. the €3.75 billion budget of the framework program, together with the budget for esprit of €750 million, signified a threefold increase in the community's research spending in 1982. moreover, the program sparked off a steady and fast increase of the community's research budgets. peter tindemans has observed that after esprit, there were a growing number of scientists and industrialists involved in the consultations, projects, and evaluations, and thereby directly benefiting from the community's activity in the field. this created "an almost unstoppable dynamic of pressure [that] arose in national capitals and in the directorates-general responsible for the fp's [framework programs] to increase the budget." 7 although the role of the ec as a focal point of common european research activities remained contested, as was demonstrated by the creation of eureka, an intergovernmental initiative intended to promote "near-market research," in 1985, and by the difficult negotiations of the subsequent framework programs, the political context had changed. national governments were now more willing to see the ec take a central role in the field, and a horizontal and vertical growth of brussels-led activities ensued. all this was supported by the favorable conjuncture in european integration that ensued the single market program. the first framework programs were still focused on advancing applied, marketoriented research, but during the 1990s, these programs became more comprehensive and versatile as they included new mechanisms and stretched into different disciplines and sectors. they also opened up for countries outside the ec/eu framework, developed collaboration with other european and international organizations, and finally became more closely integrated with the ec/eu core policies. 8 an eu-centric european research space started to emerge. this is, indeed, where wedlin and nedeva see the shift to "european science," marked by a changing understanding of the "european added value." whereas the previous ec/eu activities had been primarily focused on fostering collaboration between researchers, now there was a widely shared desire to increase the level of integration in different aspects of european science and research. new tools were designed to strengthen the european knowledge base and to support basic research through competitive funding. 9 a key concept here is the european research area (era). 10 originally dreamed up by commissioner ralf dahrendorf in the 1970s, the idea was revived by commissioner alberto ruberti in the 1990s, and finally pushed to the center of the european political agenda by commissioner philippe busquin. endorsed as an ambitious effort to pool european scientific and technological resources, the initiative marked a clear break with the distributive approach that had characterized the eu activities in the preceding years. 11 while the definition of what the era stands for has evolved over the years, it has brought new inclusiveness into the eu research policy and signaled a move toward a more europeanized research policy field, "where the era agenda provides justification for the adoption of new institutions and funding tools." 12 era aimed to increase the commission's autonomy in initiating projects and programs with direct implications for national activities. 13 in 2012, the commission defined era as "a unified research area open to the world based on the internal market, in which researchers, scientific knowledge and technology circulate freely and through which the union and its member states strengthen their scientific and technological bases, their competitiveness and their capacity to collectively address grand challenges." 14 era was launched in the political framework of the lisbon european council of march 2000, where the eu set itself the new strategic goal of becoming "the most competitive and dynamic knowledge-based economy in the world capable of sustainable economic growth, with more and better jobs and greater social cohesion." 15 in lisbon, research and development were drawn to the center of the eu's strategy for achieving its goal by 2010. essentially, scientific research, technological development, and innovation were defined as key factors in growth, competitiveness, and employment in a knowledge-based european economy. 16 this trend was continued in the eu's new growth strategy, europe 2020, launched in 2010. one of the seven flagship initiatives announced in the strategy was innovation union, aiming to "improve conditions and access to finance and innovation, to ensure that innovative ideas can be turned into products and services that create growth and jobs." 17 era was considered a core element of the innovation union and the europe 2020 strategy. 18 the eu's 2002 barcelona target to achieve r&d funding of 3 percent of gdp-an objective largely motivated by the higher r&d investment levels in the united states and japan-gave era additional political support and visibility. 19 according to wedlin and nedeva, "european science" has created "an organizational space for the support of research that is aligned, and in competition with national-level research spaces." 20 a key invention in this space was the european research council (erc), created in 2007 as a part of the seventh framework program. by allowing european researchers to compete with all other researchers in the eu area on the basis of excellence, erc revolutionized the eu's approach to supporting scientific activity. with scientific excellence as the sole criterion for selection and sizeable pots of money to distribute (the first budget in the seventh framework program (2007-2013) was 7.51 billion euros, and it almost doubled for horizon 2020, constituting 17 percent of the overall program budget), 21 erc soon became a powerful tool for boosting european knowledge space and shaping science in europe. the shifting agendas and the broadening scope of the ec/eu activities have been paralleled by the gradual strengthening of the community's legal status. after the still very restricted formulation of the single european act (1986), the treaty of maastricht (1992) included a new article 130, which required that "the community and the member states shall coordinate their research and technological development activities so as to ensure that national policies and community policy are mutually consistent." moreover, the commission was granted the explicit right to take any "useful initiative" to promote such consistency. 22 the amsterdam treaty (1997) then abandoned the requirement for council unanimity for adoption of the co-decision on the framework program. from now on, the program could be adopted by a qualified majority vote. the union's competences in the domain were further widened by the article 179 of lisbon treaty (2007), stating that: 1. the union shall have the objective of strengthening its scientific and technological bases by achieving a european research area in which researchers, scientific knowledge and technology circulate freely, and encouraging it to become more competitive, including in its industry, while promoting all the research activities deemed necessary by virtue of other chapters of the treaties. 2. for this purpose the union shall, throughout the union, encourage undertakings, including small and medium-sized undertakings, research centres and universities in their research and technological development activities of high quality; it shall support their efforts to cooperate with one another, aiming, notably, at permitting researchers to cooperate freely across borders and at enabling undertakings to exploit the internal market potential to the full, in particular through the opening-up of national public contracts, the definition of common standards and the removal of legal and fiscal obstacles to that cooperation. 3. all union activities under the treaties in the area of research and technological development, including demonstration projects, shall be decided on and implemented in accordance with the provisions of this title. 23 within ten years, the ec/eu research policy activity had firmly become woven into the legal fabric of the union. while the ec's/eu's legal base strengthened and its activities broadened, the community/union gradually moved into territories traditionally occupied not only by european nation-states but also by various intergovernmental organizations promoting research. in this book we have seen how already in the 1960s and 1970s, the ec challenged more established organizations such as the oecd and the council of europe. in the subsequent years, this trend continued. indeed, as the eu is thus increasingly dominating the european research field, one can observe an incremental transformation of previously non-ec/eu projects and institutions into eu or quasi-eu projects and institutions, or alternatively, a launching of new eu operations practically identical to existing activities in other european organizations. a good example here is space research. the cooperation agreement signed between the eu and the european space agency in 2003 constituted a new framework for a comprehensive european space policy involving the coordination of the actions of the european commission and esa through a joint secretariat, a small team of eu administrators and esa executives, as well as ministerial-level meetings in the space council. in 2007 there was a further development when twenty-nine european countries expressed their support for a european space policy, prepared jointly by the european commission and the esa's director-general. moreover, the lisbon treaty gave the european union an explicit competence in space, calling for the development of a european space program. the implementation of this program has further increased cooperation between the eu and the esa. in the recent past, almost 20 percent of the funds managed by esa have originated from the eu budget. 24 the european science foundation, on the other hand, after almost nearing death in 2011, 25 has acknowledged the eu's growing role in promoting european science and wound down all its collaborative research instruments and networks. with a stated mission to serve the european research area for the sole benefit of science, it now focuses on running an expert division called science connect that provides services to the science community. this is a significant shift: since its creation in 1974, esf has run over 2000 world-class science programs and networks, with support from eighty member organizations in thirty countries. 26 through this work, it has made a solid contribution to the creation of the european research space. in the most recent years, its financial resources, however, have faced a dramatic downturn. between 2010 and 2015, the esf member contributions diminished by 15.4 million euros. these budget cuts, together with the wishes of its members, led esf to radically reduce its activities and staff and to move policy-related work into newly formed science europe. 27 cost, another intergovernmental institution supporting european research set up in the early 1970s and analyzed in this book, has weathered the emergence of a comprehensive eu research policy somewhat better. it fills a specific niche in the european research funding landscape as an organization providing financial support for the creation of european-wide multi-stakeholder research networks, called cost actions. most of cost's funding, however, comes from the eu research framework program, 28 which makes it highly dependent on the political developments in the union. the various impacts of the emergent eu research policy on the wider european research space still deserve more thorough scholarly attention. 29 one interesting trend, however, is the emergence of stronger and more organized organizations and networks promoting the interests of researchers, research funders, and the higher education sector at the european level. these include euroscience, a grassroots non-profit organization of researchers in europe, created in 1997 to shape policies for science, technology, and innovation. with its 2600 individual members, euroscience aims to be "a direct and democratic way to influence the construction of the europe of science and technology, for the benefit of europe's international position in science, and to enhance science's contribution to society, opportunities and mobility for both young and experienced researchers." 30 the european association of research and technology organizations (earto) was established two years later to promote research and technology organizations and represent their interest in europe. its current activities are geared toward influencing the eu policy. 31 in 2001, a merger between the association of european universities and the confederation of european union rectors' conferences led to the creation of the european university association (eua). eua represents over 800 universities in forty-eight countries, and its activities are targeted at influencing the eu policies on higher education, research, and innovation. 32 a year later, another belgium-based organization, the league of european research universities (leru), was formed with the objective to "advance the understanding and knowledge of decision makers, policy makers and opinion leaders about the role and activities of research-intensive universities." 33 both institutions seek to promote the interests of higher education and research institutions in eu policymaking. in 2011, twenty-three countries joined in the founding assembly of science europe, an organization representing research funders and other research organizations in the eu. science europe was built from two former advocacy groups, the esf and eurohorcs (an organization of the heads of the european research councils), aspiring to give its members a stronger and more united voice on european level policy. 34 the list could be continued, in particular if one includes more informal networks and alliances. the rise of these various groups is largely a response to the gradual strengthening of the eu's research arm, which has made advocating for researchers' and research and higher education institutions' interests in brussels a worthwhile endeavor. undoubtedly, there is a new reality for research in europe. the current eu research funding program is exceptional in its size, long duration (seven years), budgetary framework stability, and scope: it encompasses research as well as innovation; grants as well as loans, equity, and procurement; it combines a broad top-down focus on grand societal challenges with bottom-up "frontier" research; it is crossborder and cross-sectoral, encouraging inter-disciplinary collaboration, mobility, and coordination. and it is attracting increasing attention and interest within research communities both within and beyond europe. the horizon 2020 mid-term evaluation accounted a 65 percent increase in the annual number of applications compared to the program's predecessor, the seventh framework programme (fp7). with an 11.6 percent success rate, which was much lower than under fp7 (18.4 percent), the competition for horizon 2020 grants had become fierce. while 92.8 percent of funding went to participants from the 28 eu member states, the program involved people from over 130 countries. 35 moreover, eu-funded projects are also producing top-notch research. between 2014 and 2016 alone, horizon 2020, supporting approximately 340,000 researchers, produced more than 4000 peer-reviewed publications that were cited more than twice the world average. two-thirds of them were also openly accessible to the public. 36 it is also noteworthy that within the european institutions, research has taken a prominent role. in 2016, a total of 1000 of the commission's 23,000 officials worked for dg research, making this dg the fourth largest division. if this number were to include staff members in the eu joint research centre, research would occupy the first place. research also continues to be the third largest item in the eu budget. 37 despite the prevailing uncertainties about the future of european integration and the different priorities of the member states, the trend of strengthening the role of the eu in supporting and shaping european research is likely to continue. in june 2018, the commission published its proposal for the next eu funding program, horizon europe, which would cover the years of 2021-2027, involve a budget of 100 billion euros-an increase from horizon 2020-and be "the most ambitious research and innovation funding programme ever." 38 there was little modesty in the commission's statement that "'[b]eneficiaries' research capacities and scientific outputs would have significantly decreased had they received national funding instead. this decrease would have been especially large in terms of their ability to collaborate with industry and business, transfer of knowledge, the number of participations in scientific conferences and the knowledge in new areas." 39 the covid-19 outbreak in 2020, effectively highlighting the importance of research in tackling global crisis is likely to give a further boost to eu research and innovation activities. the eu acted relatively fast by providing emergency funding from horizon 2020 and processing proposals at a record speed. one could note emerging tensions between european and national research spaces, as the national funding bodies and the eu instruments might increasingly compete for resources, applicants, and legitimacy. 40 the larger the eu research budget grows, and the more extensive the european level programs become, the more accentuated this competition will become. already now the eu research funding programs include almost all research themes and forms of research promotion that exist in national research and technology policies. 41 linda wedlin and maria nedeva explain the shift from "science in europe" to "european science" by two important changes in policy rationales and framing. first, the understanding of "european added value" shifted from focusing on coordination to incorporating competition. epitomized in the creation of the european research area, which signaled a move away from collaboration toward integration, this new framing precipitated the implementation of policy instruments that stretched beyond simple support for collaboration between researchers and encouraged genuine competition between them. second, there was growing evidence and concern that europe was not doing so well in science compared with its main commercial competitors. this new version of the technology gap debate argued for a european retard that was more fundamental than failure in making the link between scientific research and commercial applications. "by 2000," wedlin and nedeva write, "the long-standing assumption of this 'european paradox' morphed into a full-blown 'gap' argument, that is, that europe was clearly lagging behind the usa and japan both in terms of science and its application." 42 this concern led to a change of rationales and the target for policy intervention. it served as a justification for a powerful move to the realm of basic science and the creation of the european research council. tim flink, through an analysis on the creation of erc, supports this finding. a renewed concern of european global retard and a conviction of the need to strengthen the european knowledge base underpinned a political discussion that ushered the birth of erc. moreover, language played a critical role: with the concept "frontier research," the european commission avoided directly violating the principle of subsidiarity, which had curtailed its activity in basic research-an area traditionally belonging to the nation states. "frontier research," falling somewhere in between basic and applied research, aligned well with the eu's traditional mission of fostering european competitiveness and the geopolitical objective of the lisbon strategy to make europe the world's leading commercial power, drawing its strength from knowledge. "frontier research" projected an image of global competition, and it made a solid reference to vannevar bush's monumental report science, the endless frontier 43 and the founding myth of the us national science foundation. "[i]n this policy process," concludes flink, "the narrative structure only seemed to be successful if it followed the chimera of a geostrategic security understanding (isolation by the european research area) and a prosperity identity (market imperative of the eu)." 44 also, terttu luukkonen, while noting the critical role of stakeholder groups, such as the leading life sciences organizations, stresses the role of the gap debate in the formation of the erc. "there was a concern," she writes, "about funding being too low for basic research and about quality of science and its institutions in europe and, as in european research policy in general, usa provided a benchmark with which comparisons were made." furthermore, the focus on frontier research, provided "a strong argument that the erc is justified from the point of view of technological and economic competitiveness, not just of scientific competitiveness." 45 this is confirmed by just a cursory reading of the commission's documents from that time period. the prominence of economic concerns and the gap narrative is striking, as well as the discourse that highlights the insufficiency of national initiatives. the commission's proposal for era, for example, argues that in europe, "the situation concerning research is worrying. without concerted action to rectify this the current trend could lead to a loss of growth and competitiveness in an increasingly global economy. the leeway to be made up on the other technological powers in the world will grow still further. and europe might not successfully achieve the transition to a knowledge-based economy." 46 the discursive continuity is remarkable. throughout this book we have seen how european commission officials and other supporters of greater eu competences in the field of research used a specific language and political framing to advance their initiatives. this language presented scientific research as an engine for economic growth and material prosperity, which were widely accepted as favorable political goals by the european governing elites. combined with arguments about european technological delay vis-à-vis its main commercial competitors, it presented an increasingly convincing case for new european level activity. by the early 1980s, these framings had become dominant truth claims in the european debates, and they started to essentially determine political agendas. at the same time, the scope and nature of the scientific enterprise changed, the pace of discovery and innovation accelerated, and as a result, not only did competition between research institutes, nations, and individual researchers accentuate, but science and technology became increasingly vital forces shaping societies and determining the geopolitical and economic success of countries. it could be argued that one reason for the continuous popularity of the instrumental-economic conception of research policy has been its malleability and extraordinary ability to adapt to different political conditions. as amenable as it seemed to the western european expansive welfare economies of the 1960s and 1970s, it has proved perfectly compatible with the intensifying drive for market liberalism since the early 1980s. this is not only because of the prevailing appeal of growth. research policy has proved useful in facilitating and accelerating the shift to the world of open markets. in this study we have seen how research policy, especially at european level, was commonly pictured as a means to adapt to an exogenous and irreversible transformation that later became labeled as globalization. the eu research policy came into being with an explicit objective of enhancing european economic performance in an international framework in which competition was accelerating. this goal remains as one of the guiding principles of the current eu research policy. when research commissioner máire geoghegan-quinn in november 2011 said: "fundamentally, support through horizon 2020 for research, innovation and science is an economic policy," 47 she reiterated the principle on which the union's activity had been based since the very beginning. the economic framing remains sturdily in place. the horizon 2020 mid-term evaluation report, for example, made a blatant calculation a gdp gain, concluding that "[e]very euro invested under horizon 2020 brings back 6 to 8.5 euros." 48 the explanatory memorandum included in the commission's proposal for establishing horizon europe included similar calculations. according to the memorandum, horizon europe was expected to generate positive effects on growth, with an increase of gdp on average by 0.08 percent to 0.19 percent over twenty-five years, "which means that each euro invested can potentially generate a return of up to 11 euro of gdp over the same period"-better ratio than in horizon 2020. the memorandum went on to calculate that discontinuing the union research and innovation program could result in a decline of competitiveness and growth up to 720 billion euros of gdp loss over twenty-five years. 49 to some degree, the eu is tied to this language. initially, the lack of a solid juridical basis for research policy forced the commission to frame research as a tool for achieving prosperity, which has traditionally been one of the union's core objectives. although the gradual strengthening of the juridical basis of research policy during the last three decades has granted the commission more room for maneuver, the eu's activity and ambitions are still limited by the principle of subsidiarity and the constant search for european added value. the eu is most likely to gain legitimacy by anchoring its initiatives and programs to the objectives of competitiveness and growth-a territory where eu activity is seldom questioned. but continuously liking research and growth and articulating science and innovation policy in economic terms, is more than a smart political strategy. it is a durable policy framing that was constructed in the early 1960s and that has been broadly embraced and absorbed by national decisionmakers, european officials, and a number of other actors shaping research policy. it embodies a very specific understanding of the role of science and research in society and the objectives of public support for research and innovation communities. policy framings can and need to change if they become unsuited to responding to the society's most pressing needs and challenges. johan schot and w. edward steinmueller, for example, have argued for a new framing for innovation policy, "linked to contemporary social and environmental challenges such as the sustainable development goals and calling for transformative change." this framing should take priority over the two existing framings, which emerged in the 1960s and 1980s, and which, while still relevant, "offer little guidance for managing the substantial negative consequences of the socio-technical system of modern economic growth to which they have contributed and of which they are a part." 50 the first framing, which dominated during the time period analyzed in this book and-as we have seen-still influences eu policy, emphasized the role of research and innovation for increasing economic growth, aimed at boosting the potential for science and technology for prosperity, and cultivated socio-technical systems supporting mass production and consumption. the second framing gained ground toward the late 1980s and more explicitly aimed to address challenges related to intensifying international competition and globalization. with a focus on developing and analyzing national systems of innovation, enhancing capacities for learning, and supporting connectivity between different societal sectors within the system, it added a layer of sophistication and complexity to the first framing. however, it didn't depart from the premises of increasing growth through maintained and improved competitiveness. 51 the third framing suggested by schot and steinmueller draws upon the recognition that a deep and rapid transformation of socio-technical systems is needed in the backbone systems of modern societies, including energy, mobility, food, water, healthcare, and communication, and that research and innovation policy has a vital role to play in supporting this transformation. that requires a dramatic change in thinking, broadening of perspectives and alliances, and setting entirely new goals and objectives. according to the two authors, this new framing "focuses on innovation as a search process on the system level, guided by social and environmental objectives, informed by experience and the learning that accompanies that experience, and a willingness to revisit existing arrangements to deroutinize them in order to address societal challenges." further, the innovation process in this framing "is likely to be effective in achieving these goals if it is inclusive, experimental and aimed at changing the direction of socio-technical systems in all its dimensions." 52 essentially, this framing will propose building a new knowledge base, setting up mission-oriented policies with missions formulated in an open-ended way, encouraging new forms of engagement and networks between public, private, and third sector actors, and supporting intermediary actors to advocate competitive niches, as well as new visions and policies. it will mean a shift away from the old research and innovation policy proposition that social and economic goals can be achieved through economic growth if surpluses are redistributed and technocratic elites can regulate the externalities of growth. a more comprehensive and ambitious-if not radical-approach is needed to ensure the continued relevance of research and innovation policy in the contemporary world in rapid transition. 53 schot and steinmueller are not alone with this proposition. in the last few years, there has been increasing scholarly interest in rethinking the premises of science and innovation policy and exploring ways of better aligning policy objectives with broader social and environmental challenges. 54 a new policy paradigm is emerging, "layered upon but not fully replacing earlier paradigms of science and technology and innovation systems policy." according to gijs diercks, henrik laren, and fred steward, this "'normative turn' that is currently taking place insists that innovation policy must not only optimize the innovation system to improve economic competitiveness and growth, but also include strategic directionality and guide processes of transformative change towards desired societal objectives." further, this "emerging paradigm of transformative innovation policy is still a heavily contested discursive space" and "there is considerable uncertainty regarding the paths of this paradigm shift in the making." 55 looking at the most recent eu language on research and innovation policy, one can discern elements of this shift. while competitiveness and growth retain a solid place in the framework programs, with the increasing focus on strengthening the european knowledge base and the objective of tackling grand societal challenges through research, the political framing of the eu research policy has widened. 56 one of the earliest visible expressions of this ambition was the declaration, endorsed by over 300 researchers, policy-makers, and representatives from industry and research funding institutions during the 2009 "new world -new solutions" conference in lund, sweden. 57 the declaration stated that "european research must focus on the grand challenges of our time moving beyond current rigid thematic approaches. this calls for a new deal among european institutions and member states, in which european and national instruments are well aligned and cooperation builds on transparency and trust." the "grand challenges" listed in the declaration included global warming; tightening supplies of energy, water, and food; aging societies; public health; pandemics; and security. the lund declaration also states that the "european knowledge society must tackle the overarching challenge of turning europe into an eco-efficient economy." 58 since then, broader social and global concerns have found a firmer footing in the eu's research policy agenda. 59 between 2014 and 2016, a total of 37 percent of horizon 2020 funding went to reinforcing and extending the excellence of european science base and consolidating the era. the second biggest pot, 36 percent, went to stimulating a critical mass of research and innovation efforts to help address grand societal challenges. promoting industrial leadership came only as third, with 22 percent of funding. the remaining 5 percent was dedicated to other priorities, such as widening participation, including society, euratom, and the pilot for fast-tracking innovation. 60 the three pillars of horizon europe-excellent science, global challenges and european industrial competitiveness, and innovative europe-seem to continue this trend, although the commission notes that "[i]industrial leadership will be prominent in this [global challenges] pillar and throughout the program as a whole." 61 indeed, the proposal for horizon europe was "framed by the premise that research and innovation (r&i) delivers on citizen's priorities, boosts the union's productivity and competitiveness, and is crucial for sustaining our socio-economic model and values, and enabling solutions that address challenges in a more systematic way." in other words, "horizon europe will strengthen the union's scientific and technological bases in order to help tackle major global challenges of our time and contribute to achieving the sustainable development goals (sdgs). at the same time, the programme will boost the union's competitiveness, including that of its industries." 62 these quotes reveal a striking feature in the commission's blueprints for horizon europe: an effort to achieve the double objective of responding to global challenges and maintaining economic growth. overall, however, the program seems to be defined as serving the european economy. in march 2019, carlos moedas, the research commissioner, noted that "ware now on track to launch the most ambitious ever european research and innovation programme in 2021, shaping the future for a strong, sustainable and competitive european economy and benefiting all regions in europe." 63 even the lund declaration underlines that "[m]eeting the grand challenges will be a prerequisite for continued economic growth." 64 a vital task for the commission and the union more broadly in the future will be resolving the tension between its traditional policy goals of pursuing growth and competitiveness and its newer mission of tackling grand challenges and promoting sustainability transitions. can both objectives be successfully pursued in parallel, and how possible conflicts between growth and broader socio-environmental issues can be reconciliated, has not explicitly been addressed in any of the key documents or declarations-until very recently. ursula von der leyen's commission's proposal for a european green new deal contains explicit language, suggesting that the challenge of climate change can be addressed without compromising economic growth and competitiveness. it presents the european green new deal as "a new growth strategy that aims to transform the eu into a fair and prosperous society, with a modern, resource-efficient and competitive economy where there are no net emissions of greenhouse gases in 2050 and where economic growth is decoupled from resource use." moreover, "careful attention will have to be paid when there are potential trade-offs between economic, environmental and social objectives." the language stressing the eu's "collective ability to transform its economy and society to put it on a more sustainable path," outlines an ambitious and transformative vision that departs from narrow sectorial propositions. in the european new green deal, science and innovation also has a solid place. the document calls for "new technologies, sustainable solutions and disruptive innovation" and notes that "conventional approaches will not be sufficient." the eu's new research and innovation agenda will emphasize experimentation, and working across sectors and disciplines, thereby taking the "systemic approach needed to achieve the aims of the green deal." 65 for now it seems that four of horizon europe's five research missions would be closely linked to the green deal objectives. 66 also, how the covid-19 pandemic transforms the european research landscape, remains to be seen. in the last few decades, the eu has shown an important capacity of selfcriticism and learning. horizon europe is being built on lessons learned in horizon 2020, such as the need for increasing support for breakthrough innovation; adopting mission-orientation and encouraging citizen involvement; strengthening international cooperation; reinforcing openness; rationalizing the funding landscape; and encouraging participation. new initiatives in horizon europe, such as european innovation council, address these objectives. 67 ursula von der leyen's commission has set a new level of ambition for achieving a pressing transformative change that transcends several sectors of european society. the rapid response to covid-19 also shows proactivity and agility from an institution often seen as stiff and bureaucratic. these serve as demonstrations that the eu does not need to or even cannot be constrained by its past policy framings and discourses. and this is a real opportunity. in today's europe, torn by nationalism and distrust in governing elites, preserving peace and producing prosperity no longer suffice to provide the legitimacy that carried the process of european integration this far. it is time for a more powerful and compelling mission, aiming at a profound socio-technological transformation that a union-wide science and research effort is well positioned to shape and realize. despite its contested origins, research policy has become one of the eu's core instruments for advancing its policies, promoting european integration, and achieving change. it has won the support of researchers, both in europe and beyond, gained prestige, and found a solid place on the eu political agenda. with its extensive programs and significant funding, it has transformed the european research landscape for good. however, to remain relevant, the eu research policy needs to be tailored to serve the most compelling needs of the european societies. if designed right, it can be a powerful force, enabling critical and truly transformative effort for which none of the individual member states would be capable alone. from 'science in europe' to 'european science qualitative study on the image of science and the research policy of the european union european commission, qualitative study on the image of science and the research policy of the european union the process of politics in europe. the rise of european elites and supranational institutions europeanization in the twentieth century: historical approaches post-war research, education and innovation policy-making in europe history and memory of an institution towards european science. dynamics and policy of an evolving european research space (cheltenham and political dynamics of the era," in changing governance of research and technology policy − the european research area explaining changes and continuity in eu technology policy: the politics of ideas european research area: an evolving policy agenda political dynamics european commission communication: a reinforced european research area partnership for excellence and growth the 'european research area' idea in the history of community policy-making european research area european commission communication: europe 2020 flagship initiative innovation union european commission communication: a reinforced european research area partnership for excellence and growth broadening aims and building support in science, technology and innovation policy: the case of the european research area towards european science die entstehung des europäischen forschungsrates: marktimperative -geostrategie -frontier research (weiserswist: velbrück wissenschaft consolidated version of the treaty on the functioning of the european union-part three: union policies and internal actions, title xix: research and technological development and space-article 179 (ex article 163 tec) esa website the european science foundation; death or mid-life crisis? the science connect website the european science foundation from 'science in europe science europe lobby group hit by sudden exodus. brussels-based advocacy group aimed to provide single voice for scientists in the eu-but is losing members key findings from the horizon eu-forschungspolitik-von der industrieförderung zu einer pan-europäischen wissenschaftspolitik? proposal for a decision of the european parliament and of the council on establishing the specific programme implementing horizon europe-the framework programme for research and innovation eu funding for research and innovation key findings from the horizon from 'science in europe eu-forschungspolitik from 'science in europe vannevar bush, science, the endless frontier. a report to the president by vannevar bush, director of the office of scientific research and development 20-21; 327-328. the author's translation from german european research area european commission: communication from the commission to the council, the european parliament, the economic and social committee, and the committee of the regions: towards a european research area innovation and science: remarks at press conference launching horizon 2020 press conference brussels key findings from the horizon2020 interim evaluation european commission: proposal for a regulation of the european parliament and of the council establishing horizon europe-the framework programme for research and innovation, laying down its rules for participation and dissemination three frames for innovation policy: r&d, systems of innovation and transformative change goal conflicts and goal alignment in science, technology and innovation policy discourse combining insights from innovation systems and multi-level perspective in a comprehensive 'failures' framework next generation innovation policy and grand challenges in addition to scholars in sts and sustainability transitions studies, there have also been historians arguing for a change. for instance, andrew jamison wrote in 2014 that "as in the 1960s, there is a need for fundamentally rethinking the relations between science, technology, and society, in europe as well as internationally. in particular, there needs to be much more coordination between policies for science and technology and all the other policies that national governments, as well as local authorities and intergovernmental bodies pursue. in order to meet the challenge of climate change and sustainable development, science and technology need to be reconfigured so that the 'solutions' they provide can be relevant for the problems that humanity faces. and in order to provide appropriate solutions, scientists and engineers will need to be better educated about the problems that need to be solved transformative innovation policy european research area," 39; ulnicane swedish presidency: research must focus on grand challenges european commission: the lund declaration: europe must focus on the grand challenges of our time european research area key findings from the horizon 2020 interim evaluation european commission: proposal for a regulation of the european parliament and of the council establishing horizon europe-the framework programme for research and innovation, laying down its rules for participation and dissemination the next eu research and innovation investment programme european commission, the lund declaration european commission: communication from the commission to the european parliament, the european council, the european economic and social committee, and the committee of the regions, the european green deal the next eu research and innovation investment programme key: cord-293542-o0zspgrk authors: ippolito, g.; fusco, f.m.; caro, a. di; nisii, c.; pompa, m.g.; thinus, g.; pletschette, m.; capobianchi, m.r. title: facing the threat of highly infectious diseases in europe: the need for a networking approach date: 2014-12-12 journal: clin microbiol infect doi: 10.1111/j.1469-0691.2009.02876.x sha: doc_id: 293542 cord_uid: o0zspgrk in recent years emerging and re-emerging infections, as well as the risk of bioterrorist events, have attracted increasing attention from health authorities because of the epidemic potential that renders some of them a real public health challenge. these highly infectious diseases (hids) are occurring more and more frequently in europe, and despite the many initiatives in place to face them, many unsolved problems remain, and coordinated efforts for dealing with hids appear mandatory. whereas uncoordinated measures would lead to only partial and poor responses to these emerging threats, networking represents a valuable approach to these diseases, in order to: (i) ensure a rapid and effective response; (ii) stimulate complementarity and prevent duplication; (iii) promote international cooperation, exchange of experience, good practice and protocols; and (iv) support the less prepared countries in the european community. despite hopes to the contrary, infectious diseases appear far from being defeated and continue to claim the attention of public health authorities. particularly in recent years, yet to be fully understood changes in the environment, increased movement of goods and persons, and the local influence of global warming and other phenomena concerning vectors and hosts, seem to have promoted and accelerated changes in the presentation of old infectious diseases and the development of new ones [1] [2] [3] . the relevance of the 'emerging and re-emerging' infectious diseases, usually defined as 'infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range', is further noted by the who in its recent world health report 2007 [4] . the who stressed that infectious diseases are spreading faster and emerging more quickly than ever before. some emerging and re-emerging diseases represent a real challenge because of their epidemic potential. recently, many global alarms involving infectious diseases-such as the anthrax crisis in the usa, the emergence of sars, the pandemic threat posed by the highly pathogenic avian influenza a (h5n1), and the cases of imported or autochthonous viral haemorrhagic fever (vhfs) in europe-have highlighted the need to improve preparedness for these highly infectious diseases (hids), also in order to increase certain aspects of what is perceived in many areas as an issue of collective and national security [5] . emerging hids are of particular concern because they usually hit relatively unprepared public health systems, and appropriate diagnostic tests, vaccines, drugs, containment and mitigation measures are frequently not available or not immediately so. a similar situation could occur if a pandemic strain of influenza virus emerges: several surveys conducted in european countries and in the usa have revealed many gaps in their preparedness plans, in particular in terms of making such plans truly operational, in stepping up prevention measures against seasonal influenza, in ensuring essential services, in enhancing collaboration with adjacent countries, and in extending and better directing influenza research [6] [7] [8] . research on emerging infectious diseases has been funded since the inception of the european union (eu) framework programmes (fp) for research in 1985. in 2002 the eu developed recommendations for early diagnosis and management of bioterrorism-related infections, with the aim of providing member states with a common basis for dealing with these diseases [9] . among activities/projects covered in the fp6 2002-2006, more than half are focused on various aspects of influenza, which makes the commission's fps arguably the single largest funding source for influenza research in europe. the other topics covered include: vhfs, sars, transmissible spongiform encephalopathies, food-and water-borne diseases, other zoonoses, as well as issues such as preparedness and capacity building for different diseases in a more generic fashion. in total, both influenza research and research on other emerging infectious diseases have received more than €100 million of eu funding each since 2002. a complete searchable list and short descriptions of all projects, grouped into different categories (as well as a downloadable pdf version) is available online [10] . concurrent with the increasing awareness of the threat of a new influenza pandemic, the current fp7 2007-2013 introduces for the first time a specific area dedicated to 'potentially new and re-emerging epidemics', specifying that its 'focus will be on confronting emerging pathogens with pandemic potential including zoonoses'. the term 'potentially new and re-emerging epidemics', which is uncommon in the scientific literature, refers mainly to those emerging viral diseases of current or future relevance for europe. this new mandate to cover research systematically in the area of emerging epidemics establishes a focal point within the fp from which calls for proposals in this area can be strategically planned. the past calls in the area of emerging and re-emerging infectious diseases were frequently published ad hoc, in response to specific threats, and the lack of a dedicated area was responsible for the limited coordination and long-term planning. the new mandate in fp7 specifically dedicated to diseases should overcome these problems. although research on influenza will continue to receive support in view of the magnitude and likelihood of an influenza pandemic, future calls will increasingly build a strategic european research capacity for other emerging and re-emerging hids. a definition of hids and the agents/diseases included are summarized in table 1 . several cases of these diseases have been reported in europe since 2000: 32 cases of sars were imported in eight countries, and approximately 15 imported confirmed or suspected cases of vhfs have been reported, mainly lassa fever [11] [12] [13] [14] . very recently, two isolated cases of lassa fever have been diagnosed in london in travellers who returned to the uk from nigeria and mali [15, 16] , and several cases of autochthonous crimean-congo haemorrhagic fevers have been reported in the european region (in turkey and in some states in the balkans) and in some countries within the eu (bulgaria and greece) [17, 18] . no human cases of highly pathogenic influenza a (h5n1) virus have occurred in europe, but two suspected cases were managed in the netherlands and belgium, and public health authorities in greece faced a pseudo-outbreak [19] [20] [21] . moreover, several recent cases of cowpox infections have been reported recently in europe: 18 confirmed cases in germany, one suspected case in the netherlands, five confirmed and seven suspected cases in france. although human cowpoxvirus infections are not classified as hid, these cases are worth mentioning here as an example of how an unexpected agent can disseminate rapidly. some of the cases described above were proven to be caused by the same virus, indicating exposure to a common source of infection related to an international trade in pet rats by a czech rat breeder [22] . two cases of human infection with an orthopoxvirus, similar to but distinct from cowpox, have been identified in north-eastern italy in two veterinary doctors who had been exposed to infected cats [23] . this finding, and the fact that the two infections occurred independently of one another, underscore the need to enhance awareness of zoonotic poxvirus transmission (possibly endemic) also in regions where this problem has not been addressed so far, e.g. the southern alps. almost all of the cases requiring isolation were first admitted to a general hospital without adequate isolation capabilities, and later transferred to a high-level isolation unit. despite the fact that no outbreaks occurred in europe, these experiences exposed weaknesses in terms of recognition, public health response, and diagnostic and clinical management. indeed, despite the wide availability of national and international plans and guidelines, their application in 'real-life' scenarios remains poor. not surprisingly, public health policies and diagnostic and clinical approaches to hids differ widely among european countries, and a common platform that would enable scientists to respond in a quick and powerful manner is still lacking. hids require multidisciplinary expertise. experts in microbiology (especially virology), public health, epidemiology, infectious diseases, and communication need to work together to respond to such incidents. for hids in particular, because of the rarity of their occurrence, strong collaboration and exchange of data, and attention to lessons learned from previous episodes, are advisable. for these reasons, creating new networks and enhancing those functioning well should be strongly promoted, in order to: 1 ensure a rapid and effective response to health threats deriving from natural infection by or deliberate release of hid agents; 2 stimulate complementarity and prevent duplication; 3 promote international cooperation, exchange of experience, good practice and protocols; 4 support the less prepared countries in the european community. a continuous effort is necessary for sustaining and promoting research on hids, whether basic or translational, in order to promote the increase of general knowledge concerning on these issues and to support the development of new tools for facing them in an effective manner. the development and refinement of new diagnostic tests, new therapeutics and innovative vaccines is mandatory as never before. the use of networking and international partnership could represent the successful strategy in this context. the traditional boundaries between basic science and clinical medicine should be dropped, and through effective networks the few hid events that occur worldwide should be studied thoroughly. a network of top-quality scientists and clinicians will provide the complementarity required for the development of these new approaches. moreover, improved funding for research on hids could come from the involvement of networks in the private sector, which could be encouraged to invest in this area because of the epidemic potential and the possible large-scale economic consequences. early recognition and prompt reaction to hids rest upon adequate preparedness, which should include the availability of adequate infrastructures and specific training for healthcare workers. several differences exist among european countries, due to government policies, as well as to pre-existing conditions, and these may result in delayed and dissimilar public health interventions and non-standardized training programmes. a better coordination of public health approaches to hids may lead to standardization of interventions and protocols, such as the prompt isolation within structures with adequate technical and logistic features, to the development of a common core-curriculum, and substantial improvement in the application of international health regulations. moreover, from a practical perspective, a network involving the main public health institutes may play a key role in the management of: 1 a returning hid patient travelling through more than one country (e.g. in the case of one or more connecting flights), in order to coordinate public health interventions; 2 an hid patient admitted in a country without adequate healthcare settings for isolation (in this case, a cross-border transport by ground or air may be the most appropriate solution); 3 multi-country outbreaks. due to the current perceived international security threats, several eu member states are considering establishing biosafety level (bsl)-4 diagnostic facilities. to improve and sustain the existing initiatives and networks aimed at promoting collaboration among the existing bsl-4 laboratories appears mandatory, as well as to provide assistance, through these networks, to other european countries not equipped with such sophisticated and costly facilities [24] . moreover, among the critical points identified in the context of the laboratory diagnosis of hid agents are the scarcity of biological samples to validate the diagnostic methods and the fact that few commercial diagnostic tests are available for these pathogens. thus, a well-functioning network is essential for: 1 the sharing of diagnostic and research experience of the currently operating bsl-4 european laboratories, as well as diagnostic protocols, samples, reagents, and personnel for training; 2 the review of current laboratory diagnostic capability for hid agents; 3 the development of new hazard-free diagnostic tests suitable to be transferred to other non-bsl-4 laboratories; 4 the standardization of procedures for biosafety and biosecurity. intra-hospital procedures for clinical assistance and infection control for hid cases represent 'the core' of managing these diseases, and represent effective measures for hid containment. on the other hand, hospitals may play an important role in the amplification of an outbreak if infection control measures are inconsistently applied. consequently, common protocols for infection control and biosafety during the clinical and diagnostic management of hids patients, based on the available evidence and on 'reallife' experiences, are strongly advisable [25] [26] [27] [28] . moreover, in order to offer to these patients the best available standards of care, a set of specific skills is required, and thus, given the scarcity of these events, a functioning network for expert consultation, second opinion, and scientific support is needed. as more and more persons, animals and goods move within europe, the need for improved and coordinated responses to hids continues to grow. furthermore, it is increasingly recognized that hids can pose a significant threat to each country's national security. innovative research and coordinated efforts, through the establishment of well-functioning networks, are the only way to deal with these issues, in order to improve preparedness and to react quickly: in short, to be 'prepared for the unknown'. a key role may be played by the european centre for disease prevention and control, whose mission is, among others, to 'coordinate the european networking of bodies operating in the fields within the centre's mission' [29] . uncoordinated measures can lead to only partial and poor responses, and different approaches to similar health threats in various eu countries are likely to negatively affect the compliance by health professionals, and the perception of the population. although well-functioning networks are already in place, many gaps still exist, as well as opportunities for future collaboration. fortunately, new scientific developments, and new perceptions of these health threats, make this field one of the most stimulating research areas with a direct impact on the health of millions of people. global trends in emerging infectious diseases climate change and infectious disease: a dangerous liaison? european lab network prepares for high-risk pathogen threat world health organisation: geneva infectious diseases and national security how prepared is europe for pandemic influenza? analysis of national plans challenges remain in preparedness european centre for disease prevention and control gouvras g task force on biological and chemical agent threats, public health directorate, european commission, luxembourg. bichat clinical guidelines for bioterrorist agents european commission quality assurance for the diagnostics of viral diseases to enhance the emergency preparedness in europe no authors listed e-alert 24 july: case of lassa fever imported into germany from sierra leone marburg hemorrhagic fever -the netherlands ex uganda a fatal case of lassa fever in london the first case of lassa fever imported from mali to the united kingdom crimean-congo hemorrhagic fever in greece: a public health perspective probable cases of crimean-congohaemorrhagic fever in bulgaria: a preliminary report management of potential human cases of influenza a/h5n1: lessons from belgium a dutch case of atypical pneumonia after culling of h5n1 positive ducks in bavaria was found infected with chlamydophila psittaci a pseudo-outbreak of human a/h5n1 infections in greece and its public health implications european centre for disease prevention and control. cowpox in germany and france related to rodent pets cat-to-human orthopoxvirus transmission, northeastern italy networking for infectious-disease emergencies in europe risk management of febrile respiratory illness in emergency departments the initial hospital response to an epidemic framework for the design and operation of highlevel isolation units: consensus of the european network of infectious diseases infection control in the management of highly pathogenic infectious diseases: consensus statement from the european network for infectious diseases the authors wish to thank c. schmaltz (european commission, research directorate general, brussels) for the data about eu-funded research projects, and for his invaluable suggestions and critical reading of the manuscript. all authors declare no dual or conflicting interests. key: cord-317153-2la3hkzv authors: kauhala, kaarina; kowalczyk, rafal title: invasion of the raccoon dog nyctereutes procyonoides in europe: history of colonization, features behind its success, and threats to native fauna date: 2011-10-01 journal: curr zool doi: 10.1093/czoolo/57.5.584 sha: doc_id: 317153 cord_uid: 2la3hkzv we aimed to review the history of the introduction and colonization of the raccoon dog nyctereutes procyonoides in europe, the features behind its successful expansion and its impact on native fauna. the raccoon dog quickly colonized new areas after being introduced to the european part of the former soviet union. today it is widespread in northern and eastern europe and is still spreading in central europe. features behind its success include its adaptability, high reproductive potential, omnivory, hibernation in northern areas, multiple introductions with > 9000 individuals from different localities, and tendency to wander enabling gene flow between populations. firm evidence of the raccoon dog’s negative impact on native fauna, such as a reduction in bird populations, is still scarce. raccoon dogs may destroy waterfowl nests, although a nest predation study in latvia did not confirm this. predator removal studies in finland suggested that the raccoon dog’s impact on game birds is smaller than expected. however, raccoon dogs may have caused local extinction of frog populations, especially on islands. raccoon dogs may compete with other carnivores for food, for example for carrion in winter, or for the best habitat patches. in northern europe potential competitors include the red fox vulpes vulpes and the badger meles meles, but studies of their diets or habitat preferences do not indicate severe competition. the raccoon dog is an important vector of diseases and parasites, such as rabies, echinococcus multilocularis and trichinella spp. and this is no doubt the most severe consequence arising from the spread of this alien species in europe. invasive species have many ecological effects and may threaten biological diversity (e.g., ebenhard, 1988; hulme, 2007; vilà et al., 2010) . alien species may alter habitat, and predate on or compete with native fauna or be important vectors of diseases and parasites. they may also hybridize with native species and thus affect their genetic variability. besides ecological effects, they may have considerable economic impacts on invaded areas (vilà et al., 2010) . there are 44 alien mammal species in europe, 33 of which are considered established, i.e. they form self-sustaining populations (genovesi et al., 2009) . these include several carnivore species, such as the american mink neovison vison, raccoon procyon lotor and raccoon dog nyctereutes procyonoides. they were brought to europe because of their valuable fur or as pets and either escaped or were intentionally introduced into the wild (genovesi et al., 2009) . these carnivores are widespread in europe, occurring in over 10 european counties. the raccoon dog is one of the most successful alien carnivores in europe. it has spread rapidly into many european countries after being introduced by russians during the first half of the 20 th century (e.g., lavrov, 1971; lever, 1985; helle and kauhala, 1991) . the raccoon dog has been suspected of causing damage to native fauna through predation, but firm evidence of this is scarce (lavrov, 1971; nasimovič and isakov, 1985; kauhala, 2004) . raccoon dogs may also compete with native medium-sized carnivores, such as the eurasian badger meles meles and the red fox vulpes vulpes (jędrzejewska and jędrzejewski, 1998; kowalczyk et al., 2008) . furthermore, the raccoon dog is an important vector of zoonoses and parasites, such as rabies echinococcus multilocularis and trichinella spp (e.g., oivanen et al., 2002; deplazes et al., 2004; holmala and kauhala, 2006; romig et al., 2006) . its role as a vector of diseases and parasites is likely to cause considerable ecological and economic impacts and may also cause health problems to humans. our aim was to review the published literature on the history of the introduction and colonization of the raccoon dog, the features behind its success and its ecological effects in europe. the raccoon dog originates from the far east. six subspecies are usually distinguished: n. p. procyonoides (gray, 1834) in most of china and northern vietnam, n. p. orestes (thomas, 1923) in the mountainous region of yunnan in china, n. p. koreensis (mori, 1922) in korea, n. p. ussuriensis (matschie, 1907) in the amur and ussuri regions of siberia and eastern china, n. p. viverrinus (temminck, 1838) in japan (except hokkaido) and n. p. albus (beard, 1904) in hokkaido (ellerman and morrison-scott, 1951; ward and wurster-hill, 1990) . the climate in the original distribution area varies from the subtropical regions of japan, northern vietnam and southern china to a harsh continental climate with cold winters in mongolia and southeast siberia. accordingly, raccoon dogs in different areas have adapted to different climates, habitats and diets, which can be seen in their body size, fat reserves, thickness of fur, and their behavioral and dental characteristics (kauhala and saeki, 2004a) . a total of about 9100 individuals of the ussuri raccoon dog n. p. ussuriensis were introduced, mainly to european parts of the former soviet union, between 1929 and 1955 (lavrov, 1971 ). this subspecies is now widespread in northern and eastern europe (mitchell-jones et al., 1999; kauhala and saeki, 2004b) . its original range in south-east siberia covers the valleys of the amur and ussuri rivers and the khankai lowland, the shores of the sea of japan and also areas as far inland as komsomol'sk (novikov, 1962) . in its native range the winters are cold with thick snow cover, and raccoon dogs are forced to hibernate. it has thick winter fur and accumulates large fat deposits in autumn to survive through the harsh winter (stroganov, 1969) . the ussuri raccoon dog was thus pre-adapted to survive in areas with long winters in northeast europe. its thick fur was the reason that russians introduced it into the western parts of their country. russians first bred the animals in fur farms and then released them deliberately so as to have a new valuable fur animal in the wild. the first introductions in 1928 or 1929 (415 pregnant females) were made to transcaucasia, abkhazia, southern ossetia and karatalinia (lever, 1985) . in many areas, especially on the asian side of the caucasus, the populations did not flourish but remained small or vanished completely. more raccoon dogs were released in the mid-1930s e.g., in leningrad, novgorod and kalinin provinces, in north caucasus, ryazan province south of moscow, kirgizia and ukraine ( fig. 1; lavrov, 1971) . raccoon dogs were introduced to astrakhan between 1936 and 1939 and to moldavia between 1949 and 1954 (lever, 1985 . they were also released in estonia in the 1950s, in pskov in 1947 and in the karelian isthmus near finland in 1953 (lavrov, 1971) . one hundred raccoon dogs were released in belarus in 1963 (lever, 1985) . some individuals were also introduced further north, to the kola peninsula in 1936 and to archangel in 1950 -1953 (lavrov, 1971 ). many introductions made to the european part of the soviet union were successful and the populations started to increase rapidly. populations spread at a rate of 40 km per year (and even up to 120 km per year) from the introduction sites (lavrov, 1971 ). the first wandering raccoon dogs were seen in finland in the 1930s and 1940s (siivonen, 1958; suomalainen, 1950; fig. 1) . the raccoon dog started to truly colonize finland in the mid-1950s, but there was a time-lag of about 10 years until rapid population increase started in the mid-1960s. the phase of rapid population growth lasted for another decade and by the mid-1970s most of southern and central finland was inhabited (helle and kauhala, 1991) . after this phase of increase the population growth seemingly ceased and numbers fluctuated for 10-15 years until they started to increase again. the raccoon dog population is still increasing, and today the raccoon dog is the most common medium-sized carnivore in finland (kauhala, 2007) . the hunting bag increased from 818 in 1970/71 to 172,000 in 2009 (finnish game and fisheries research institute, 2010 1 ). raccoon dogs were found all over estonia in the 1950s (lavrov, 1971) . their numbers remained low, however, because of numerous wolves canis lupus and lynx lynx lynx, the natural enemies of raccoon dogs in estonia. in contrast, wolves and lynx were very scarce in finland in the 1960s and 1970s (ermala, 2003) , which may have contributed to the rapid spread of raccoon dogs in the country. raccoon dogs were found all over lithuania in the late-1950s and thus colonized the country in about 10 years (lavrov, 1971; fig. 1) . in latvia 1000 raccoon dogs were observed or hunted as early as 1951. the first raccoon dogs were seen in sweden in 1945 (notini, 1948) but after that raccoon dogs were observed only occasionally in norrbotten, until they started to spread a few years ago (p.-a. åhlèn, pers. com.). the reason for this long time-lag between the first observations and the rapid population increase in sweden is not known. in norway (finnmark) the first records of raccoon dogs are from 1983 (wikan, 1983) . there were no other observations in norway until winter 2007/2008 when a few raccoon dogs were shot in central norway (r. andersen, pers. com.). they most probably invaded central norway via sweden. raccoon dogs were first noticed in poland in 1955 and in east germany in 1961 (dehnel, 1956 nowak and pielowski, 1964; nowak, 1984) . fifteen years later, i.e. by the end of the 1960s, almost all of poland, with the exception of higher parts of the mountains in the south, was occupied by the species (fig. 2) . nowadays the raccoon dog is among the most common carnivores in some areas of the country (jędrzejewska and jędrzejewski, 1998) . over 11,000 raccoon dogs are caught in poland annually, and the hunting bag increases from year to year. in germany, the raccoon dog population remained sparse until it started to increase in the 1990s, thirty years after the first observations, especially in eastern parts of the country (ansorge and stiebling, 2001) . the hunting bag has increased exponentially since the early 1990s in germany (drygala et al., 2008a, b) , and in brandenburg (eastern germany) alone the hunting bag increased from 398 in 1995/1996 to (baagøe and jensen, 2007) . the first observations of raccoon dogs were made in eastern and central europe between 1951 and 2002 (nowak and pielowski, 1964; artois and duchêne, 1982; nowak, 1984; lever, 1985; weber et al., 2004; fig. 1 ). for instance, in france the first observation of the species was made in 1975 or 1979 and the first case of reproduction was observed in 1988 (léger and ruette, 2005) . in northern italy raccoon dogs were seen and photographed in 2005 (p. genovesi, in litt.) , showing that the species has managed to cross the alps. today the raccoon dog is also found occasionally in the netherlands, moldova, slovenia, croatia, bosnia-herzegovina, and serbia. it has also been seen once in macedonia (ćirović and milenković, 1999; mitchell-jones et al., 1999; ćirović, 2006) . one raccoon dog was run over by car in se spain in 2008 (anon, 2008 4 ). the northern limit of the raccoon dog's distribution is determined by climate. it can live in areas where the mean annual temperature is above 0°c, the thickness of snow cover is < 80 cm, the snow cover lasts < 175 days and the length of the growing season for plants is at least 135 days (lavrov, 1971) . today the northern limit of its permanent distribution lies at the arctic circle (helle and kauhala, 1991) . raccoon dogs will possibly widen their distribution area northwards due to climate change. increased spring precipitation in the form of snow at higher latitudes may, however, compensate for the effect of global warming (melis et al., 2010) . one of the main factors responsible for the successful expansion of raccoon dogs in europe was mass introduction over a wide area coupled with a large amount of genetic variation. together with their natural tendency to disperse and high migratory ability this allowed raccoon dogs to invade neighboring areas in a relatively short time. more research on the colonization process should be done, because the exact details are still poorly known. genetic data on raccoon dogs is still scarce. so far, populations from several locations in finland and germany have been investigated by pitra et al. (2010) . reconstructed phylogenies reveal two major clades in european raccoon dogs, which diverged approximately 457,800 years ago. in total, nine haplotypes were found in raccoon dogs in europe with a sequence divergence of 0.2%-3.2% (mean 1.3%). as suggested by pitra et al. (2010) , a combination of factors including multiple translocations with use of individuals from different geographical areas, secondary contact and admixture of two co-occurring separate maternal lineages with divergent evolutionary histories are probably the main determinants of the genetic variability of raccoon dogs in europe. it was probably a sequential, two-step process that included reduction in genetic variation due to the founder effect and population bottlenecks during initial introductions in the european part of the former soviet union in 1929-1955, followed by an increase in genetic variation by hybridization of individuals from multiple native-range sources representing divergent haplogroups (pitra et al., 2010) . however, according to ansorge et al. (2009) there was no indication of the founder effect or inbreeding in the european populations, indicated by the same level of variability that can be seen in the native amursk population. additionally, phylogenetic analysis indicates different invasion corridors of the species in the western range of raccoon dog distribution in central europe, as earlier suggested by ansorge et al. (2009) , with the secondary contact zone between previously geographically and genetically different source populations in germany (pitra et al., 2010) . an important factor behind the raccoon dog's success is the very high plasticity of the species. they are true omnivores and eat anything they can catch (reviewed in sutor et al., 2010) . in białowieża forest, the index of food niche breadth for raccoon dogs was 6.25, nearly twice as high as in the next species with the widest niche -the red fox (3.77; jędrzejewska and jędrzejewski, 1998) . the diet of raccoon dogs varies between areas and seasons, according to the availability of different food sources (e.g., ivanova, 1962; nasimovič and isakov, 1985; sutor et al., 2010) . in many areas, small mammals form the bulk of their diet in all seasons (bannikov, 1964; nasimovič and isakov, 1985; kauhala et al., 1998a; bao et al., 2005; sutor et al., 2010) . carrion may reach up to 76% of biomass consumed during harsh winters (jędrzejewska and jędrzejewski, 1998; sidorovich et al., 2000) . frogs, lizards, invertebrates and birds are also frequently consumed (e.g., barbu, 1972; jędrzejewska and jędrzejewski, 1998; sutor et al., 2010) . raccoon dogs eat berries and fruit, especially in late summer and autumn because they serve as an important food source when raccoon dogs fatten themselves before entering winter dormancy (e.g., nasimovič and isakov, 1985; kauhala et al., 1993a; kauhala, 2009; sutor et al., 2010) . the preferred habitats of raccoon dogs are wet open habitats: damp meadows and forests with sparse canopy but abundant undergrowth, marshlands, river valleys and gardens. however, they may occupy various habitats from continuous forests to open agricultural landscapes and suburban areas (jędrzejewska and jędrzejewski, 1998; drygala et al., 2008c) . however, habitat preferences at the western and southern edge of the distribution area are poorly known. the raccoon dog has a high reproductive capacity; higher than expected for a medium-sized carnivore species (kauhala 1996a ). this has also contributed to its success. mean litter size is 8-10 in areas with favourable conditions, both in native and introduced ranges (judin, 1977; helle and kauhala, 1995; ). the maximum litter size at birth in a sample of 203 adult females from southern finland was 16. the maximum number of embryos was 18, and that of corpora lutea was 23 . raccoon dogs are monogamous and the male participates in pup-rearing by warming and guarding the pups when the female is foraging (ikeda, 1983; yamamoto, 1987; kauhala et al., 1998b; drygala et al., 2008a) . females can thus spend a lot of time foraging and produce enough milk for a large litter. the raccoon dog's opportunistic diet further contributes to the large litters and also survival rate of juveniles. the survival rate is highest when the crop of berries is good . the mean annual mortality rate of juveniles during their first year of life is as high as 88% -89% in southern finland (helle and kauhala, 1993) . raccoon dogs thus produce many pups, but most of them die early in their life, and the mortality rate of juveniles is the major mortality factor of the species. the mortality rate is lowest (ca. 43%) among middle-aged (2-4 year old) raccoon dogs and increases after 5 years of age. only one per cent of individuals reach the age of 5 years, with the maximum life span being about 8 years . raccoon dogs generally reach sexual maturity at the age of 10 months, but the reproductive value is highest among 2-3-year old females which thus produce most of the pups in the population . in europe, raccoon dogs are found from the warmer conditions of hungary and the balkans to the much harsher conditions of northern europe (kauhala and saeki, 2004b) . in cold climates raccoon dogs hibernate during winter. during hibernation their body temperature is 1.4 -2.1 °c lower than during summer. this habit is unique among canids, and may also have contributed to the successful spread of raccoon dogs in northern europe (mustonen et al., 2007) . in winter, raccoon dogs settle in shelters which protect them against cold and predation (kowalczyk and zalewski, 2011) . in poland, active badger setts are most often selected by raccoon dogs. badger setts can also be used as breeding dens (kowalczyk et al., 2008) . hibernation usually lasts from november until march (in finland), but when the winter is mild raccoon dogs may be active even in mid-winter. they usually sleep when the air temperature is < -10 °c, snow depth > 35 cm and day length < 7 h . most raccoon dogs are active when the temperature is above zero, there is no snow and day length is > 10 h. for instance, in germany raccoon dogs do not usually hibernate (drygala et al., 2008b) . raccoon dogs are very well adapted to a long period of food deprivation in winter . they fatten themselves during autumn and almost double their body weight between early summer and late autumn (korhonen, 1988a, b; kauhala, 1993; mustonen et al., 2007) . fattening in autumn and sleeping in winter are regulated by hormonal changes . thyroid hormone levels are low during winter and the animal thus adapts its general metabolism to the availability and requirements of energy (korhonen, 1987 1 ). in fur farms, raccoon dogs lose their appetite when air temperature decreases to -5 °c, which indicates an endogenous behavioural pattern: when it is too cold raccoon dogs stop eating and hibernate. another feature behind the success of raccoon dogs is their tendency to wander (nasimovič and isakov, 1985) . after introduction in europe, raccoon dogs wandered as far as 300 km in a year (nasimovič and isakov, 1985) or 500 km within three years (nowak, 1973) . adults may disperse in a colonizing population (sutor, 2008) whereas in stable populations only juveniles usually disperse (nasimovič and isakov, 1985; kauhala et al., 1993b; kauhala and helle, 1994) . the mean dispersal distances, estimated on the basis of home range sizes, were 14 km for females and 19 km for males in south-east finland, with the mean maximum distances being 48 km and 71 km respectively . the maximum straight line distance in a couple of months was 145 km in southern finland (kauhala and helle, 1994) . in north-east germany, the mean and maximum dispersal distances of both sexes were 13.5 km and 91 km respectively (drygala et al., 2010) . very little is still known about dispersal routes and more research on the subject is required. the successful expansion of raccoon dogs in europe was also possible due to the secretiveness of the species and low persecution at the beginning of invasion. raccoon dogs are nocturnal animals, utilising mainly wet habitats covered with dense vegetation and showing inactivity in winter. these facts decrease their vulnerability to persecution kowalczyk et al., 2008) . in many countries the species was only persecuted once it had successfully established its population. in some areas hunters are not very interested in hunting raccoon dogs because the fur of wild animals has low value. population density varies according to the structure of the landscape. in finland, described an inverse relationship between home range size and the proportions of meadows and gardens in the home range. habitat richness (number of habitat patches per ha) also affected home range size: home ranges were small in areas where the landscape was a small-scale mosaic consisting of meadows with abundant undergrowth, gardens where raccoon dogs could find fruit and berries and small patches of mixed forests . because home range size and population density tend to be negatively correlated in monogamous canids with exclusive home ranges (trewhella et al., 1988; contesse et al., 2004; woodroffe et al., 2004) , population density can be estimated from home range size. the maximum density is then two adults in each home range in pup-rearing season when overlap of home ranges is smallest (kauhala et al., 1993b) . for instance, in the 'best' areas of southern finland home ranges are only 100 ha and raccoon dog density can be up to two adults per km 2 , whereas in poorer areas with large spruce forests pup rearing home ranges are about 260 ha and the corresponding density is < 0.8 adults per km 2 . in northern germany pup rearing home ranges are about 200 ha (drygala et al., 2008b) and the density would thus be up to one adult per km 2 . the area is a mosaic of mixed forests, wetlands and maize fields. as the raccoon dog population in germany is still increasing and spreading, population density may also increase. in forests of suwałki landscape park, nw poland, raccoon dog density was estimated to be only 0.37 individuals per km 2 (goszczyński, 1999) . in białowieża primeval forest (poland) density was 0.5 -0.7 ind./km 2 , and mean home range size 5.0 km 2 (jędrzejewska and jędrzejewski, 1998; kowalczyk et al. unpublished) . hunters in particular have suspected that raccoon dogs destroy the nests of game birds (lavrov, 1971 ). according to naaber (1971 naaber ( , 1984 , raccoon dogs robbed 85% of waterfowl nests in some areas of estonia. ivanova (1962) found remains of birds (mainly water birds) in 45% of raccoon dog scats collected in a river valley in voronez. when the raccoon dog population increased rapidly in russia, it was thought to be very harmful but, according to lavrov (1971) , this was not based on fact. raccoon dogs were accused of causing the decline of grouse populations even in areas where raccoon dogs did not occur (lavrov, 1971 ). even today robust scientific studies clearly demonstrating that raccoon dogs cause damage to native birds are scarce. birds eaten by raccoon dogs are mainly passerines (kauhala, 2009; sutor et al., 2010) . they are more important for raccoon dogs when voles are scarce than during vole peak population times (ivanova, 1962; judin, 1977; kobylińska, 1996) . it is not known whether raccoon dogs have caused a decline in passerine populations. the occurrence of birds in the diet increases with latitude, i.e. birds are consumed especially in northern europe (sutor et al., 2010) . the increase of carnivory with increasing latitude has also been detected among other omnivorous mammals (vulla et al., 2009) . according to diet studies (84 data sets from different parts of native and introduced ranges) it is unlikely that raccoon dogs affect game bird populations in general. this is because, excluding some finnish data, there were remains of waterfowl or grouse in only 0-5% of the feces or stomachs of raccoon dogs (kauhala, 2009) . although raccoon dogs may prey on ground-nesting birds such as waterfowl (barbu, 1972; włodek and krzywiński, 1986; schwan, 2003; sutor et al., 2010) , they probably consumed many of the non-passerine birds as carcasses (novikov, 1962; barbu, 1972; woloch and rozenko, 2007; kauhala and auniola, 2001) . waterfowl, especially female eiders somateria mollissima, occurred commonly in the feces of raccoon dogs in the sw archipelago of finland (kauhala and auniola, 2001 ). however, a viral disease killed many brooding eiders during the years (1998) (1999) when the data were collected and raccoon dogs probably found most of the eiders as carcasses. raccoon dogs also catch sick or injured birds left behind by hunters (samusenko and goloduško, 1961; pavlov and kiris, 1963; barbu, 1972; naaber, 1974; viro and mikkola, 1981; kauhala et al., 1993a) . remains of egg shells, including those of domestic poultry, occurred in 0 -41% of the samples (kauhala, 2009) . in most studies, they are not mentioned at all. it is thus hard to know the extent of egg consumption by racoon dogs. opermanis et al. (2001) found, however, that raccoon dogs destroyed only 0.3% of waterfowl nests in a wetland area of latvia. amphibians (e.g., rana spp., bufo spp., bombina spp. and triturus cristatus) commonly occur in the diet of raccoon dogs in spring and summer (e.g., ivanova, 1962; lavrov, 1971; barbu, 1972; viro and mikkola, 1981; kauhala et al., 1993a kauhala et al., , 1998a jędrzejewska and jędrzejewski, 1998; sutor et al., 2010) . both adult frogs and tadpoles are easy prey for raccoon dogs and this may cause a decline in frog populations, especially on islands and in other fragmented or isolated areas (kauhala and auniola, 2001; sutor et al., 2010) . frogs were scarce in the diet of raccoon dogs in the outer archipelago in southern finland, although they occurred commonly in the diet on the mainland (kauhala and auniola, 2001) . it is possible that raccoon dogs had already caused a decline in the frog populations of the archipelago. predator removal studies do not provide firm evidence of the harmfulness of raccoon dogs to game bird populations. studies in finland indicated that the breeding success of ducks improved in only one study area in northern finland where raccoon dogs occurred only occasionally even at the beginning of the experiment (kauhala, 2004) . the most frequently removed predators in the area were red foxes and pine martens martes martes. in southern finland where raccoon dogs are common, the breeding success of dabbling ducks was positively correlated with a raccoon dog index. furthermore, the breeding success of ducks improved in the predator protection area of southern finland during the experiment (kauhala, 2004) . in the predator removal area chick production declined at the end of the study with a simultaneously increasing fox population. the most frequently removed predators in this area were raccoon dogs, which may have resulted in an increase in fox populations which, in turn, may have affected the breeding success of ducks. the raccoon dog index also correlated positively with the reproductive success of black grouse in southern finland (kauhala et al., 2000) . another predator removal study in finland indicated, however, that raccoon dog removal might have had some effect on the breeding success of ducks (väänänen et al., 2007) , but the change was not significant. furthermore, chick production of, for example, mallards anas platyrhynchos and coots fulica atra, increased at first but then declined after the second year of raccoon dog removal. this happened simultaneously with the decline in the raccoon dog index. these results resemble those of the predator removal study described above and probably relate to the interactions between different predators. on the other hand, when different areas were compared there was a negative relationship between the breeding success of mallards and raccoon dog abundance index, so more research is needed on this topic in order to understand these contradictory outcomes. raccoon dogs consume carrion during all seasons if available, but carcasses are especially important for them in winter when other food sources are scarce (jędrzejewska and jędrzejewski, 1998; sidorovich et al., 2000 sidorovich et al., , 2008 . raccoon dog scavenging was recorded on 47% of carcasses available in białowieża forest (poland; selva et al., 2005) . according to sidorovich et al. (2000) raccoon dogs compete with native carnivores for carcasses in belarus in late winter. this competition can be so severe that the increasing raccoon dog population appears to have caused a decline in native carnivore populations, including the red fox, brown bear ursus arctos and pine marten. the polecat mustela putorius has probably suffered most from competition with raccoon dogs (sidorovich et al., 2000) . this information is, however, based only on correlative data and firm evidence is lacking. however, in białowieża forest, the rate of food niche overlap was very high (59%) among raccoon dogs and polecats in spring and autumn (jędrzejewska and jędrzejewski, 1998) . the polecat population has also decreased in finland during recent decades. the probable reasons for this include habitat changes and competition with other carnivores (liukko et al., 2010) . in northern europe, the red fox and the badger might compete directly or indirectly with raccoon dogs for food, habitats or den sites. correlative data from finland showed that when raccoon dogs were heavily hunted and their population decreased, the fox population started to increase (kauhala, 2004) . this may be a coincidence, but it can also indicate that raccoon dogs and red foxes compete for some resources in finland. in southern finland, there was some overlap in the diet of raccoon dogs, badgers and foxes but differences also existed: the badger consumed more invertebrates and the fox more mammals and birds than the raccoon dog (kauhala et al., 1998a) . furthermore, female foxes in finland have become more carnivorous after the arrival of the raccoon dog, as revealed by a study on dental morphology (viranta and kauhala, 2011) . this case of character displacement points to the conclusion that foxes and raccoon dogs have competed for food resources in finland. however, in winter when food is scarcest both raccoon dogs and badgers hibernate and, hence, no competition for food between the raccoon dog and other carnivores exists in this season in northern areas. in north-eastern poland, the diet of raccoon dogs overlaps 41% with red foxes and 35% with badgers in spring and summer. in winter, diet overlap between raccoon dogs and red foxes increases to 62%, when both species utilize more carrion. other species that raccoon dogs may compete with are semi-aquatic species (american mink -38% and river otter lutra lutra -33%; jędrzejewska and jędrzejewski, 1998) . a habitat preference study from southern finland indicated that the habitat preferences of raccoon dogs and badgers differed to some extent: raccoon dogs favored meadows (including clear-felled areas) and open woodlands with abundant and tall undergrowth as well as gardens, whereas badgers favored forests with a thick canopy but sparse undergrowth . management of forests using clear felling (common in finland) may thus benefit raccoon dogs at the expense of native badgers. both species were, however, flexible in their habitat use and when the most favored habitats were not available they used the same habitats, such as fields . whether they compete in these circumstances for the best habitat patches is unknown and certainly requires further research. in north-eastern poland the habitat niche of raccoon dogs overlapped 91% with that of the fox and 77% with that of the polecat (jędrzejewska and jędrzejewski, 1998) . raccoon dogs commonly use badger setts kowalczyk et al., 2008) . raccoon dogs thus benefit from the occurrence of badgers in the area. the habit of using badger setts has probably facilitated the invasion of raccoon dogs in europe (kowalczyk et al., 2008) , because deep and complex badger setts might offer refuge against the cold and predation (kowalczyk and zalewski, 2011) . common use of burrows may lead also to intra-guild predation. in białowieża forest, the killing of raccoon dog pups by badgers was recorded. raccoon dogs may also influence badger breeding success, as no concurrent breeding of badgers was recorded in badger setts in which raccoon dogs bred (kowalczyk et al., 2008). 9 raccoon dogs as vectors of diseases and parasites although the red fox has been the main terrestrial wildlife rabies vector in europe since the 2 nd world war (e.g., anderson et al., 1981) , the significance of the raccoon dog as a vector of rabies has recently increased who, 2009 ). seventythree percent of the observed rabies cases were in raccoon dogs during an epizootic of sylvatic rabies in finland in -1989 (nyberg et al., 1990 westerling, 1991; westerling et al., 2004) . in the baltic states as well, the raccoon dog is an important secondary host of rabies: the number of observed rabies cases in raccoon dogs in 2009 was 24 in estonia and 28 in lithuania (who, 2009) . the corresponding figures for fox cases were 24 and 17. in lithuania, the prevalence of rabies in raccoon dogs increased almost 2.5 times from 11.8% in 1994 to 28.9% in 2004 28.9% in (mačiulskis et al., 2006 . in russia, belarus and ukraine rabies also occurred in raccoon dogs in 2009 (who, 2009) . in poland, the raccoon dog is the second (after red fox) most important vector of rabies among wild animals. north-eastern poland (24,000 km 2 ), 131 cases of rabies were recorded in raccoon dogs (siemionek et al., 2007) . when oral vaccination was used, the number of rabies cases in raccoon dogs in poland declined to 7−15 in the whole country (smreczak et al., 2006 (smreczak et al., , 2007 (smreczak et al., , 2008 smreczak and żmudziński, 2009) . the role of the raccoon dog as a vector of rabies may further increase in europe, because the raccoon dog population is still growing and spreading (ansorge and stiebling, 2001; drygala et al., 2008a, b) . the total number of reported wildlife rabies cases (excluding bats) in europe in 2009 was 4114, 302 of which were in raccoon dogs (who, 2009) . bait vaccinations against rabies have proved to be effective and have resulted in many rabies-free countries in europe (wandeler, 1988; artois et al., 2001; pastoret et al., 2004) . the increasing raccoon dog population may, however, alter the situation: the current strategies to control wildlife rabies may not be effective enough in a community of two important vector species; the red fox and the raccoon dog singer et al., 2009) .the hibernation of the raccoon dog may further complicate the situation (schneider et al., 1988) . indeed, a modelling study showed that epizootics in the community of two species were stronger than expected for single species (singer et al., 2009) . rabies could persist in the community, even if the disease was not spreading in an individual vector species due to low density. in the community of two vector species raccoon dogs were usually the major rabies host, and the number of cases in fox populations depended on raccoon dog density. when raccoon dog density was high, invasive raccoon dogs could even outcompete native foxes (singer et al., 2009) . additionally, badgers may act as a spill-over species and suffer from rabies epizootics. other viruses also dangerous to humans, including sars (severe acute respiratory syndrome) and avian h5n1 viruses have been found in raccoon dogs in china (guan et al., 2003; changchun et al., 2004; qi et al., 2009) . raccoon dogs have additionally fallen victim to canine distemper virus (cdv) in japan (machida et al., 1993; aoyaki et al., 2000) . cdv may have the most far-reaching consequences of all infectious agents for free-living carnivores (deem et al., 2000) . data from germany indicates the possible transmission of cdv between wild carnivores and the domestic dog canis familiaris (frölich et al., 2000) . the prevalence of the virus was much higher in urban and suburban foxes than in rural ones. to our knowledge there is no data showing the role of the raccoon dog as a vector of cdv in the carnivore community (including domestic dogs canis familiaris), but this possibility cannot be ruled out. alveolar echinococcosis caused by echinococcus multilocularis is a dangerous emerging zoonosis in europe. the parasite can even cause lethal diseases in humans (eckert et al., 2000; kern et al., 2003; moks et al., 2005) . the red fox has been the definite host in central europe, but recently cases have been detected in raccoon dogs too (thiess et al., 2001; machnicka-rowinska et al., 2002; deplazes et al., 2004; kapel et al., 2005) . prevalence in foxes is high (35%−65%) in the core area of this zoonosis . small mammals, mainly rodents, are the intermediate hosts of the parasite (schantz et al., 1995) . e. multilocularis is spreading in europe and new endemic areas have been detected in recent years (eckert et al., 2000) . e. multilocularis has even invaded cities (hofer et al., 2000; deplazes et al., 2004) . the parasite is found in denmark, the netherlands, belgium, france, germany, poland, czech republic, slovakia, switzerland, austria, northern italy, slovenia and lithuania (romig et al., 2006; vergles rataj et al., 2010) . e. multilocularis has reached as far as latvia and estonia in the north: prevalence in foxes was 35.6% in latvia and 29.4% in estonia (moks et al., 2005; bagrade et al., 2008) . the parasite is so far absent in finland (oksanen and lavikainen, 2004) . the reason behind the spread of e. multilocularis in europe is probably the growing fox and raccoon dog populations romig et al., 2006) . the raccoon dog is highly susceptible to e. multilocularis infection and may provide an additional pool of definitive hosts in europe (romig et al., 2006) . in poland prevalence in raccoon dogs was 8% (machnicka-rowińska et al., 2002) . due to high densities of the species in some areas of the country, it is a serious source of infection. in northern brandenburg, germany, prevalence in raccoon dogs was 6.3%-12.0% (s. schwarz et al., unpubl. data). the parasite is an increasing public health concern, because efficient control measures are not available (eckert et al., 2000) . however, baiting foxes in an urban area of zurich using baits with praziquantel (an antihelminthic) has decreased the prevalence of e. multilocularis in the city (hegglin et al., 2003 . sarcoptic mange, a zoonosis caused by a parasite sarcoptes scabiei, is an important mortality factor of raccoon dogs both in native and introduced ranges (kauhala, 1996b; shibata and kawamichi, 1999; kowalczyk et al., 2009) . raccoon dogs may also transmit the parasite to other animals including foxes, lynx and even brown bears (mörner et al., 2005) . mange has caused significant declines in red fox populations in, for example, sweden, in the city of bristol, uk (lindström et al., 1994; harris and baker, 2001) and also temporarily in finland (k. kauhala, pers. obs.) . the occurrence of infected raccoon dogs in the area may increase the risk of serious epizootics among foxes, because both species may use badger setts as den sites kowalczyk et al., 2008) . also, badgers may be infected on rare occasions (collins et al., 2010) . trichinella spp. are parasitic nematodes that cause trichinellosis (gottstein et al., 1997) . the disease is common in carnivores, especially scavengers, all over the world. foxes are the most common reservoirs of sylvatic trichinellosis in europe, although in finland the raccoon dog is another important reservoir (pozio, 1998; oivanen et al., 2002) . sylvatic trichinosis is more common in northern europe than in central and southern parts of the continent, because the human impact on natural ecosystems is less intense in the north (pozio, 1998) . domestic trichinellosis occurred only in two countries in the european union, finland and spain, in the 1990s (pozio, 1998) . the raccoon dog may be an important reservoir species in finland, because it carries the most intense infections and is the only species that hosts all four trichinella spp. (t. spiralis, t. nativa, t. pseudospiralis and t. britovi) that occur in finland (oivanen et al., 2002) . the prevalence and risk of infection in wild animals (e.g., foxes) is lower in northern than in southern finland, probably due to the sparse raccoon dog population in the north. the prevalence in foxes has increased simultaneously since the 1960s along with the increase in the raccoon dog population in finland (oivanen et al., 2002) . prevalence in foxes is much higher (44%) in estonia where raccoon dogs are more common than in sweden (10%) where raccoon dogs are sparse (oivanen et al., 2002) . these facts point to the conclusion that the role of the raccoon dog as a reservoir of trichinella spp. is remarkable (oksanen et al., 1998; oivanen et al., 2002) . the raccoon dog is one of those invasive species which extended its range quickly after introductions and invaded neighboring areas. by the 1980s, raccoon dogs had colonized over 1.4 million km 2 of europe (nowak, 1973; novak and pielowski, 1964; kauhala and saeki, 2004b) and in many areas became the most numerous of carnivores (jędrzejewska and jędrzejewski, 1998; sidorovich et al., 2000; . the success of the raccoon dog invasion in europe was enabled thanks to an exceptional combination of factors including: widely distributed and multiple introductions, great migratory ability and the high reproductive capacity of the species, plasticity of food habits, hibernation in areas where climate is harsh and its general adaptability to different climatic and environmental conditions, and the admixture of individuals from divergent matrilineages (e.g., lavrov, 1971; helle and kauhala, 1995; kauhala 1996a kauhala , 1996b kauhala et al., 2007 , kowalczyk et al. 2008 , 2009 pitra et al., 2010; sutor et al., 2010) . few projects have been conducted in europe on the ecology of the species, so little is still known on the impact of raccoon dogs on native fauna. it seems that in many areas raccoon dogs fit very well into the local communities and successfully coexist with native medium-sized carnivores. locally, the 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specialisation and possible management historical perspective of rabies in europe and the mediterranean basin. paris: the world organisation for animal health diet of raccoon dogs in marshlands of temruk. trudy vsesoûznogo naučno-issledovatel'skogo instituta životnogo syp'â i pušniny report about game animals in poland. warsaw: biblioteka monitoringu środowiska going west: invasion genetics of the alien raccoon dog nyctereutes procyonoides in europe trichinellosis in the european union: epidemiology, ecology and economic impact molecular characterization of highly pathogenic h5n1 avian influenza a viruses isolated from raccoon dogs in china the present situation of echinococcosis in europe minsk: izdatelstvo ministerstva vysshego, srednego specialnogo i professionalnogo obrazovaniâ bssr epidemiology and control of hydatid disease current oral rabies vaccination in europe: an interim balance food ecology of the raccoon dog (nyctereutes procyonoides, gray, 1983) and the raccoon (procyon 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procyonoides in southern brandenburg diet of the raccoon dog nyctereutes procyonoides: a canid with an opportunistic foraging strategy helminth findings in indigenous raccoon dogs nyctereutes procyonoides (gray, 1843) dispersal distance, home-range size and population density in the red fox vulpes vulpes: a quantitative analysis echinococcus multilocularis in the red fox vulpes vulpes in slovenia how well do we understand the impacts of alien species on ecosystem services? a pan-european, cross-taxa assessment increased carnivory in finnish red fox females: adaptation to a new competitor? food composition of the raccoon dog nyctereutes procyonoides gray, 1834 in finland carnivory is positively correlated with latitude among omnivorous mammals: evidence from brown bears, badgers and pine martens the effect of raccoon dog nyctereutes procyonoides removal on waterbird breeding success control of wildlife rabies: europe nyctereutes procyonoides first records of raccoon dog nyctereutes procyonoides (gray, 1834) in switzerland rabies in finland and its control 1988-90 historical perspective of rabies in europe and the mediterranean basin. paris: the world organisation for animal health distribution of rabies in europe raccoon dog found dead in sör-varanger : a new norwegian mammal biology and behavior of raccoon dogs nyctereutes procyonoides in poland acclimatization of the raccoon dog in southern ukraine infectious disease: infectious disease in the management and conservation of wild canids male parental care in the raccoon dog nyctereutes procyonoides during the early rearing period we are grateful to dr. amy eycott for her linguistic revision of our manuscript. we thank four anonymous reviewers for their critical comments on the manuscript. key: cord-321911-kqbvt9v2 authors: arbyn, marc; bruni, laia; kelly, daniel; basu, partha; poljak, mario; gultekin, murat; bergeron, christine; ritchie, david; weiderpass, elisabete title: tackling cervical cancer in europe amidst the covid-19 pandemic date: 2020-07-13 journal: lancet public health doi: 10.1016/s2468-2667(20)30122-5 sha: doc_id: 321911 cord_uid: kqbvt9v2 nan geographical distribution of the world age-standardised incidence rate of cervical cancer by country, in europe (+ cyprus & turkey), estimated for 2018 (source iarc, globocan 2018) 1 . estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis age-standardised incidence (100 000 women-years) key: cord-022264-flf9o3nw authors: nan title: cruise geography date: 2009-11-16 journal: cruise operations management doi: 10.1016/b978-0-7506-7835-3.50008-x sha: doc_id: 22264 cord_uid: flf9o3nw nan cruise geography by the end of the chapter the reader should be able to: ■ consider geography from a cruise industry perspective ■ evaluate the primary and secondary cruise sectors ■ identify major cruise ports in each sector ■ consider the attractions and features that are important in defining a cruise port and destination in a practical sense, cruise companies regard the world as a series of sectors that meet various market needs. for the largest brands, this outlook allows companies to configure operations to take account of: ■ seasonality, weather patterns, and optimum conditions for cruising ■ sales and marketing ■ supply and servicing of ships this chapter considers the influence and effect of geography on the cruise industry. to start with, it is impossible to consider cruising without reflecting on the conditions that arise from the prevailing climate. passenger comfort and safety are directly affected if a cruise ship sails in a particular part of an ocean or sea at a particular time of the year. this also holds true for destinations visited and shore activities that may be offered. to avoid potential discomfort for customers, cruise ships tend to steer clear of parts of the world where difficult sea conditions occur because of geography, climate, and seasonal variations (burton, 1995) . many stories are told of severe weather conditions in specific locations. for example, the bay of biscay, the cape of good hope, the bay of bengal, and the north atlantic have reputations suggesting they can provide extremes of weather for seafarers or navigators. yet knowledge of weather patterns and records of tidal variations permit cruise operators to predict where ships can travel with a high degree of safety to enable virtually all the world's oceans and seas to be traversed and all coastal ports to be visited (see figure 4 .1). weather patterns are complex. they are influenced by many factors, including the sun's rays, the world's rotational axis (which tilts 23.5°from the perpendicular, thus creating seasonal variations), the land masses and oceans, currents, and the moon's gravitational pull (which creates tidal variations). southern and eastern caribbean islands have fared less well than western caribbean islands, because itineraries have switched from 2-week tours to shorter 4-or 7-day excursions (burton, 1995) . competition for the tourist dollar has led to a situation where port fees for many caribbean islands are relatively inexpensive, at between us$4 to us$6 per customer. in this way, a vessel such as the diamond princess, with 2,500 customers, would pay approximately us$12,500 in port fees. in addition, cruise companies own some islands: royal caribbean has ownership of coco cay, holland america owns half moon cay, disney cruises owns castaway cay, norwegian cruise lines owns great stirrup cay, and princess cruises has an island called princess cay. the benefits of such ownership include generating revenue from shore-based activities and controlling costs associated with ports of call (a cay, or key as it is known in the united states, is a low island or reef of sand or coral). some islands are less tranquil or accommodating to tourists than may be expected. cuba, the largest of the caribbean islands and located 145 km south of florida, has a history of being opposed to the politics of the united states and this posture has inhibited us tourist trade growth. other recent examples include political instability in haiti (bbc news, 2004 ) that has had a detrimental effect on the island's economy and has negatively affected cruise visits. however, in general, the situation on the majority of these "island paradises" is calm and settled. the cruise line industry association (clia, 2005a) describes three specific parts to the caribbeanthe eastern caribbean and the bahamas, the western caribbean and the southern caribbean. selected destinations from these areas are described in this section. the caribbean tourism organization (2005) is a trade organization that represents many of the caribbean islands: anguilla, antigua and barbuda, aruba, bahamas, barbados, belize, bermuda, bonaire, the british virgin islands, the cayman islands, cuba, curacao, dominica, grenada, guadeloupe/st. barts the islands of the bahamas are close to the caribbean but are not part of this region (mancini, 2000) . however, the bahamas' close proximity to both the south florida coast and the eastern caribbean makes them a natural itinerary option for cruise planners, which means the islands are a frequent stop in caribbean cruises. the combined bahamas and eastern caribbean area is relatively accessible from us ports such as miami, port everglades, and port canaveral, as well as from san juan in puerto rico. however, because of the cumulative distance involved for this type of itinerary, the duration for some cruises is likely to be in excess of 7 days. there is a diversity of ports in the region, including the aforementioned cays and islands that are privately owned by cruise companies (caribbean tourism organization, 2005) . several ports are described below, followed by a table that presents information about population, language, and currency. in all cases, for this and subsequent tables relating to destinations that appear in this chapter, populations of the port or island community are approximate. nassau and freeport on new providence island are the primary ports of call in the bahamas. in 2004, nassau was the sixth most visited port in the world and freeport was the sixteenth (wild and dearing, 2004a) . the name bahamas is a derivation of the spanish "baha mar," or shallow sea, and there are approximately 700 islands in this popular self-styled "paradise archipelago" of sun, sea, and sand. the beaches are held in high regard, but the islands also offer a variety of attractions beyond miles of white or pink sand. the islands claim the world's third largest barrier reef and a diversity of sea life, including whales and dolphins. the bahamas have a population of 302,000 (70% on new providence island) and relys on tourism for 50% of employment and gross domestic product (gdp), or the total amount of revenue generated from sales of products and services. san juan, puerto rico is both a port of call (or destination) and a base port. this dual role makes the island the seventh most visited destination in the world, according to wild and dearing (2004a) . puerto rico is described as an "island of enchantment," with a broad range of multifaceted attractions including the archetypal tropical beach scene, diverse natural attractions, and a rich cultural heritage. islanders came from a mix of cultures reflecting the scope of the island's origins, which includes african, spanish, indigenous, and us influences. the population of puerto rico is just under 4 million. the currency is us dollars, and both english and spanish are spoken (puerto rico tourist office, 2005) . st. thomas and the island's port, charlotte amalie, are celebrated by shoppers. over the years, the island has become a leading tax-free haven and this, combined with the natural allure of the scenery and the island attractions, creates a powerful draw (us virgin islands tourism authority, 2005) . as a result, the island is the eighth most frequented port in the world (wild and dearing, 2004a) . cruise visitors to the islands have easy access to a shopping mall next to the pier and can also enjoy water sports, such as snorkeling and scuba diving expeditions, and land based activities (dervaes, 2003) . the term scuba is an acronym that stands for "self-contained underwater breathing apparatus." philipsburg is st. maarten's port. with one half dutch and the other half french (referred to as st. martin) the island has two national identities and two personalities. the half of the island where most cruise ships call at philipsburg is dutch. the island is the ninth most visited port in the world according to wild and dearing's (2004a) survey. visitors enjoy beach activities, water based excursions, and cultural experiences when visiting this island (mancini, 2000) . this island is the eighteenth most visited port in the world by cruise passengers (wild and dearing, 2004a) . antigua is a verdant tropical island that boasts the historical attraction of nelson's dockyard, the eighteenth-century base for the british naval fleet (mancini, 2000) . the island is popular for snorkeling and scuba diving, and is said to be one of the sunniest of the eastern caribbean islands (antigua barbuda tourist information, 2005 the western caribbean is convenient for cruises that depart from florida or ports such as houston, galveston, and new orleans (mancini, 2000) . in addition, the itineraries for this region can be supplemented with mexican destinations such as cozumel (the third most visited port in the world george town in grand cayman is the main port of call and is the fifth most visited port in the world (wild and dearing, 2004a) . the islands are famous for the opportunity to swim with stingrays, although many other attractions and experiences are available. the islands have a reputation for spectacular diving around the coral reefs, which are generously endowed with marine life. grand cayman island is also home to the world's first sea turtle farm, the spectacular limestone and coral formations known as hell, and the popular seven mile beach (cayman islands department of tourism, 2005). jamaica is the caribbean's second largest island, and ocho rios, jamaica's port, is fifteenth in wild and dearing's survey (wild and dearing, 2004a) . jamaica has an array of natural wonders such dunn's river falls. cruise passengers have the opportunity to climb the waterfall, take an expedition to the blue mountains, and go on an undersea tour or visits to caves (visit jamaica, 2005) . the options are very wide, reflecting the natural and cultural diversity of the island. music, as epitomized by the late bob marley, plays a part in jamaican culture. jamaica is the home of reggae and boasts a rich historical heritage. this part of the caribbean tends to be seen as more exotic because the islands are located close to venezuela in south america and the itinerary usually requires using a home port from within the area, such as barbados and aruba. many cruises to the southern caribbean originate from san juan in the eastern caribbean and include a mixed itinerary of ports from both the eastern and southern caribbean. this region enjoys the caribbean's sunniest climate. georgetown is the port for the island of barbados which lies at the eastern edge of the southern caribbean. the countryside has a softly rolling landscape, in contrast to some of the other volcanic islands that have been considered so far. barbados has a strong british connection (barbados tourism authority, 2005) and is a former colony (it gained full independence in 1966). attractions include rum factory tours, touring the island, water sports, and visiting the many beautiful beaches. willemstad is curaçao's capital. curaçao is the main island of the group of islands known as the dutch antilles. curaçao has an unmistakable dutch heritage, reflected in its style of architecture (curaçao tourist board, 2005) . the island has a host of activities for cruise passengers, who may wish to visit the island's shops, the underwater park and seaquarium, or the island's ostrich farm. there are many other islands in this area including bonaire, trinidad, and tobago. itineraries may also include venezuelan ports such as la guaira (for caracas or venezuela) and cartagena. while the caribbean has benefited from the changing pattern of cruising in the aftermath of 9/11, europe and the mediterranean (figure 4 .3) are poised to develop exponentially as tensions concerning travel begin to ease (wild and dearing, 2004b) . barcelona and palma in spain and venice in italy lead the rankings list of most visited ports in southern europe, reflecting a trend for itineraries to be located more toward the west of the mediterranean or the adriatic (wild and dearing, 2004c) . southampton in the uk has emerged as a leading port for the northern region, being appropriately located to service a diversity of itineraries and, according to wild and dearing (2004c) , it is close to the types of facilities that allow effective service of passenger and cruise ship needs. this cruise region has a number of advantages. for us passengers it offers familiarity with the culture, the geography, and the attractions offered by the major cities (mancini, 2000) . for european passengers it provides an easy departure from home ports. the countries and ports are, for the most part, highly sophisticated (cruise europe, 2005) and able to cope with the complex demands that accompany the arrival of the largest of cruise ships. a number of cruise brands, such as the cunard line and p&o cruises in southampton, have traditional roots in this region. indeed, historically the uk is the home of cruising. the season for cruising in northern europe is relatively short, but the ports are popular so traffic can be concentrated for the short cruising season (wild and dearing, 2004c) . wild and dearing (2004c) note that the majority of passengers for this type of vacation are likely to be first, north american passengers; secondly, uk passengers; and thirdly, german passengers. when marketing cruises in northern europe, cruise companies can focus on the british isles, the baltic, iceland, the arctic and the north cape, the norwegian fjords, and western europe (wild and dearing, 2004b: 17) . the following describes key destinations from this area. southampton is a city with a long maritime heritage. the city has experienced both growth and decline because of the historical development associated with shipping in general and the cruise industry in particular. it is currently experiencing growth. the port is well located for london, and it cruise geography has excellent transport links and the infrastructure to service cruise ship needs. the port provides a launch pad for ships to travel with or across the atlantic, to the mediterranean, to the ports of northern europe. because of this, it is listed by wild and dearing (2004c) as the first-ranked port in northern europe. helsinki is the capital of finland. from a cruise perspective, the city is located in a strategically convenient part of the baltic for itinerary planning. it is a bustling port with as many as 40 ferry departures daily at the height of season. the port is attractive and closely located to the city center (cruise europe, 2005) . finland is different from other scandinavian countries for two reasons. first, it has a different language that is more similar to russian and estonian than to the languages of the neighboring scandinavian countries. secondly, it shares a border with russia, which has resulted in finland possessing a different history and culture. with two thirds of the country covered by forest and one tenth made up of inland lakes, the finnish tourist board emphasizes nature and the environment (boniface and cooper, 2005) . the port is a secondary base port as well as a port of call, or destination. copenhagen is the capital of denmark, the smallest scandinavian country, and, after helsinki, it is the third most visited port in northern europe (wild and dearing, 2004c) . copenhagen has a reputation for having lively nightclubs and bars and is a major cultural destination (boniface and cooper, 2005) . it is the home of the carlsberg brewery, which is both a tourist attraction and working production center, and the world famous tivoli gardens, which is europe's oldest amusement center. much is made of the figure of the little mermaid, a statue in the harbor area representing a character from hans christian andersen's stories. the city was the recipient of the world travel award as europe's leading cruise ship destination in 2004 (cruise europe, 2005). st. petersburg in russia has seen major growth in numbers of cruise passengers over the last five years and it was slated for 313 calls in 2004 compared to 263 in 2003. the city is said to be the most beautiful in russia (boniface and cooper, 2005 tallinn is a united nations educational, scientific, and cultural organization (unesco) heritage site. it is the capital of estonia and boasts what is said to be one of the few examples of an old city that has been kept intact. tallinn has a history as a port that can be traced back to the tenth century, and evidence suggests there was a settlement on the site as long as 3,500 years ago. the city offers a number of attractions including parks, heritage buildings, palaces, and museums (cruise europe, 2005) . tallinn is the fifth most visited port in northern europe (wild and dearing, 2004c) . stockholm is the sixth leading northern european port (wild and dearing, 2004c) . it is the capital of sweden, a country that has the largest unspoiled wilderness in europe (bonifac and cooper, 2005) . the city of stockholm is located on a number of interconnected islands at one end of lake mälaren. the city offers a broad range of attractions such as museums, royal palaces, and heritage attractions. the city itself is attractive to visitors, with its narrow pedestrian streets, good shopping and restaurants. the northern european region may have a short season because of frequent inclement weather patterns from late autumn through to early spring, but the ports are popular and tourist-friendly. whether a cruise is seeking the "land of the midnight sun" while cruising past the fjords of norway or the northern lights of aberdeen on the northeast coast of scotland, passengers have many opportunities for memorable moments. in cruising terms, this region encompasses the eastern and western mediterranean and provides access to a range of countries from a large number of ports. with long dry sunny summers, the mediterranean climate is conducive to vacations (boniface and cooper, 2005) . the region offers a great diversity of attractions, including historical sites, sophisticated cities, and beach playgrounds, all within relatively accessible cruising parameters (mancini, 2000) . the distances between ports and attractions allow cruise planners to schedule itineraries in this region to take advantage of the best timing and economical fuel consumption and, in addition, to take advantage of high-caliber supply networks. the mediterranean is popular with many cruise passengers. us passengers can take advantage of "grand-tour" approach to visiting europe and facilitate border crossings, minimize language problems, and maintain a desired level of comfort. one drawback for us passengers can be the need to fly long distances to board the ship, although passengers are served by a multiplicity of arrival airports that provide easy access to base ports. another factor that concerns some passengers is political unrest in countries and regions close to the mediterranean. passenger concerns about destinations are easily remedied by changing itineraries-a factor that has helped to generate the growth in popularity of cruising. uk and european passengers have relatively easy access to the mediterranean. p&o cruises, cunard, saga cruises, and other cruise brands operate a variety of cruises that depart from the uk. other cruises that depart from the mediterranean are usually between 1 and 2 hours flying time away from local airports. the season in the mediterranean is being reappraised to stretch the shoulder periods (the months between high and low seasons). barcelona, in the western mediterranean, is a spanish city that has become the most visited port in the region (wild and dearing, 2004c) . in addition to its status as a major base port, the city offers a broad range of attractions to make it a destination in its own right. the city is peppered with characterful architecture that was designed by antonio gaudí, and many tours visit his unfinished cathedral, the sagrada familia. the ramblas provides a main walkway through the center of the city past the barrio gótico, the medieval core of old barcelona (boniface and cooper, 2005) . the port offers a contemporary setting for passengers to embark and disembark, with modern terminal facilities and network of services for passengers and cruise ships (medcruise, 2005) . palma is also a spanish city in the western mediterranean. the island of majorca is one of the balearic islands located off the southern coast of spain. the other principal balearic islands are ibiza and minorca, which are also ports of call for cruise ships. majorca is well known as a holiday destination, and, in recent years, the port has become a popular fly, cruise, and stay product (medcruise, 2005) . the island provides a variety of resorts and accommodation for this type of package. palma, the capital of majorca, is an attractive city that has a typical spanish atmosphere, an impressive cathedral, a variety of shopping options, and close proximity to the beaches and other attractions. venice is actually in the adriatic sea, not the mediterranean. this northern italian city has had a long and turbulent history, and seems to be continuously struggling against the ravages of nature and time. yet, in its unique setting, with its canals and car-free environment, venice is special. the vast scale of a grand class cruise ship drifting past st. mark's square beside antiquities such as the doges palace and the basilica presents an incongruous sight. as a sea-based trading center, venice has a maritime culture and has always made a living from the sea. its excellent terminal facilities provide a point of arrival and departure and easy access to this attractive destination (medcruise, 2005) . recently, proposals have been made to construct a tidal barrier to counter flooding problems caused by a combination of the city sinking into the lagoon (2 cm in 100 years) and rising tides (bbc news, 2003) . naples is located in italy, just to the south of rome. the city is overshadowed by the ominous presence of mount vesuvius. this slumbering giant of a volcano provides a most impressive backdrop to naples and is responsible for creating two of the area's attractions-the excavated roman ruins of pompeii and herculaneum. the port gives easy access to the vast city, which can appear both lively and chaotic. this is the mediterranean's fourth most visited port after barcelona, palma, and venice (wild and dearing, 2004c) . this unfamiliar italian port provides the gateway into rome. the city of rome is a "must see" destination for travelers to europe. the city boasts a veritable cornucopia of classical ruins and architectural gems, including the forum, the colosseum, the vatican, and st. peter's square, all within a modern metropolitan setting. getting from civitavecchia to rome usually involves a taxi or coach cruise operations management journey, although the town also has a train station, which provides regular and easy connection. the port is a large sprawling area, and ships can be located quite far from the port gate. this distance can be traversed by a coach link or shuttle service, or taxi service, to the town center. savona in liguria, northern italy, is the seventh most visited port in the mediterranean area (wild and dearing, 2004c) . costa cruises, one of carnival corporation's cruise brands, has leased the modern terminal building in the city and makes good use of the facility to support its operations. savona is in the heart of the italian riviera, a region of pretty seaside towns, spectacular coastlines, and a wide range of attractions. livorno is a large, bustling port that services the surrounding region of tuscany in italy by providing a focal point for cargo, ferry, and cruise traffic. the cruise terminal is approximately a third of a mile from the city center. however, for many passengers that may be irrelevant because a key attraction is the city of florence, which is approximately 55 miles (88 kilometers) from the port. the port also provides access to the beaches of the area, the famous wine region (tuscany is well known for wines, including its famous chianti), and many other attractive towns such as pisa, lucca, san gimignano, volterra, and siena. dubrovnik is a major croatian city and port. despite suffering heavy shelling during the serb-croat war in 1991 and 1992, this famous old walled city has been completely restored to enable visitors to experience its atmospheric street scenery. dubrovnik offers contrasting experiences to visitors. the city holds much interest, with its ancient walled ramparts and fortresses, narrow pedestrian lanes, and historical town buildings. the surrounding countryside and coastline provide a rich mix of geography, culture, and leisure activities. piraeus is a greek port that may be seen by some as the civitavecchia of athens. yet piraeus has long been the gateway to athens, and, as a result, it has a lively and bustling character. the harbor area is large and accommodates a diversity of shipping traffic, such as cruise ships, cargo vessels, and the ferries and hydrofoils that connect athens and the mainland to the many outlying greek islands. the 2004 olympics led to considerable investment in the infrastructure of athens and surrounding areas. athens is another key destination for cruise passengers. the city has many treasures that attract visitors, including the acropolis, the parthenon, and the agora, or marketplace (boniface and cooper, 2005) . athens can be reached from piraeus by taxi, public bus, tour coach, and subway. santorini is a greek island in the cycladic island group in the aegean sea, some 130 miles from piraeus. the island offers spectacular scenery from its highest point, across the sweeping curvature of the crescent-shaped landmass out to sea. the island was originally a volcano, but when part of the cruise geography volcano collapsed into the sea the unique terrain was formed. some claim that santorini was the setting for the lost city of atlantis. rhodes, named after the phrase "the island of roses," is an attractive greek island where ancient history combines with the contemporary beach and sunshine holiday. rhodes is also the name of the capital city, which today presents itself as a medieval old town with strong historical connections to the knights of st. john. (the knights of st. john was a religious and military order that was originally founded in seventh century bc to participate in war in the holy land.) mykonos is another greek island in the aegean sea. this small island, with a population of just 15,000, transforms during the summer, when 800,000 tourists inhabit the hotels, guesthouses, and tourist accommodation. mykonos's charm is the appearance of the main town, with its winding back streets, white painted buildings, and beautiful island scenery. the mediterranean possesses many special destinations and ports that are worth a visit. the attractiveness of this region, as well as the historical and cultural values, creates a strong lure for a broad range of cruise tourists. there are those who may have ancestral links to the area, others who seek learning and cultural enrichment, some who are attracted to the beauty of the scenery and countryside, and people who enjoy the climate. invariably, there are many who seek a combination of these features. north america provides a number of embarkation points where us customers can join cruises and where overseas customers can join as fly-cruise passengers. in some cases these ports are home ports for us vessels and cruise companies. in addition, cruise itineraries can be constructed from us and canadian ports to meet passengers' needs for cultural and geographical attractions. irrespective of a cruise ship's flag or country of registration, because of the actions of us port health officials there are critical implications from the standpoint of port health for ships visiting us ports (which are examined in depth elsewhere) (figure 4 .4). north america is the world's largest cruise market. as a result of concerns about security abroad, the number of cruise passengers joining from us ports has seen considerable growth. of the top five cruise destinations in the world (wild and dearing, 2004a) , miami and port everglades are as number 1 and 2, respectively, and port canaveral is number 4. all three ports are in florida. cruise companies have benefited by consolidating their operational support in the united states and creating economies of scale from supply networks for merged brands. in addition, cruise companies have become horizontally and vertically integrated in their operations. within the cruise industry, horizontal integration is attained by using different brands strategically within a variety of market segments. vertical integration is achieved by creating synergies and generating revenue from ownership of parallel operations such as shore excursions, travel agents, terminal operations, and so on. the following list provides a brief outline of the features of major north american ports. the port of miami, on dodge island, is the busiest home port in the united states. as such, it provides a home base to carnival cruise lines, norwegian cruise line, royal caribbean international, oceania cruises, and windjammer barefoot cruises. the port has state-of-the-art facilities and has eight terminals with designated berths that can be used flexibly depending on the type of shipping. in addition to hosting passengers who are embarking on cruises, the port also provides facilities for cruise passengers arriving in miami, with many options for excursions. it can also host those arriving in the city a day or so before departure (port of miami, 2005) . while cruises can depart for many places, the main target is the caribbean. port everglades is located close to fort lauderdale airport, making for a relatively easy transfer for fly-cruise passengers who are primarily cruising to the caribbean. port everglades, the number 2 port in the world, hosts many cruise brands, including carnival, celebrity, costa, crystal, cunard, holland america, imperial majesty, mediterranean shipping, orient, princess, radisson seven seas, regal, royal caribbean international, royal olympic, seabourn, and silverseas. the port provides a breadth of shore excusions (see chapter 5) in the area (port everglades, 2005). port canaveral has six cruise terminals with another two under construction. the port is home to carnival cruise lines, disney cruise line, royal caribbean international, sterling casino lines, san cruz casino, holland america, and norwegian cruise lines. the port is in what is known as florida's space coast, and visitors can take the opportunity to tour the kennedy space center or indulge in a range of other activities (port canaveral, 2005) . the port of juneau provides access to the seasonal (may to september) attractions of alaska. juneau was a gold-rush town that became alaska's capital. as a cruise destination, the city provides opportunities for exploring the area's mining heritage, participating in outdoor pursuits, visiting glaciers, whale watching, and even dog sledding. glacier trips are available by helicopter. the city is more than simply a departure point for environmental pleasures, boasting an air of sophistication with its many art galleries and quality restaurants. most of the major cruise brands that are marketed to us passengers sail to juneau. ketchikan is alaska's southernmost city. despite a high average rainfall, many outdoor pursuits are available, including kayaking, trekking, and visits to national parks, lakes, and forests. the city is a center for native culture, with an array of related museums and attractions. los angeles was the original home for the love boat television series that ran between 1977 and 1986. la is famous for its many attractions, including hollywood, disneyland, and universal studios. the world cruise center in la can manage a visit by the largest cruise ships (cruise the west, 2005). long beach is fast approaching the scale of operation at neighboring port los angeles (wild and dearing, 2004a) . carnival corporation has a terminal at this port, and many cruise brands use long beach as a departure and home port. itineraries from this port can include baja california, the mexican riviera, and alaska. tampa handles a quarter of the numbers of passengers that miami does (wild and dearing, 2004a) . however, tampa in florida is expanding rapidly and attracts many of the leading cruise brands, including carnival cruise line, holland america line, royal caribbean cruise line, and celebrity cruises. the port has a well developed, tourist-friendly, downtown waterfront area, and many excursions are available to augment the passenger experience. a host of other ports lie within this large area, including vancouver, new orleans, galveston, skagway (alaska), new york, new jersey, boston, san francisco, galveston, philadelphia, and seattle. competition is fierce and growth, combined with recent trends, means many ports are experiencing "boom" conditions (mott, 2004) . oceania, including australasia (australia, new zealand, and asia) and the islands of the pacific, is a major expanse of sea and land. this cruise region offers great diversity from the culturally vibrant and exotic ports of asia, such as indonesia, malaysia, the philippines, singapore, thailand, india, vietnam, china, hong kong, japan, sri lanka and the maldives, to the tropical islands of the pacific, such as tahiti, fiji, papua new guinea, new caledonia, vanuatu, samoa, tonga, and the cook islands. australia offers the attractions of her cities of sydney, melbourne, and freemantle and the uniqueness of the coast, the coastal resorts, and the countryside (cruise down under, 2004) . new zealand is still basking in the lord of the rings effect, which has followed the success of the movie trilogy. publicity from feature films has frequently created heightened interest in travel destinations, and this has also been evident in the increased number of ships visiting the ports of auckland and wellington in new zealand. this region is located in the southern hemisphere, so the seasons are a reversal of the pattern recognized in the northern hemisphere. as a result, the summer cruising season for australia and the south pacific extends from november to april (mancini, 2000) . this vast geographical area is likely to experience continuous growth, with emerging economies such as china and india fuelling opportunities for new consumer markets and new, relatively accessible itineraries (figure 4 .5). sydney is probably the best-known city in australia, although it is not the capital (which is canberra). the city has a highly picturesque setting, with its harbor, the sydney opera house, and the sydney harbor bridge, which were blatantly and successfully exposed to the world media during the millennium new year celebrations. sydney has two cruise terminals-the overseas passenger terminal at circular quay and the wharf 8 darling harbor passenger terminal-that are in close proximity to the city's attractions (sydney ports, 2005) . auckland is the largest city in new zealand's northern island. it has an idyllic setting surrounded by islands and beautiful scenery. the city is both cosmopolitan and close to nature, with tours available to volcanic regions, rainforests, and beaches and the city's attractions within easy reach for passengers. the city has polynesian and maori culture, which is reflected in the people, the place names, the history, and the heritage of the area. fiji is a group of 300 islands in the south pacific with a population of approximately 893,000. the largest two, viti levu and vanua levu, contain 80% of the country's population. the islands represent many peoples' vision of what tropical islands should be like. there are white beaches, coral reefs, and clear seas with a myriad variety of fish and sea-life, alongside rainforests and native villages. contemporary fiji also has attractive shopping facilities in the capital, suva, along with modern hotels, a wide variety of restaurants, and nightlife for all types of tourists. new caledonia is a french island that lies halfway between australia and fiji. the island, with its capital noumea, is the third largest in the pacific after new zealand and papua new guinea. the french cultural influence, coupled with the influence of the melanesian region in this part of the pacific (melanesia is the name given to the island group that new caledonia is part of), creates an interesting backdrop for this island. the geography is a mix of tropical features, with attractive sandy beaches, a large lagoon that surrounds the region, mountains, and rain forests. hong kong was formerly a british protectorate, but it was returned to china in 1997. it retains a mix of eastern and western influences and a dynamism that reflects a city on the cutting edge of a changing world. the city promotes itself as a shopper's paradise, but, in reality, there is more to this energetic, self-styled "cruise capital" of asia. to the western tourist a visit to hong kong by cruise ship is a special opportunity to savor its unique blend of sights and sounds (hong kong tourism, 2005) . the republic of singapore is one main island surrounded by 63 smaller islets. it is an economically successful country, which is proud of its contemporary feel, its diverse culture, and its friendliness. visitors can experience gardens, skyscrapers, the famous raffles hotel (home of the singapore sling), a strong sense of fashion, and a technologically aware community. the capsule descriptions of the aforementioned cruise regions are, of course, flawed because they only scrape the surface of the options for creating a cruise itinerary. further research will undoubtedly reveal a plethora of destinations that are unmentioned in this chapter but, nonetheless, hold vital importance as part of a cruise itinerary. at the end of this chapter, the reader will find links that can help with such research. some additional destinations are worth highlighting and have until now been omitted because of their geography. for instance, nothing is said about most of africa and the islands off africa, such as the canaries, mauritius, and the seychelles. south america is also omitted, despite its obvious attractiveness and a wealth of interest in the continent. a few ports from these areas are mentioned here to draw attention to their potential. a number of primarily volcanic islands form part of cruise itineraries in the northern hemisphere. these are the canary islands, madeira, and the azores. the canary islands of tenerife, lanzarote, gran canaria, and fuertenventura are governed by spain, although they fall outside the jurisdiction of the european union (eu), which means that cruise ships with an eu registration can have the opportunity to sell duty-free alcohol. an eu-registered ship that has an itinerary made up of destinations or ports that are all eu member states would not be able to make such sales. madeira and the azores are portuguese islands. the canaries are relatively close to the coastline of north africa and benefit from a temperate climate all year round. madeira has a similar climate and is a popular cruise destination for passengers who enjoy the verdant scenery and charm of funchal, the island's capital. the azores offer a different type of destination. the islands have a quietness about them that reflects their remote setting. these islands were a convenient stopping point for trans-atlantic crossings, but are now less frequented because the need for such a logistically convenient stopover is much reduced (boniface and cooper, 2005) . this major brazilian city conjures up images of sugarloaf mountain, with its world famous statue of christ facing over rio's population. copacabana beach and ipanema beach are also well known as playgrounds for locals and tourists alike. the city is representative of brazilian exuberance, as seen in the everpresent music, the dancing, and festivals. buenos aires is the capital of argentina. it is an optimistic and proud city with a much publicized past. its architectural heritage is european, with influences from britain, france, italy, and spain. its museums, theaters, and art galleries reveal the cultural proclivities of the locals. much is made of the links between the nation and the tango, a dance that embodies passion and drama (boniface and cooper, 2005) . the galapagos islands are ecuadorian islands in the pacific. despite being almost barren, these small islands are popular cruise destinations because they present an ecosystem that is unique. the water is cold, yet the islands lie on the equator so the mix of land and sea creatures is diverse. there are no natural predators, so the indigenous animals, including giant tortoises, marine iguanas, penguins, and sea lions, have no built-in fear of humans. the area is extremely sensitive, and cruise ships and passengers are managed with great care (boniface and cooper, 2005) to minimize environmental impacts. cape town is the capital of south africa. the city is located in a place where cold and warm collide, because of sea currents from both the atlantic and the southern oceans. cape town is a natural harbor that makes an excellent destination with a wealth of options for the cruise tourist, including the friendly locals, the dramatic scenery of table mountain , the famous regional vineyards, and the beaches. the seychelles in the indian ocean are idyllic islands that are truly beautiful. the clean sandy beaches, clear seas, palm trees, and granite outcrops peppering the shores offer a relaxing port of call for cruise itineraries. the flora and fauna on these islands are unique because of their distance from the nearest landmass. cruise tourists are most likely to visit mahe, the main island. the panama canal is not really a destination in its own right, but it is vital as a link between the atlantic and the pacific oceans and a fascinating experience for cruise passengers. the first ships used the canal in 1914. from then it was operated by the united states until 1999, when it was returned to the panamanian government. it has three sets of locks to facilitate the different sea and water levels, and, on average, it takes about 8 to 10 hours for vessels to get from one side to the other. ship dimensions must not exceed 32.3 meters in beam, draft 12 meters, and 294.1 meters long (depending on the type of ship). the suez canal started operations in 1869 to provide a link between the mediterranean and the indian ocean. using this shortcut, ships could avoid the potentially dangerous and lengthy voyage around the cape of good hope. since that time, with occasional closures at time of war, the canal has become on of the world's most important trading routes (boniface and cooper, 2005) . the canal can allow vessels up to 150,000 grt with a 15-meter draft to traverse the canal, although plans are under way to increase this limit to a 20-meter draft by 2010. this chapter provides a description of the major cruising sectors and a brief taste of a number of destinations. considerably more can be said about all the destinations that are included, as well as those that are not. however, this is not possible in such a broad-based textbook, and it is recommended that readers undertake further research to examine key issues related to destinations and cruise sectors. many good resources exist, including web-based tourism sites, geography textbooks, and tourism guides. the cruise industry generates considerable business for destinations, but for some there is a cost. that cost may be in terms of the increase in people visiting particular destinations, the demands placed on the local population to "package" and thus taint the cultural experience, the possibility of pollution, or ecological impact. these issues can also be examined further with respect to the balance of the positive and negative impacts on destinations. the following two case studies are included to stimulate discussion and widen understanding about destinations. the first is the case of "destination southwest," a regional initiative that was introduced to increase cruise business to the southwest of england. the second examines the action taken by some cruise companies to purchase and operate private islands. questions are included at the end of each case study. resorts seeking to capitalize on the burgeoning cruise phenomenon could learn by examining the case of "destination southwest." this initiative, representing an alliance among eight ports throughout the southwest of england (ilfracombe, torbay, dartmouth, plymouth, fowey, falmouth, penzance and the isles of scilly) was supported by a combination of european regional development social funds and match-funding from county and local councils, tourists bodies, and attractions such as the eden project, the national maritime museum in cornwall, the national trust, britannia royal naval college, and the ports (a total of 21 public and private partners). the funds helped support a new partnership that aimed to develop and extend the number of cruise ship visits to ports within the region. bob harrison, an experienced professional with 30 years of industry experience, coordinated destination southwest at sea and ashore. he was appointed director of cruise operations. harrison used his knowledge and contacts to gain access to senior managers involved with itinerary planning, and his insights into the experience and requirements of cruise passengers have been invaluable. he also recognized the difficulties that cruise executives face when planning itineraries and can orient his strategy accordingly. the £230,000 three-year project was launched in february 2002. destination southwest started by establishing an informative website, www.destinationsouthwest.co.uk. the website allowed visitors to click on the port name and get access to a lot of information, including a cruise calendar to identify which ships are calling and when, marine charts, town maps, suggested shore excursions, video clips of some attractions, 360-degree shots of the port area where passengers land, and distances and times between ports and attractions. this information, which helps the itinerary planner make decisions, was also replicated on a dvd to provide an easy-to-use reference in support of direct selling and to give away at exhibitions. websites and dvds were produced in german and english to appropriately target the us and german cruise markets. there were a few problems. events such as the terrorist attack on new york, the outbreak of foot and mouth disease in the uk in 2003, and the emergence of sars all affected purchasing decisions by potential cruise passengers. in many cases, people were ill informed about the implications of these critical incidents. passengers to a port in cornwall were overheard asking whether purchasing a woolly pullover might create a risk of catching foot-and-mouth disease. cruise companies such as holland america, princess, cunard, and seabourne all liked the uniform packaged approach. the results of the project show an increase from 10 vessels calling into ports in the area in 2001, to 106 cruise ship calls in 2004. by all accounts, this is a dramatic increase. some ports in this region offer berths where the ship can go alongside. indeed, the busiest port, falmouth, has such facilities. harrison believes that passengers prefer as few tender operations as possible (where launches transport passengers from ship to shore). this despite the fact that many cruise brands include a tender operation as part of the total cruise experience. in his opinion, more than two tender operations in a cruise is too many, because passengers begin to object to the time delay, the potential discomfort if sea conditions are not calm, and queues that can form at either end of the operation because of security and logistical factors. the business generated by destination southwest includes 21 turnarounds. a turnaround port is one where the cruise starts and finishes. dartmouth is reported to operate one turnaround while falmouth has 20. the falmouth turnarounds involve a ship called the van gogh, which has itineraries to the mediterranean, the canary islands, and the caribbean. harrison describes recent research on passenger spending, which focused on cork in southern ireland. he quotes this irish research because he believes that cruises based in cork and those in the destination southwest program have much in common. this research identified that each passenger spends £197 and that crew members spend marginally less. there is, however, disagreement about spending levels, and some sources suggest that at times the crew can actually spend more than some passengers. this is explained by patterns in port manning. minimum levels of crew must remain on board when the ship is in port to ensure safety. as a result, crew members cannot go ashore in every port but when they do go ashore they are more likely to spend greater amounts of money. harrison estimates that cruise passenger spending in the southwest of england is £16.7 million, while crew spending is £1.7 million. that is a total of £18.4 million from a project with a £285,000 budget, which could equate to 438 jobs for the local community. when a cruise ship comes to falmouth, the local department store, marks and spencer, takes on extra staff. the project has attracted high-profile vessels to the ports in the partnership and it is reasonable to highlight the benefit to the port's image. when the 'world ' was visiting falmouth as part of her itinerary, there were 2,000 people standing on the headland to see the ship as she sailed out of the harbor. how was this level of success achieved? the website was seen to be important. the quality of information and the ease of use are fundamental. destination southwest possessed a tacit understanding of the cruise industry and its requirements. the project used business-to-business (b2b) marketing. personal contacts that, developed relationships and encouraged visits to the area by decision makers were also important. attendance at trade and travel conventions was of importance because it gave destination southwest a presence. douglas ward, the author of the berlitz guide to cruising, was appointed as honorary president, and this link was also thought to be useful because of opportunities to enhance networking and raise the project's profile. the initiative has helped to develop the level of support for cruise tours, quality of welcome for cruise passengers, and overall focus for customer service. in torbay, for example, shop-mobility trolleys were made available, and the mayor attended personally to welcome the passengers. in other ports, such as plymouth and falmouth, portable tourist information display units were available for passengers to consult. local problems that negatively affect business include conflicting schedules from ferry operators competing for berths and limited under-keel clearance in port areas that inhibits ship mobility and access during certain tides and times. the project has helped lengthen the tourist season and has brought many people from the us, europe, and the uk to the region. the potential for cruising is continually expanding. the passenger shipping association states that there was a 37 percent increase in visits to the uk between 2003 and 2004 and identifies it as the fastest growing market in the world. the potential for the southwest of england is high. even the weather, often regarded by some as a turn-off, is seen by many us passengers as an attractive experience. the local government office is impressed with the project and aims to extend it for a further two years. levels of investment are low, however, and there is a constant struggle to persuade members to contribute. there are major benefits to acting in concert. ports that do not act in competition can derive benefits through cooperation. harrison says that cruising is for everyone, and the challenge is to inform those who do not recognize how it has changed. the preceding case study presented an account of how one region in a country created a plan to develop and sustain cruise tourism growth. 1. consider the key actions and identify the critical elements that led to the outcome of this initiative. 2. what are the risks for this project and how can they be addressed with respect to the following? a. internal competition between neighboring ports b. ensuring the ports remain attractive as cruise destinations c. securing finance to ensure that the project develops private beaches, such as those owned or leased by cruise brands in the caribbean or the bahamas, are seen as a useful alternative to neighboring popular ports of call. often the beaches are on cays, the local name given to small islands, which is a derivative of the word key (as in key west). cays are small, lowlying islands consisting mainly of coral and sand. cruise lines such as disney, princess cruises, norwegian cruise line, holland america line, costa cruise lines, royal caribbean international (which has two islands), and radisson seven seas cruises are all involved in this type of investment. but what are the advantages and are there any disadvantages in having a private beach port? most of the islands are constrained by their location and facilities, thus requiring that the ship anchor off the coast, with passengers then ferried to the island jetty by tender. this transfer can add an exciting dimension to a cruise, although those with small children or with a disability may be inconvenienced. the notion of a private cay or beach can be attractive to passengers because of the implied romance or because the idea may signify to some a prestigious and unique benefit. the visit to the cay is often scheduled to include a morning arrival and late afternoon departure. this optimizes usage of the cay and allows the company to build in additional services such as barbeques, water sports, and organized games and activities. this in turn creates opportunities to generate revenue for the activities and for facilities. kayaking, sailing, snorkeling, scuba diving, and a range of children's activities can be scheduled. in addition, some companies have scheduled special activities such as massages in private cabanas (disney and holland america) and "surf and turf " olympics (costa cruises). royal caribbean has built a replica of a spanish galleon and sunk a small airplane in the waters off its bahamian island, 140-acre coco cay, for snorkeling tours and scuba divers. services may be provided by the cruise company or subcontracted to local employees or contract providers. the services are under the quality assurance and control of cruise management with, in some cases, shipboard staff being used ashore to create a seamless service. in addition to this approach to developing their "products," cruise companies are also introducing "beach clubs" in popular destinations, which are managed and operated directly or as part of a contract by the cruise companies. some observers are critical of this approach (robertson, 2004) , noting that issues relating to the environment and the amount of waste generated by tourists, both on the ship and when visiting these fragile islands are important and in need of further examination. in addition, points are raised about the ethical position of cruise companies in relation to the playgrounds of the caribbean and the bahamas. cruise companies generate large amounts of revenue from their islands by selling products and services but, it is claimed, in doing so, the direct contribution to locals trading in the caribbean is being eroded (robertson, 2004) . where tourists are sheltered from a local environment by barriers intended to protect the tourists and manage their experience (boniface and cooper, 2005: 453). why is this so and what are the implications? glossary archipelago: a group of many islands. duty-free: the status claimed when goods are sold without the need to port fees: levies charged per passenger for a cruise ship entering a destination port. sars: severe acute respiratory syndrome what are the primary cruising sectors? 2. what are the important factors that define a port or destination? 3. what part does weather play for cruise destinations? 4. what are the secondary and emerging cruise sectors? additional reading and sources of further information antigua and barbuda aruba cruise passengers experience the bahamas exploratory research of tourist motivations and planning venice launches antiflood project worldwide destinations caribbean-everything you want it to be cayman islands-close to home bahamas and the caribbean selling the sea life and learning in further education: constructing the circumstantial curriculum all about hong kong cruising: a guide to the cruise line industry cruising in the mediterranean home comforts. lloyd's cruise international cruising from port canaveral go to puerto rico mitchell beazley's family encyclopedia of nature cruise ship tourism sydney ports: first port, future port. retrieved 27april 2005 explore jamaica caribbean stronghold. lloyd's cruise international (69) growth culture. lloyd's cruise international high achievers. lloyd's cruise international key: cord-354738-4rxradwz authors: kohl, claudia; kurth, andreas title: european bats as carriers of viruses with zoonotic potential date: 2014-08-13 journal: viruses doi: 10.3390/v6083110 sha: doc_id: 354738 cord_uid: 4rxradwz bats are being increasingly recognized as reservoir hosts of highly pathogenic and zoonotic emerging viruses (marburg virus, nipah virus, hendra virus, rabies virus, and coronaviruses). while numerous studies have focused on the mentioned highly human-pathogenic bat viruses in tropical regions, little is known on similar human-pathogenic viruses that may be present in european bats. although novel viruses are being detected, their zoonotic potential remains unclear unless further studies are conducted. at present, it is assumed that the risk posed by bats to the general public is rather low. in this review, selected viruses detected and isolated in europe are discussed from our point of view in regard to their human-pathogenic potential. all european bat species and their roosts are legally protected and some european species are even endangered. nevertheless, the increasing public fear of bats and their viruses is an obstacle to their protection. educating the public regarding bat lyssaviruses might result in reduced threats to both the public and the bats. the european continent is inhabited by 52 hibernation. many bat species migrate over vast distances while others are rather territorial. all bats in europe utilize echolocation to navigate. contrary to the worldwide efforts in protecting bats, they have been increasingly gaining attention as potential reservoir hosts of some of the most virulent viruses we know. various publications reviewed bats globally as carriers and potential reservoir hosts of human-pathogenic and zoonotic viruses [3] [4] [5] [6] [7] [8] [9] [10] , while hardly anything is known about human-pathogenicity of european bat viruses apart from lyssaviruses. in this review, we discuss a selection of viruses as possible threats posed by european bats to the public from our point of view. a summary of viruses that have been detected in european bats is given in table 1 at the end of the manuscript. a more comprehensive and up-to-date list of bat-associated viruses can be found online at the database of bat-associated viruses (dbatvir) [11] . european bat lyssaviruses (family rhabdoviridae) are the most important zoonotic bat-borne viruses in europe and have been comprehensively reviewed by banyard et al. in this special issue on bat viruses (title: lyssavirus infections of bats: emergence and zoonotic threat) [12] . therefore, we will provide a short overview. [13, 14] nyctalus noctula rhinolophus ferrumequinum hungary pcr [15] myotis myotis germany pcr [16] astroviridae myotis myotis germany pcr [16] mamastrovirus italy pcr [22, 28] the postulates drafted by jacob henle and robert koch in the late 19th century constitute a framework regarding the principles of cause-and-effect in microbiology [55] . back then, it was comparatively straightforward to limit cause-and-effect to four postulates, although viruses had not yet been discovered nor was molecular biology developed ( table 1 ). all of the postulates are hard to fulfill for viruses, as they do not grow on nutrient media, but require living cells for replication. when looking for viruses on a molecular level, it is necessary to consider that only the first postulate can be accomplished. studies identifying a host-pathogen relationship solely at the molecular level do not take into consideration that detection does not equal etiology. even though polymerase chain reaction (pcr) screening and metagenomic studies are indispensable and valuable tools, virologists should stay close to the henle-koch postulates when assuming a possible virulence of viruses detected in bat hosts. a plethora of coronaviruses has been detected in bats, mostly belonging to the alphaand betacoronaviruses [11, 56] . the genus alphacoronavirus hosts human-pathogenic strains (i.e., human cov 229e and nl63); however, in this review, we will focus on selected highly human-pathogenic betacoronaviruses and their european bat virus relatives [56] . from november 2002 until july 2003 the world was confronted with the first pandemic of the new millennium, caused by a novel coronavirus (cov) inducing the severe acute respiratory syndrome in humans (sars) [57] [58] [59] . the pandemic spread from its origin, a wet-market in the guangdong province in china, through 33 countries on five continents resulted in more than 8000 infected humans of whom more than 700 eventually died [60, 61] . the search for the animal reservoir began, identifying masked palm civets and bats as possible sources. subsequently, a plethora of diverse coronaviruses of distinct groups have been detected in various bat species around the world via molecular-biological techniques. in 2012, another human-pathogenic coronavirus, called middle east respiratory syndrome coronavirus (mers-cov), began spreading from the arabian peninsula, so far resulting in globally 707 laboratory-confirmed cases of infection with mers-cov, including at least 252 deaths [62] . dromedaries and bats are suspected as reservoirs for mers-cov [63] . recent findings support the plausibility of dromedaries as reservoir species [64] . although numerous studies in european bats report the presence of sars-like-cov and mers-like-cov sequences [21, [24] [25] [26] 65] , no final conclusion can be drawn regarding their zoonotic potential. a related virus detected in bats cannot necessarily be considered as zoonotic. a few alterations in the sars-cov spike protein enabled its binding to the host receptor ace-2, thus sars-cov became capable of infecting humans [66] . so far, the sars-like cov detected in european bats lack these alterations and thus are not predicted to be capable of infecting humans. although virus strains might be similar or related on a nucleic acid level, the distinct function of proteins is crucial when determining the host range. therefore, mere similarity is not sufficient to examine the potential of viruses to infect humans or even predict their virulence. it took ten years from the emergence of sars-cov for the first bat cov to be isolated from rhinolophus bats in china, that displayed the human ace-2 receptor, which enabled the virus to infect human cells [67] . these findings provide evidence for the reservoir theory. from the european perspective, nevertheless, no sars-like cov or mers-like cov has been isolated from any european bat, nor has any transmission of sars-like cov or mers-like cov to humans been reported. the case of mers-cov is slightly different, as a sequence of 190 base pairs with 100% identity to mers-cov was detected in a bat (taphozous perforates-the species identification performed was not beyond doubt, as it was based on exclusion criteria (no cytochrome b sequence of taphozous perforates is available in genbank [68] )) in saudi arabia [8] . this finding initiated a controversy among leading cov experts, as the journal nature recently reported [69] . they discussed that the complete genome sequence of mers-cov obtained from the bat should confirm that the virus was indeed identical and not coincidentally just a short conserved region of the virus genome. furthermore, a prevalence study might provide insights into the distribution of mers-cov in bat populations. although taphozous perforates are not abundant in europe, climate change and environmental factors may have an effect on the future distribution of this bat species (figure 1 ) [70] . the case of mers-cov emergence impressively demonstrates the necessity of virus discovery and prevalence studies. with the first sequence of mers-cov that became available, bats were suspected as reservoir hosts, not only because mers-cov is a sars-cov relative, but also because previous bat virus discovery studies had provided eligible sequences of bat cov to genbank, allowing for correlations with the novel mers-cov. recently, a quasi-species of mers covs was recovered from nasal swabs of dromedaries of the kingdom of saudi arabia [64] . the mers cov consensus genome variants from dromedaries and humans are indistinguishable, supporting the plausibility of dromedaries in the role of transmission [64] . in 2002, the first reported outbreak of filovirus, named lloviu virus (llov), in a european bat population occurred in france, spain, and portugal [29] . several colonies of schreiber's bats (miniopterus schreibersii) suddenly declined due to an unknown disease. llov was found in animals that showed signs of viral infection, but not in healthy bats co-roosting in the caves (myotis myotis). llov is distinctly related to filoviruses found in african bats and was classified in 2013 as type species of the novel genus cuevavirus [56] . unfortunately, the lack of successful isolation of llov prohibits the experimental infection of schreiber's bats to clarify whether llov is the first filovirus capable of inducing disease in bats. this would challenge the hypothesis of bats as potential reservoir hosts for other filoviruses like ebola and marburg virus. schreiber's bats are distributed in distinct lineages throughout oceania, africa, southern europe, and south-east asia (figure 2 ) [72] . they are thought to transmit and maintain llov across different lineages throughout their habitats, although no studies are available to prove this hypothesis. consequently, the sole demonstration of a novel filovirus sequence does not provide evidence of a possible public health threat. following the henle-koch postulates, the virus should be isolated and further characterized to draw conclusions on the evolution of filoviruses in their respective bat host. as most filoviruses are described as highly pathogenic for humans, the occurrence of llov should be carefully monitored by prevalence studies in the highly abundant miniopterus schreibersii (figure 2 ). in 2012, three distinct paramyxoviruses were detected in german bats, two of which were related to the proposed genus jeilongvirus (myotis mystacinus, pipistrellus pipistrellus) and one was related to the genus rubulavirus (nyctalus noctula) [34] . another study published in the same year described another 12 different paramyxoviruses in bats from germany (myotis bechsteinii, m. daubentonii, m. myotis, and m. mystacinus) and bulgaria (myotis alcathoe and m. capaccinii), all of which belong to the genus morbillivirus [35] . none of the novel bat paramyxoviruses are closely related to viruses of the highly pathogenic genus henipavirus or other human-pathogenic paramyxoviruses [34, 35] . there is no evidence to suggest that any of these novel paramyxoviruses are capable of infecting humans. similar to the case of the llov filovirus, virus isolates and prevalence studies in both humans and bats could improve knowledge and clarify their zoonotic potential. few studies have documented the negative results from pcr testing of european bats for other human-pathogenic viruses. for instance following generic pcr screening for flavi-, hanta-and influenza-a viruses in 210 european bats in 2011 [73] , testing of another 1369 central european bats for influenza-a viruses [74] and testing 42 european bats for hepadnaviruses in 2013 did not lead to the detection of any viral nucleic acids [75] . pcr screening of 468 european bats for orthopoxviruses has not revealed any known or novel virus sequences [76] . so far, the only virus isolates (beside lyssaviruses) obtained from european bats are one bunyavirus, one adenovirus and 22 orthoreoviruses [13, 19, 36, 37] . these represent the only isolates that would allow for further characterization and potential clarification of their zoonotic potential. nevertheless, recombinant viruses, constructed on sequence information, are also valuable tools to study prevalence and pathogenicity in vitro. toscana virus (tosv) was isolated from a bat's brain in 1988, while simultaneously tosv was isolated from sandflies in the laboratory [19] . as tosv has never been reported in bats afterwards and no hemagglutination-inhibiting antibodies has been initially found in the bat, there is a reasonable chance that this tosv isolation may have been a cross-contamination [77] . bat adenovirus 2 (bat adv-2) was isolated from a bat's intestine in 2009 [13] , and the whole genome was obtained and circumstantially analyzed [14, 78] . bat adv-2 displays a monophyletic relationship to the adenoviruses of canids (cadv). moreover, open trading frames (orf) in the bat adv-2 genome and the cadv are identical and not present in other members of the mastadenoviruses. the closely related canine adv contribute to the severe kennel cough syndrome in canids and show an unusually broad host range [79] . this provides evidence suggesting an ancestral inter-species transmission of mastadenoviruses between bats and canids. like in the case of rabies virus, which is prevalent in both bats and terrestrial mammals (e.g., dogs, raccoons, skunks, and foxes) of the americas, a continuing exchange and transmission between bats and canids or other terrestrial animals might be possible [80] . there is no evidence of a zoonotic potential of bat adv-2. in 2012, three novel orthoreoviruses were isolated from plecotus auritus and myotis mystacinus in germany [36] . a subsequent pcr screening obtained identical viral sequences also in other bat species: pipistrellus pipistrellus, pipistrellus nathusii, pipistrellus kuhlii, and nyctalus noctula. at the same time, a group in italy detected further 19 orthoreoviruses in myotis kuhlii, rhinolophus hyposideros, tadarida teniotis, and vespertilio murinus [37] . summing up the data for the reovirus isolates from germany and italy, a close relationship was revealed to the genus mammalian orthoreovirus (mrv), in particular to an orthoreovirus obtained from a dog (strain t3/d04) with hemorrhagic enteritis in italy [36, 37, 81] . no ancestral relationship was assumed here, but rather an opportunistic -behavior‖ of the novel closely related mrvs, as they were detected in various different bat species. moreover, the newly isolated mrvs are phylogenetically related to viruses capable of inducing severe meningitis in humans [82] . recently, a study published by steyer et al. described the detection of an mrv from a child hospitalized with acute gastroenteritis in slovenia [83] . the causative agent was determined to be an mrv with the highest similarity of 98.4%-99.0% in the respective segments to a bat mrv (t3/bat/germany/342/08) [83] . this might indicate a human-pathogenic potential of strain t3/bat/germany/342/08. as the case of sars-cov has shown that even small changes in the genome are important for determining the host range, this has to be determined for the bat mrvs in further studies. interestingly, no contact was reported between the infected child and bats, but contact to a domestic dog was assumed [83] . the isolated viruses will allow for a seroprevalence study (cross-reactivity and cross-neutralization with other strains) in humans, which shall be initiated to examine the prevalence of specific antibodies to bat mrvs in germany and italy (where these viruses have been found) to clarify their zoonotic potential. this is especially interesting as asian bat orthoreoviruses of the genus pteropine orthoreovirus have already been linked to potentially zoonotic respiratory diseases in humans [84, 85] . rhabdoviruses of the genus lyssavirus that have been detected in europe are considerably harmful and truly zoonotic agents, inevitably causing the death of unvaccinated humans if not treated in time before onset of the rabies disease [86] . even though bat-transmitted lyssaviruses have a fatality rate of virtually 100% and are suspected to be transmissible by bat biting and scratching, the reported total number of human fatalities in europe is low (n = 2-5 since 1963) [86] [87] [88] . all described hosts of european bat lyssaviruses (eblv-1 and eblv-2) are synanthropic, hence sharing their habitats with humans [87] . eblv-1 has been predominantly detected in eptesicus serotinus and e. isabellinus in europe, both living in buildings, roofs, and attics usually in the southern regions of europe (e. serotinus until 55° north, e. isabellinus in southern portugal-e. isabellinus is a north african population of e. serotinus that is controversially but not concludingly discussed as a novel species [1]), and male bats are reported to co-roost with multiple bat species [90] . eblv-1 was also detected in v. murinus, m. schreibersii, m. myotis, m. nattereri, r. ferrumequinum, and t. teniotis. whether these bat species constitute accidental hosts infected by spillover from co-roosting e. serotinus species, or whether they are additional reservoirs, has not yet been determined [38] [39] [40] [41] 91] . two human cases described by johnson et al. were confirmed as infected with eblv-2, which is prevalent in european m. daubentonii and m. dasycneme [40, 86] . m. daubentonii is prevalent in north-eastern europe and is frequently found co-roosting with p. pipistrellus and m. nattereri, whereas m. dasycneme is found throughout europe and in the mediterranean, co-roosting with m. capaccinii. so far, none of the co-roosting bats have been reported to carry eblv-2 [90] . however, spillover transmission to other animals (stone-marten, sheep, and cat) was described for eblv-1 [92] [93] [94] . overall, lyssaviruses prevalent in european bats pose a risk to public health, and preventive measures have already been implemented by many european countries for decades (e.g., surveillance, vaccination plans, and post exposure prophylaxis) [87] . especially the high-risk occupational groups (i.e., bat workers, bat carers in bat bat hospitals) are at increased risk. however, lyssavirus prevalence in european bats is very difficult to determine and results are very heterogenic [40] . the lyssavirus prevalences are considerably low, but changes of behavior as a result of a lyssavirus infection may be more likely to bring bats into contact with humans. however, it is necessary to balance the risk with the total number of fatal human cases during the last 35 years (five cases in 590 million people living in greater europe) [87] . accordingly, the risk is relatively low and would probably fall to zero if people were educated appropriately. direct contact (bites and scratches) with certain bat species might be risky and require post exposure prophylaxis. only few of the european bat species are known to be reservoirs of eblv-1 and eblv-2, but all of the european species are endangered or close to extinction. relocation or culling of bat colonies, in spite of being an obvious solution from the viewpoint of the general public, increases the risk of lyssavirus exposure and transmission and should not be considered [95] . only education can channel public fear to avoid further threats to the bats and the general public. alexander von humboldt discovered the latitudinal gradient in species diversity as early as 1799 [96] : the richness of species is subject to a global diversity gradient, abating from the species-rich tropics toward the higher latitudes [97] . bats influence this gradient significantly. more than 1100 bat species have been described worldwide. although they are abundant worldwide except for the polar regions, a steep diversity gradient is present from the tropics towards the poles [97] [98] [99] [100] . are fewer viruses prevalent in european bats because of the lower abundance of species in the more temperate europe? and is the zoonotic risk posed by bats decreased accordingly? only few studies on the biogeography of microorganisms are available. these studies indicate that the latitudinal diversity gradient has either no or a top-down effect on microbial diversity [101] [102] [103] [104] [105] . two studies hypothesized that the local diversity and dispersal of viruses is very high, though overall, the viral diversity is limited on the global scale [106, 107] . therefore, no assumptions can be made regarding the viral diversity in species abundant in temperate climates. as the total number of abundant species might not be essential, the change in biodiversity might play a role. the effect of decline in biodiversity on the emergence of diseases is subject of numerous publications [108] [109] [110] [111] [112] [113] [114] . basically, there are arguments in favor of two controversial theories; reduced biodiversity could either increase (dilution effect) or decrease the risk of disease transmission. for almost half of the zoonotic diseases that have newly emerged by spillover since 1940, a preceding change in land-use, agriculture, and wildlife hunting was reported [108] . all of the above-mentioned effects contribute to changes in biodiversity and increased contact situations between human and animal hosts, also in europe. once spillover in novel hosts has occurred, a high density of the novel host population eventually facilitates the establishment in the novel niche. thus, human overpopulation and a decreased biodiversity might be mutual factors promoting the establishment of emerging infectious diseases. in conclusion, the baas becking hypothesis from 1932 might still be appropriate: -everything is everywhere, but the environment selects‖ [115] . until now, lyssaviruses have been the only proven zoonotic viruses in european bats and may cause rabies in humans. however, only few bat species are known to transmit lyssaviruses in europe, and the number of human cases is rather low. nevertheless, education of the general public should be intensified to avoid easily preventable infections. although viruses with zoonotic potential have been detected in european bats, no clear assumption can be made without further studies. sero-prevalence studies should be conducted on the orthoreoviruses isolated from european bats, especially as a closely related virus was detected in a diseased child in slovenia [83] . other bat viruses detected by using molecular techniques should be isolated (e.g., mers-like cov or bat bunyavirus) to allow for characterization and follow-up sero-prevalence studies. in general, bats are special reservoir hosts because of their biological features, long-time co-evolution and high diversity of viruses that can be found. furthermore, there is neither a clearly decreased risk in the emergence of zoonotic viruses in temperate climates compared to 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their valuable comments. both authors reviewed the literature and wrote the manuscript. the authors declare no conflict of interest. key: cord-326532-2ehuuvnx authors: götzinger, florian; santiago-garcía, begoña; noguera-julián, antoni; lanaspa, miguel; lancella, laura; calò carducci, francesca i; gabrovska, natalia; velizarova, svetlana; prunk, petra; osterman, veronika; krivec, uros; lo vecchio, andrea; shingadia, delane; soriano-arandes, antoni; melendo, susana; lanari, marcello; pierantoni, luca; wagner, noémie; l'huillier, arnaud g; heininger, ulrich; ritz, nicole; bandi, srini; krajcar, nina; roglić, srđan; santos, mar; christiaens, christelle; creuven, marine; buonsenso, danilo; welch, steven b; bogyi, matthias; brinkmann, folke; tebruegge, marc title: covid-19 in children and adolescents in europe: a multinational, multicentre cohort study date: 2020-06-25 journal: lancet child adolesc health doi: 10.1016/s2352-4642(20)30177-2 sha: doc_id: 326532 cord_uid: 2ehuuvnx background: to date, few data on paediatric covid-19 have been published, and most reports originate from china. this study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection across europe to inform physicians and health-care service planning during the ongoing pandemic. methods: this multicentre cohort study involved 82 participating health-care institutions across 25 european countries, using a well established research network—the paediatric tuberculosis network european trials group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. we included all individuals aged 18 years or younger with confirmed sars-cov-2 infection, detected at any anatomical site by rt-pcr, between april 1 and april 24, 2020, during the initial peak of the european covid-19 pandemic. we explored factors associated with need for intensive care unit (icu) admission and initiation of drug treatment for covid-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with icu admission. findings: 582 individuals with pcr-confirmed sars-cov-2 infection were included, with a median age of 5·0 years (iqr 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required icu admission, 25 (4%) mechanical ventilation (median duration 7 days, iqr 2–11, range 1–34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. significant risk factors for requiring icu admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% ci 1·72–14·87; p=0·0035), male sex (2·12, 1·06–4·21; p=0·033), pre-existing medical conditions (3·27, 1·67–6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16–21·23; p<0·0001). the most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir–ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). four children died (case-fatality rate 0·69%, 95% ci 0·20–1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. interpretation: covid-19 is generally a mild disease in children, including infants. however, a small proportion develop severe disease requiring icu admission and prolonged ventilation, although fatal outcome is overall rare. the data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. funding: ptbnet is supported by deutsche gesellschaft für internationale zusammenarbeit. in late december, 2019, who was notified of an unusual cluster of pneumonia cases in wuhan, china. the disease, later termed covid-19, spread quickly beyond the borders of china, with the first cases in europe being recorded on jan 25, 2020. 1 subsequent investigations identified a novel betacoronavirus now designated as severe acute respiratory syndrome coronavirus 2 (sars-cov-2). 2 currently, there are no antiviral treatment options with proven efficacy, but several randomised controlled trials are investigating agents such as hydroxychloroquine, lopinavir-ritonavir, favipiravir, and remdesivir (eg, nct04336904, nct04328285, and nct04280705). other trials are focusing on immunomodulators, including tocilizumab and anakinra (eg, nct04317092 and nct04330638). to date, data on covid-19 in children and adolescents remain scarce, despite the number of confirmed covid-19 cases now exceeding 8 million globally. 3, 4 most published data originate from china, which cannot necessarily be extrapolated to children in europe and elsewhere. [5] [6] [7] [8] [9] [10] [11] [12] also, existing papers from china contain very few clinical data on children, and most lack details regarding supportive measures required by children with covid-19. similarly, recent epidemio logical reports from europe and north america contain little clinically relevant information. 13, 14 determining the level of support required by children is essential for paediatric service planning during the ongoing covid-19 pandemic. by use of a well established research network, predominately comprising paediatric infectious diseases specialists and paediatric pulmonologists, the aim of this study was to rapidly capture key data on covid-19 in children in europe on a large scale, to aid physicians in europe and in other geographical locations with service planning and allocation of resources. for this cohort study, european members of the paediatric tuberculosis network european trials group (ptbnet)-which currently includes 304 clinicians and researchers, most of whom are based at tertiary or quaternary paediatric infectious diseases or paediatric pulmonology units, across 128 paediatric health-care institutions in 31 european countries [15] [16] [17] [18] [19] [20] -were invited to contribute cases of confirmed sars-cov-2 infection that had been managed at or managed remotely by their health-care institution (including individuals admitted to other hospitals or identified during community screening) before or during the study period. any individual aged 18 years or younger with sars-cov-2 infection confirmed by rt-pcr was eligible for inclusion. a standardised data collection spreadsheet was used by collaborators to record data from their centre. all data were reviewed by three of the investigators (fg, bs-g, and mt), and any inconsistencies and other data queries were clarified with the reporting collaborators. units that did not see any cases before or during the study period were asked to report the absence of cases fulfilling the inclusion criteria at the end of the study period. the study was done over a 3·5-week period, from april 1 to april 24, 2020. the study was reviewed and approved by the ptbnet steering committee, and the human research ethics committees of the university of bochum, germany (19-6545-br), the hospital gregorio marañon, spain (ceim hgugm-177/20), and the city of vienna, austria (ek 20-071-vk). the study was conducted in accordance with the declaration of helsinki and its subsequent evidence before this study we searched medline on may 7, 2020, through the pubmed interface to identify publications describing clinical studies in children with covid-19. to ensure a broad search, the search terms used were "(child or children or pediatric or paediatric) and covid-19". no additional limits were set. this search yielded 809 papers: 104 case reports or case series; 38 epidemiological reports; 66 guidelines and consensus statements; 184 reviews, perspectives, or editorials without original data; and 53 letters; 332 were unrelated to children with covid-19. 22 papers presented original data, but exclusively in adults. only ten papers reported clinical studies in children with covid-19: eight papers originated from china, one from spain, and one from italy. the study by tagarro and colleagues was reported in letter format, and only included 41 children with confirmed severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in madrid. the study from italy by parri and colleagues was also reported as a letter and included 100 cases across several italian hospitals. however, the study only featured a single patient who required mechanical ventilation, and consequently very few data on children with covid-19 at the severe end of the disease spectrum. to our knowledge, this study is the first multinational, multicentre study in children with covid-19, and provides a detailed overview on sars-cov-2 infection in children in europe during the initial peak of the pandemic, which was facilitated by a collaboration of 82 units across 25 european countries. the study has several key findings. first, the data show that covid-19 is generally a mild disease in children, including infants. second, the study found that a substantial proportion (8%) of children develop severe disease, requiring intensive care support and prolonged ventilation. several predisposing factors for requiring intensive care support were identified. third, the study confirms that fatal outcome is rare in children. there was considerable variability in the use of drugs with antiviral activity as well as immunomodulatory medication, reflecting current uncertainties regarding specific treatment options. this study confirms previous reports from china suggesting that the case-fatality rate of covid-19 in children is substantially lower than in older adult patients. however, some children develop severe disease and require prolonged intensive care support, which should be accounted for in the planning of health-care services and allocation of resources during the ongoing pandemic. finally, the findings highlight that data on antiviral and immunomodulatory drugs are urgently needed from well designed, randomised controlled trials in children, to enable paediatricians to make evidencebased decisions regarding treatment choices for children with severe covid-19. amendments. no personal or identifiable data were collected during the conduct of this study. a confirmed case was defined as a patient in whom sars-cov-2 was detected in any clinical sample (respiratory tract, blood, stool, or cerebrospinal fluid) by rt-pcr. pcr testing was done as part of routine clinical care, and therefore done according to local testing guidelines in place at the time. date of symptom onset was defined as the day when the first symptom or sign occurred, and date of diagnosis as the day when sars-cov-2 was first detected. pyrexia was defined as a body temperature at least 38·0°c. the index case was defined as the most likely source case based on history; if multiple family members were affected, the person who displayed symptoms first was recorded. diagnosis of upper respiratory tract infection was based on clinical signs and symptoms, encompassing any of the following: coryza, pharyngitis, tonsillitis, otitis media, or sinusitis. lower respiratory tract infection was based on clinical signs and auscultation findings. inotropic support was defined as administration of dopamine, dobutamine, epinephrine, or norepinephrine by continuous infusion. non-parametric two-tailed mann-whitney u tests were used to compare continuous variables and χ² or fisher's exact tests to compare categorical variables, as appropriate. in children younger than 2 years, age was calculated as fraction of a whole year (365 days); from 2 years of age, age was rounded to the nearest year. the 95% ci around the case-fatality rate (cfr) was calculated with the wald method. normality of data distribution was assessed with the shapiro-wilk test. the clinical endpoint was the need for admission to an intensive care unit (icu; either neonatal or paediatric intensive care). the association of baseline characteristics and clinical findings with icu admission was initially evaluated using univariable logistic regression. subsequently, multivariable logistic regression analysis with the backward stepwise method was used to explore variables that were independently associated with icu admission. only variables that were significant in univariable analyses were introduced into the model. factors associated with drug treatment for covid-19 were also explored with univariable analysis. all probabilities are two tailed. p<0·05 was considered statistically significant. all analyses were done with prism (version 8.0; graphpad, la jolla, ca, usa) and spss (version 25.0; ibm, armonk, ny, usa). the funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. the corresponding author had full access to all the data and had the final responsibility for the decision to submit for publication. 585 cases of sars-cov-2 infection were reported from 77 health-care institutions located in 21 european countries: austria, belgium, bulgaria, croatia, denmark, estonia, germany, greece, hungary, ireland, italy, lithuania, norway, portugal, slovakia, slovenia, spain, sweden, switzerland, turkey, and the uk (figure 1). three cases did not meet the inclusion criteria (one 21-year-old individual and two individuals diagnosed with covid-19 based on serological testing, but pcr negative). five participating units in the netherlands, moldova, ukraine, and russia reported not having encountered any cases. 582 individuals with pcr-confirmed sars-cov-2 infection were included in the final analyses. 454 (78%) were contributed by tertiary or quaternary health-care institutions, whereas 54 (9%) had been diagnosed in secondary and 74 (13%) in primary health-care settings. the median age of the study population was 5·0 years (iqr 0·5-12·0), ranging from 3 days to 18 years (table) . age was non-normally distributed (w=0·8710; p<0·0001), with 170 (29%) participants younger than 12 months (figure 2). the sex ratio was 1·15 males to every female. the most common source of infection was a parent, considered the index case in 324 (56%) individuals; for 24 (4%) individuals, the most probable index case was a sibling. in the remaining 234 (40%) individuals, the index case was a person outside of the immediate family or unknown. 363 (62%) individuals were admitted to hospital and 48 (8%) required admission to an icu for additional support, corresponding to 13% of those admitted to hospital. 437 (75%) individuals had no pre-existing medical conditions. among the remaining 145 (25%) individuals, the most common conditions were chronic pulmonary disease (29 individuals, of whom 16 had asthma and six bronchopulmonary dysplasia), followed by malignancy (27 individ uals, of whom 14 had leukaemia or lymphoma and 11 had solid tumours), neurological disorders (26 individuals, of whom nine had epilepsy and eight had cerebral palsy), congenital heart disease (25 individuals), chromosomal abnormalities (ten individuals, of whom eight had trisomy 21), and chronic kidney disease (nine individuals; table). 17 (3%) individuals had two or more pre-existing medical conditions. 29 (5%) individuals were receiving immunosuppressive medication at the time of covid-19 diagnosis (table) . three (1%) had a previously diagnosed immunodeficiency, comprising common variable immunodeficiency, congenital neutropenia, and schimke immuno-osseous dysplasia. 25 (4%) individuals were receiving chemotherapy at the time of their diagnosis or had received chemotherapy in the preceding 6 months. three (1%) had previously undergone human stem cell transplant. pyrexia was the most common sign at presentation, observed in 379 (65%) individuals (table). approx imately half had signs or symptoms of upper respiratory tract infection and approximately a quarter had evidence of lower respiratory tract infection; 128 (22%) had gastrointestinal symptoms. 40 (7%) individuals with gastrointestinal symptoms had no respiratory symptoms; the majority (65%; n=26) of these individuals had pyrexia. 92 (16%) individuals were asymptomatic. dates when sars-cov-2 infection was confirmed by rt-pcr in the study population are summarised in figure 3 . the median interval between symptom onset and diagnosis was 2 days (iqr 1-4; range 0-23); in the baseline characteristics in the entire cohort and by requirement of icu admission majority (n=391; 67%) of cases, the interval was no more than 3 days. in eight cases, sars-cov-2 infection was confirmed before any signs or symptoms were presentmainly neonates born to sars-cov-2-positive mothers and household members of symptomatic adults with confirmed covid-19. a chest x-ray was done in 198 (34%) patients. of those, 93 (47%) had changes consistent with pneumonia (table). ten (5%) had changes suggestive of acute respiratory distress syndrome (ards), all of whom required mechanical ventilation. in 29 (5%) patients, additional viruses were detected in respiratory samples, comprising enterovirus or rhinovirus (n=18), influenza virus (n=5), parainfluenza virus (n=3), adenovirus (n=3), respiratory syncytial virus (rsv; n=2), bocavirus (n=2), and coronavirus nl63, coronavirus hku1, coronavirus oc43, and human metapneumovirus (n=1 each). in 22 patients one virus was detected in addition to sars-cov-2; in six patients, two additional viruses were detected simultaneously; and in one patient, three were detected. patients with one or more viral co-infections were more likely to have signs or symptoms of upper or lower respiratory tract infection at presentation compared with those in whom no additional viral agent was identified (appendix p 1). furthermore, individuals with viral co-infection were significantly more likely to require icu admission, respiratory support, or inotropic support. 507 (87%) individuals did not require respiratory support at any stage. 75 (13%) patients required oxygen support: 31 (5%) were started on continuous positive airway pressure (cpap) and 25 (4%) on mechanical ventilation (including 14 who had been managed with cpap initially). the median duration of mechanical ventilation was 7 days (iqr 2-11; range 1-34). one (<1%) patient was started on extracorporeal membrane oxygenation. 19 (3%) patients required support with inotropes. when comparing individuals by their requirement of icu admission, we found that patients who required icu admission were younger than those who did not (ie, individuals in the community and those admitted to hospital but not needing icu support), but this was not statistically significant (table; figure 2 ). in univariable analysis, being younger than 1 month of age, male sex, pre-existing medical conditions, pyrexia, signs or symptoms of lower respiratory tract infection, radiological changes suggestive of pneumonia or ards, and viral coinfection were associated with icu admission (table) . in multivariable analysis, the factors that remained associated with icu admission were being younger than 1 month (odds ratio [or] 5·06, 95% ci 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), signs or symptoms of lower respiratory tract infection at presentation (10·46, 5·16-21·23; p<0·0001), and presence of pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015). the most commonly used drug with antiviral activity was hydroxychloroquine, used in 40 (7%) patients, followed by remdesivir, which was used in 17 (3%) patients. lopinavir-ritonavir was used in six (1%) patients and oseltamivir in three (1%), two of whom had influenza virus co-infection. three (1%) patients received two drugs with antiviral activity and one (<1%) patient received three; all four patients had ards on chest x-ray. no patient received chloroquine, favipiravir, zanamivir, or ribavirin. with regard to immunomodulatory medication, 22 (4%) patients received systemic corticosteroids, seven (1%) intravenous immunoglobulin, four (1%) tocilizumab, three (1%) anakinra, and one (<1%) siltuximab. in univariable analysis, factors associated with treatment initiation of drugs with antiviral or immunomodulatory activity comprised pre-existing malignancy (or 6·3, 95% ci 2·8-14·2), cardiac disease (4·2, 1·8-10·0), or respiratory disease (6·5, 3·0-14·2); immuno suppressive therapy at presentation (6·5, 3·0-14·2) or recent chemo therapy (6·1, 2·6-14·1); radiological findings suggestive of pneumonia (4·5, 2·3-8·6) or ards (22·3, 2·7-180·5); and viral coinfection (5·5, 2·5-12·2; all p<0·0001; appendix p 2). four patients, all older than 10 years, had a fatal outcome (cfr 0·69%, 95% ci 0·20-1·82), with death occurring at 3, 9, 11, and 17 days after symptom onset. two patients had no known pre-existing medical conditions; one had a cardiorespiratory arrest before arrival at the hospital and resuscitation was unsuccessful and the other died while being mechanically ventilated in icu. the third patient had undergone human stem cell transplant 15 months earlier. the fourth patient was managed palliatively (without intubation), due to the severity of their pre-existing medical conditions. the remaining 578 patients were alive when the study closed. 93 (16%) individuals never developed clinical symptoms. in 460 (80%) individuals, all symptoms had resolved without apparent sequelae, whereas 25 (4%) were still symptomatic or were requiring respiratory support when the study closed. to our knowledge, this is the first multinational, multicentre study on paediatric covid-19, and also the largest clinical study in children outside of china to date. the inclusion of such a substantial number of cases was made possible by involving a large number of specialist centres across europe via a well established collaborative paediatric tuberculosis research network, allowing this study to provide one of the most detailed accounts of covid-19 in children and adolescents published to date. it is important to highlight that this study has primarily captured data from children and adolescents who were seen or managed within the hospital setting, and that the majority of participating units were part of tertiary or quaternary health-care institutions. consequently, the study population is likely to primarily represent individuals at the more severe end of the disease spectrum. notably, a recent letter summarising 171 pcr-confirmed cases in wuhan suggests that close to 20% of children and adolescents with sars-cov-2 infection are asymptomatic. 10 at the time our study was conducted, testing capacity for sars-cov-2 in many european countries was lower than clinical demand, and therefore many children with symptoms consistent with covid-19 in the community were not tested and consequently not diagnosed. nevertheless, our data indicate that children and adolescents are overall less severely affected by covid-19 than adults, particularly older patients. previous, large-scale data suggest that the cfr in adults older than 70 years is close to 10%, 6 potentially due to immuno senescence. 21 it is reassuring that our data show that severe covid-19 is uncommon in young children, including infants, despite their immune maturation being incomplete, 22, 23 with only few requiring mechanical ventilation. it was striking that all children who died in our cohort were older than 10 years. the centers for disease control and prevention (cdc) reported 2572 confirmed cases of covid-19 in individuals younger than 18 years in the usa as of april 2, 2020, representing only 1·7% of the total number of recorded cases (n=149 760). 14 the australian health protection agency has reported that children accounted for only 4% of confirmed covid-19 cases in australia. 24 unfortunately, in the cdc report, clinical data were only available in a small proportion of patients (n=291; 11%). in concordance with our observations, fever and cough were the predominant clinical features at presentation (present in 56% and 54% of individuals, respectively), with similar rates observed in a study from italy. 25 in our cohort almost a quarter of patients had gastrointestinal symptoms, some of whom had no respiratory symptoms, and a substantial proportion of children were entirely asymptomatic. the cdc report also mentions three deaths, 14 but it is unclear how many patients were still hospitalised by the time of publication, so it is difficult to come to firm conclusions regarding the cfr in us children. our data indicate that the cfr in children and adolescents across europe is less than 1%. considering that many children with mild disease will never have been brought to medical attention, and therefore not diagnosed, it is highly probable that the true cfr is substantially lower than the figure of 0·69% observed in our cohort. this hypothesis is further supported by an epidemiological study from china, in which the cfr in individuals aged 19 years or younger was only 0·1% (one death in 965 confirmed cases). 6 furthermore, our data indicate that sequelae related to covid-19 are likely to be rare in children and adolescents. however, after the closure of our study, reports of a hyperinflammatory syndrome affecting children that is temporally, and potentially causally, associated with sars-cov-2 infection have emerged, which has sub sequently been named paediatric inflammat ory multisystem syndrome temporally associ ated with sars-cov-2 (pims-ts; sometimes known as mic-s). 26, 27 further research will be required to characterise this emerging disease entity in detail, and determine the longterm outcome of affected children. importantly, our data show that severe covid-19 can occur both in young children and in adolescents, and that a significant proportion of those patients require icu support, frequently including mechanical ventilation. a small study from madrid also found that four (10%) of 41 children with sars-cov-2 infection required admission to icu. 28 in our cohort, being younger than 1 month, male sex, presence of lower respiratory tract infection signs or symptoms at presentation, and presence of a pre-existing medical condition were associated with increased likelihood of requiring icu admission. our results also show that the majority of children who are intubated due to respiratory failure require prolonged ventilation, often for 1 week or more. this contrasts with observations in children with rsv infection who, on average, only require mechanical ventilation for 5-7 days, 29 but is not dissimilar to observations in children with influenza. 30 this has important implications for service planning, as although the overall demand for icu support might be lower in children than in adults, each patient is likely to occupy icu space for an extended period of time. at this time of intense strain on health-care services worldwide, it is vital that adequate resources are allocated to paediatric services to sustain the provision of high-quality care for children. the observation that, in our study, individuals with viral co-infection (ie, infected with sars-cov-2 and one or more other viral agents) were more likely to require icu support than those in whom sars-cov-2 was the only viral agent identified might have implications for the winter period 2020-21, when the incidence of other viral respiratory tract infections, including rsv and influenza virus infections, is bound to increase. this could result in a greater proportion of paediatric patients with covid-19 requiring icu support than in the cohort described here, as the influenza season 2019-20 was already over in europe before the study commenced. our data also reflect the uncertainties regarding drug treatment options for covid-19. in some countries, including spain and italy, national guidelines were encouraging the use of hydroxychloroquine for selected cases, as reflected in our data, while in other countries, recommendations were more guarded regarding the use of antiviral agents in the absence of robust human data. an expert consensus statement from the usa has emphasised that antiviral treatment should be reserved for patients at the severe end of the disease spectrum, ideally within a clinical trial. 31 overall, the expert panel appeared to favour the use of remdesivir over other agents, based on the currently available data from invitro and animal studies, including in non-human primates, and recent data from compassionate use in humans. 32, 33 the panel members' opinion was split regarding the use of lopinavir-ritonavir, given the disappointing results of a recently published randomised controlled trial. 34 the main limitation of this study relates to the number of variables for which data were collected. in the context of the ongoing covid-19 pandemic, to ensure high levels of participation and avoid diverting substantial time away from clinical front-line duties, a decision was made not to collect detailed data on laboratory parameters or icu interventions. a further limitation was that a variety of inhouse and commercial pcr assays were used across different participating centres, precluding an assessment of diagnostic test performance. also, the number of children receiving antiviral or immunomodulatory treatment was too small to draw meaningful conclusions regarding their effectiveness, which will be addressed by the aforementioned randomised trials. a further limitation is that different countries were using different thresholds to screen for sars-cov-2 at the time the study was done, with some recommending screening of all children admitted to hospital or conducting community screening, whereas others were using more selective testing strategies. despite those limitations, to our knowledge, this study provides the most comprehensive overview on covid-19 in children and adolescents to date. in conclusion, our data, originating from a large number of specialist centres across europe, show that covid-19 is usually a mild disease in children, including infants. nevertheless, a small proportion of children and adolescents develop severe disease and require icu support, frequently needing prolonged ventilatory support. however, fatal outcome is rare overall. our data also reflect the current uncertainties regarding specific treatment options, highlighting that more robust data on antiviral and immunomodulatory drugs are urgently needed. mt conceived of the study. fg, bs-g, sbw, mb, fb, and mt designed the study. fg, bs-g, and mt cleaned and analysed the data, constructed the figures, and wrote the first draft of the manuscript. all authors contributed data to the study, contributed to the data interpretation, critically reviewed the manuscript, and approved the final manuscript for submission. fg has received funding from gilead for research related to hepatitis e. bs-g and mt have received assays free of charge from cepheid for tuberculosis diagnostics projects. mt has received assays at reduced pricing or free of charge from cellestis/qiagen for tuberculosis diagnostics projects, has received support for conference attendance from cepheid, and is currently receiving funding from biomérieux as an investigator of an ongoing tuberculosis diagnostics study. uh reports personal fees from cepi for being a member of the speac-cepi meta-data safety monitoring board for covid-19 vaccine trials, outside of the submitted work. the other authors declare no competing interests. michael buettcher (lucerne children's hospital, lucerne cantonal hospital references 1 who. novel coronavirus (2019-ncov) situation report 5 coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2 who. novel coronavirus (2019-ncov) situation report 148 severe and fatal covid-19 occurs in young children characteristics of pediatric sars-cov-2 infection and potential evidence for persistent fecal viral shedding novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records clinical characteristics of a case series of children with coronavirus disease 2019 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review sars-cov-2 infection in children epidemiology of covid-19 among children in china detection of covid-19 in children in early spread of sars-cov-2 in the icelandic population cdc covid-19 response team. coronavirus disease 2019 in children-united states performance of immune-based and microbiological tests in children with tb meningitis in europe-a multi-center paediatric tuberculosis network european trials group (ptbnet) study tuberculosis disease in children and adolescents on therapy with anti-tumor necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study use of xpert mtb/rif ultra assays among paediatric tuberculosis experts in europe availability and use of molecular microbiological and immunological tests for the diagnosis of tuberculosis in europe european shortage of purified protein derivative and its impact on tuberculosis screening practices paediatric tuberculosis network european trials group. shortage of purified protein derivative for tuberculosis testing immunosenescence: a review protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny neonatal innate tlr-mediated responses are distinct from those of adults covid-19 national incident room surveillance team. covid-19 children with covid-19 in pediatric emergency departments in italy hyperinflammatory shock in children during covid-19 pandemic rapid risk assessment: paediatric inflammatory multisystem syndrome and sars-cov-2 infection in children screening and severity of coronavirus disease 2019 (covid-19) in children in high flow nasal cannulae therapy in infants with bronchiolitis characteristics and outcomes of a cohort hospitalized for pandemic and seasonal influenza in germany based on nationwide inpatient data multicenter initial guidance on use of antivirals for children with covid-19/ sars-cov-2 compassionate use of remdesivir for patients with severe covid-19 therapeutic options for the 2019 novel coronavirus (2019-ncov) a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 we express our gratitude to all colleagues and research personnel involved in the data collection for this study, as well as the members of the human research ethics committees and institutional review boards that have kindly fast-tracked this study. we are also grateful for the kind support of the clinical microbiology & infectious diseases department and the covid-19 group at hospital general universitario gregorio marañón, madrid, spain. this project did not receive specific funding. ptbnet is supported by the deutsche gesellschaft für internationale zusammenarbeit. bs-g is funded by the spanish ministry of health-instituto de salud carlos iii and co-funded by the european union (feder; contrato juan rodés, grant jr16/00036). an-j was supported by "subvencions per a la intensificacio de facultatius especialistes"-departament de salut de la generalitat de catalunya, programa peris 2016-2020 (slt008/18/00193).editorial note: the lancet group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. key: cord-354814-frlc6694 authors: sanchez-lorenzo, a.; vaquero-martinez, j.; calbo, j.; wild, m.; santurtun, a.; lopez-bustins, j.-a.; vaquero, j.-m.; folini, d.; anton, m. title: anomalous atmospheric circulation favored the spread of covid-19 in europe date: 2020-05-01 journal: nan doi: 10.1101/2020.04.25.20079590 sha: doc_id: 354814 cord_uid: frlc6694 the current pandemic caused by the coronavirus sars-cov-2 is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march 2020. it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february 2020 (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is a new coronavirus first noticed in late 2019 in the hubei province, china 1,2 . the virus has a probable bat 3, 4 respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (>5 μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (<5 μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin 6 . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs 7 , where cell receptors for some infectious respiratory viruses are located, including . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint the angiotensin converting enzyme ii (ace2) used by sars-cov-2 to infect the individual 3 . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [8] [9] [10] . a recent study has described that the sars-cov-2 virus can remain viable at least up to 3 hours in airborne conditions 11 . respiratory droplets and aerosols loaded with pathogens can reach distances up to 7-8 meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person 12 . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov-2 virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people 13 . another study has also shown evidence of potential airborne transmission in a health care institution 14 . recent studies have pointed out a main role of temperature and humidity in the spread of covid-19. warm conditions and wet atmospheres tend to reduce the transmission of the disease [15] [16] [17] [18] [19] [20] [21] [22] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around 5-11ºc, never falling below 0ºc, and specific humidity of 3-6 g/kg aproximately 18 . the first major outbreak in europe was reported in northern italy in late february 2020. following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present (28 th march 2020) italy and spain are still the two main contributors of cases and deaths in the . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february 2020 has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february 2020 was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure 1 , figure s1 ). this spatial configuration represents the well-known north atlantic oscillation (nao) 23,24 in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe 25 . figure s2 show maps for february 2020 for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis 18 , the sars-cov-2 virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around 5ºc and 11ºc, which are the conditions shown in figure 2 for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao 26 . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid-19 outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries 29 . thus, the sars-cov-2 virus was already in europe in early 2020, but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid-19 spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries ( figure s4 ) with the highest number of covid-19 cases reported so far (see data and methods). figure 3 (top) shows that there is a statistically significant . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint (r 2 =0.481, p<0.05) second order polynomial fit between the anomalies of the 500 hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than 1,000 cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of 500 hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r 2 =0.50, p<0.05), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid-19 in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid-19 and meteorological data within spain (see data and methods, figure s5 ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure 4 ). they indicate that lower mean temperatures (i.e., average of around 8-11ºc) and lower specific humidity (e.g., <6 g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r 2 =0.838, p<0.05) and are not independent of each other. the temperatures as low as 8-10ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint of higher potential for the spread of the virus, as reported so far in the literature [15] [16] [17] [18] [19] [20] [21] [22] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than 13ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid-19 mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure 3 ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid-19 described above has some intriguing resemblances with the 1918 influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the 1918 flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors 30 . in spain, a south-north gradient is also reported in the 1918 flu after controlling for demographic factors 31 . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions 31 . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november 1918) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s6 ). in other words, the nao was also in its positive phase just before the major outbreak of the 1918 influenza pandemic. this resembles the spatial . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint patterns described above for the current covid-19 outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid-19 in is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. although the outbreak of a pandemic is controlled by a high number of biological, health, political, social, economic and environmental factors, with complex and non-linear interrelationships between them, the results of this study indicate that an anomalous atmospheric circulation may explain why the covid-19 outbreak in europe developed more easily (or faster) in the south-west (mainly north of italy and inland of spain). specifically, the extreme positive phase of the ao and nao during february 2020 could have modulated the beginning of the major outbreaks of covid-19 in europe. this detected anomalous atmospheric pattern, which produces dry conditions over southwestern europe, may have provided optimal meteorological conditions for the virus propagation. in the context of anthropogenic climate change, it has been shown that in future emissions scenarios a poleward expansion of the hadley cell is expected 41 , which in turn is in line with a tendency to increase the frequency of positive phases of the nao 42 ( figure s8 ). this should be taken into account for planning against future epidemics and pandemics that arise from respiratory viruses. interestingly, the conditions during the last major pandemic experienced in europe (the spanish flu in 1918), seem to resemble the current spatial pattern of affectation with more cases in the south of europe as compared to the north. equally, the dominant atmospheric situation was strongly affected by anticyclonic (cyclonic) conditions in the south (north) of . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. ncep/ncar 1 , era5 2 and era20c 3 atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. the artic oscillation (ao) index has been extracted from the climate prediction center of the national oceanic and atmospheric administration (noaa). the ao index is constructed by projecting the daily 1000 hpa height anomalies poleward of 20°n onto the loading pattern of the ao, this latter being defined as the leading mode of empirical orthogonal function (eof) analysis of monthly mean 1000 hpa height. more details and data: https://www.cpc.ncep.noaa.gov/products/precip/cwlink/daily_ao_index/ao.shtml. covid-19 data on country basis were obtained on march 26 th , 2020 from the website https://www.worldometers.info/coronavirus/, which it is mainly based on the data provided by the coronavirus covid-19 global cases by the center for systems science and engineering (csse) at the johns hopkins university. data from spain on regional scale . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries. we have selected the slp and 500 hpa fields in order to summarize the meteorological conditions over each location, as it is known that several meteorological variables can be involved in the transmission of respiratory viruses 4, 5 . with this approach we also avoid the lack of properly updated data for all potential meteorological variables involved in the covid-19 spread, which needs further research as soon as the pandemic ends and a more reliable and complete database of both covid-19 impact and meteorological data can be compiled 6 . for spain, several meteorological variables with high-quality records were obtained from the spanish meteorology agency (aemet) based on surface observations for each of the capital cities of the provinces inside each autonomous region. specifically, monthly averages for february 2020 of 2-m temperature, 2-m maximum temperature, 2-m minimum temperature (°c), air pressure (hpa), wind speed (km h −1 ), specific humidity (g kg -1 ), relative humidity (%), total precipitation (mm) and days of more than 1 mm of precipitation. an arithmetic average has been calculated for the autonomous regions with more than one province. we have checked coupled model intercomparison project phase 5 (cmip5) simulations for two future scenarios (rcp4.5 and rcp8.5) at the end of the 21th century. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint clinical features of patients infected with 2019 novel coronavirus in wuhan , china a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov-2 related coronaviruses in malayan pangolins the role of particle size in aerosolised pathogen transmission : a review covid-19): how covid-19 spreads recognition of aerosol transmission of infectious agents : a commentary evidence of airborne transmission of the severe acute respiratory syndrome virus aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission of covid-19 aerodynamic characteristics and rna concentration of sars-cov-2 aerosol in wuhan hospitals during covid-19 outbreak transmission potential of sars-cov-2 in viral shedding observed at the university of the role of absolute humidity on transmission rates of the covid-19 outbreak role of temperature and humidity in the modulation of the doubling time of covid-19 cases. under rev the ncep / ncar 40-year reanalysis project era5: fifth generation of ecmwf atmospheric reanalyses of the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review)the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint key: cord-023993-rncleqqy authors: ramírez, j. martín title: long-lasting solutions to the problem of migration in europe date: 2020-03-12 journal: a shift in the security paradigm doi: 10.1007/978-3-030-43253-9_10 sha: doc_id: 23993 cord_uid: rncleqqy this is the following of a previous publication on the refugee crisis in europe and its security challenges. here we suggest some long-lasting solutions to the problem of migration. these may be summarize in four points: dealing with the countries of origin and of transit, adequate control of borders, and positive measures to facilitate the integration of the newcomers in their countries of destination. in a previous publication on the refugee crisis in europe and its security challenges, i concluded that a global problem like this one could not be solved without an adequate orderly, and controlled immigration policy, creating systematic and controlled arrival and integration programs, because the mental structure of european societies is not prepared to face a disorderly increase in migration flows (ramirez 2017 (ramirez , 2019 . it is thus vital to regulate the arrival of migrants if we want to achieve their real integration in our culture (espaliú berdud 2019) . here i will try to go forward, pinpointing the terrible damage made by the massive escape of young people from countries that desperately need them in their struggle for development; their great problem is precisely the continuous loss of human capital. besides of that, who emigrate are not the "poor among the poor", but people with certain economic means to be able to afford the trip and contacts in the place they are going to. what is more important, according to me, is to argue that the best way would be to encourage migrants to stay home, preventing massive uncontrolled displacements, is addressing the factors that drive emigration of their own origin countries. to stop unwanted migration, the developed countries must promote a profound democratic and economic stabilization and development. we must always remember that the first right of every human being -after the right to live-is the right not to emigrate and to have the opportunity of living peacefully and prospering in our own home, as pope pius xii wrote in the apostolic constitution exsul familia: "all men have the right to a family living space in their place of origin". the right to emigrate is only subsidiary to the main right to have a family living space in the place of origin, when this cannot be assured. migration has been a sensitive and contentious topic for ages. escaping violence, war, poverty and environmental disasters, more people than ever are migrating worldwide. since it is not a cyclical, but a structural phenomenon, which means that whatever the method put forward migration cannot be stopped. currently, according to the uno estimates, 258 million people live outside their country of birth (3.4% of the world's population). in 1970, about 2% of the world's 3.7 billion people lived abroad (unhcr 2017) . this figure grows due to inequality, climate change, conflicts, and the interconnectivity that facilitates the movement of people. 1 migration itself affects values, identities, cultures, assimilation capacities of societies, and, far from being a problem in se, it may be a solution to many problems; e.g., benefits the demographic catastrophe present in the aging western societies. but it doesn't always engender positive changes; it may also show important disadvantages. this is why immigration must be orderly, capable of duly regulating the massive arrival of people; otherwise our social protection systems will not resist. the illegal immigration requires proper vetting to identify criminals and terrorists-the crime rates of the foreign immigrant population are significantly higher than those of the natives-, and sometimes, to put in metaphorical terms, surgical excision procedure without anesthesia will frequently induce pain. no country needs a trojan horse. but we will leave this so interesting aspect for another parliament. although mass emigration to developed countries is a global phenomenon -it happens even within each country, internally displacing for instance from rural areas to urban ones: china is a clear example-, the present chapter will be focused mainly on what would be the better long-lasting solutions to its present situation in europe, one of the leading destinations in the world in terms of migratory flows, with 77 million migrants, russia included, according to the un's department for population. 2 immigration is an irresolvable problem at short-term. migration policies should follow a long-term vision, addressing economic, security and sociological points of view (de la cámara 2019), creating systematic and controlled arrival and integration programs of security, trade, development and employment issues. but, being a global problem, migration will only be solved as a consequence of a frank and sincere joint co-responsibility between all countries of origin, transit and destination, sharing the burden of dealing with both regular and irregular migration whenever possible. this was the intention of the un global compact for safe, orderly and regular migration, signed at the end of 2018 by 165 representatives of the 193 countries of the united nations (uno) met in marraquesh, in a non-mandatory and rather controversial document that says, in an indirect manner, that for the entry to be safe, orderly and regular, the conditions of entry must be safe and not subject to the mercy of smugglers, seekers' and workers' entry profiles should be differentiated, and entries should be legal. its 23 "objectives" were peppered with vague declarations, platitudes and split differences, such as the fight against the mafias that deal with human beings, the defence of the rights of immigrant workers or a change in narrative about migration towards a more positive approach. partly in the spirit of other global agreements like the paris climate deal, it encouraged states to co-operate on tricky cross-border matters without forcing them to do anything, and urged governments to treat migrants properly, but also to work together on sending them home when necessary. at least, it may help build the trust between "sending" and "receiving" countries that is the foundation of any meaningful international migration policy (economist 2018). let us offer some recommending ways of improving migration at four different levels: going to the roots in the countries of origin, dealing with the countries of transit, having an adequate control of borders, and suggesting some measures in the countries of destination. i have critized elsewhere (ramirez 2019 ) the saving buenist attitude 3 of a migrationist maximalism that wants to open the doors, the ports, the windows and throw all the walls, in favor of a weberian realism (the ethics of convictions versus the ethics of reason) (leguina 2019): even if we would welcome forty or fifty million africans a year, africa will continue to have the same population. it would be good if they start helping africans in their own countries and avoiding as much as possible the reasons why they want to emigrate (ramirez 2016) . we want the potential migrants to have a better future in their countries. as ousman umar repeats like a mantra, "the solution is in the country of origin, not in the destination. you have to feed minds (well); if you feed the mind you are satisfying hunger for more than a hundred years" (umar 2019) . some african prelates within the catholic church are calling attention to the most forgotten aspect of this debate: the terrible damage made by a massive escape of young people from countries that desperately need them in their struggle for development. in a book released recently, cardinal robert sarah, currently prefect of the congregation for divine worship and the discipline of the sacraments, 4 declares his personal position on immigration: "all migrants arriving in europe are crammed, without work, without dignity. is this what the church wants? the church cannot cooperate in this new form of slavery into which mass immigration has become" (sarah 2019a, b; indelicato 2019). the european union (eu), thus, has to structurally turn over economic resources for the development of africa (and of middle east), tackling the problems that are the main cause of migratory movements, analysing them and offering real help in their own home. consequently, their priority has to be to invest in the countries of origin, because migration control has to be paid with money: financing, companies, information, facilitating their institutional, social, political and economic conditions in order that nobody will be obliged to leave their home, and creating sources of employment in those countries of origin. some political party has proposed in its program that the eu should prepare a sort of "plan marshall" for africa, similar to the one usa did for the post-war europe. 5 3 according to the spanish royal academy (rae) dictionary, buenismo is the attitude of who reduces the seriousness of conflicts, acting with excessive benevolence and tolerance. this "goodism" is a demagogy destined to hold power through emotional blackmail, quite different to a real goodness, born of charity or philanthropy (robles, 2019) . 4 cardinal robert sarah is a native of guinea guinean who grew up under a harsh marxist dictatorship and became archbishop at the age of 34 with the task of guiding the diocese of conacry, when still in his country there was the socialist regime of sekou touré. so, i think he knows what he's talking about. 5 in the forties of the last century, america passed the economic co-operation act, better known as the marshall plan, because its inspiration from a speech at harvard university by george marshall, america's secretary of state. the marshall aid, aimed to revive europe's war-ravaged economies, encouraged the europeans to quash inflation and to narrow their deficits while eventually dismantling price controls and import barriers. these reforms had enormous benefits. before 1948 fear of inflation and taxation prompted german farmers to feed their harvests to their cattle, rather than it is not enough with assigning cooperation funds. as de la concha stresses (2019), a proper management of migration flows requires working as much as possible in cooperation with the countries of origin taking into account, as appropriate, the various causes of migration (economic, security, political prosecution, climate, etc.). thus, a more ambitious measures are required, such as generating opportunities for the local population and offering fiscal incentives to the investments of european companies in those regions that seem to be condemned to diaspora. this move will also offer new markets for european products and services, as well as opening of eu markets to exports from these countries. and, what is more important, besides of contributing to the economic development of those countries, europe has to improve their social and political quality of life, which is precisely what they try to find in europe. our main objective, therefore, has to be to strength the production base and the creation of jobs in the countries of origin, the provision of basic services (health, education) to the local populations, and the literacy, ensuring that students in their countries have the tools to decide their future and thus avoid the temptation to migrate to europe, avoiding future victims (de la cámara 2019). 6 either we offer them opportunities in their own countries, or they will come to ours looking for them zalba (2014). the best practical means for achieving it are probably inter-governmental agreements with the origin countries, giving them a generous economic aid. this is the stance taken by the visegrad group (v4) (check republic, hungary, poland, and slovakia): instead of uncontrolled massive immigration, we have to act in their origin countries; instead of importing problems, exporting help in situ. this attitude would also be "much more inexpensive", as is honestly admitted by juho eerola, a finn of the nordic freedom, or by the then slovak prime minister, peter pellegrini, during his first visit to brussels: "what we have to do is to invest in the countries where the problem is originated. each euro spent in northern africa is more efficient than 10 spent in the migrants who arrive massively to eu" (eerola, 13 april 2018). but, there is need to build up conditions to create secure environment within the transit african countries bordering the mediterranean sea. the north african governments are responsible for effective and transparent governance aimed at management of emigrants flows through their territories. eu's money poured into their accounts are wasted as they do not cooperate as they can. another effort to stem the flow of migrants to europe is "to save and protect the lives of migrants and refugees", motivating "operations of urgent evacuation" returning them to their origin countries through a repatriation programme that encourages those who have made it to northern africa to go home voluntarily, rather than risk sell it to the cities for money that might be diluted by inflation or seized by the government. its true significance laid not in the cash it provided but in the market-friendly policies it encouraged. to receive aid, european governments had to commit to restore financial stability and to remove trade barriers. 6 we have a similar problem within our own countries, migration towards big cities is up siding the living in small rural areas; we have to stop it offering them "the needed modern technology to have the best of both worlds. it is not an easy problem, but i feel a deep analysis needs to be done so we understand more of the dynamics behind the movements"! (lindhard, 2018 ). a rickety boat across the mediterranean. this is what uno, eu and african union (au) jointly agreed in abiyan (29 nov. 2017): people who turn back get a free flight-cutting out the need for a perilous return journey across the sahara. the programme has repatriated some 15,000 migrants to various west african countries, which barely scratches the surface because it reckons there are about 1 m of them in the african shores, waiting for their risky jump to europe (economist 2018). the spanish government did this unilaterally in 2006, after 39.000 immigrants arrived to the canary islands in open boats, known as cayucos: some direct forms of operative cooperation with those countries through which migrants come or transit, sending there some specific police units for working jointly with the local security forces with the aim of restraining subsequent invasions from other western african countries. since the devolution of immigrants to their origin countries is one of the best deterrent action to avoid the "calling effect", 7 governments have to launch adequate information campaigns in their own origin countries to discourage potential migrants. the eu member states are africa's largest donors, supplying more than half the aid the continent receives. africa exported twice the value of goods to the eu as it did to china in 2017. but it is not just a matter of addressing the factors that drive emigration. europe and africa share something much more fundamental: a future dependent on one another. as moroccan king mohammed vi pointed out in 2017, solidarity between europe and africa has to be "built on shared responsibility and mutual dependence." the european continent is a global player worthy of genuine partnership of equals with africa that priorities concerning mutual interests through rapid funding in education, health and infrastructure for africa's youth would contribute to global growth. europe's investment must be bolder in terms of financing, policy and governance reforms than what is currently on the table (cole 2019) . economic development, government reforms, institutional strengthening, will result in common prosperity. europe, poor in natural resources and in demographic decline, desperately needs to contribute to the unblocking of the future of africa. up to now, the -economically important-european efforts have to qualify as at least disappointing. the eu needs to encourage, promote opportunities in africa, move from a policy built around aid to cement our relationships on trade and investment (palacio 2019a) . cooperation between states that produce migrants and those that receive them can help to streamline migration flows. the european union has to structurally turn over resources for the development of africa and middle east, which are the main source of migrants nowadays, through agreements with extra communitarian countries for stopping irregular immigration towards europe. and this requires patience and diplomacy, treating the partner governments as equals. the optimism of the "refugees welcome" campaign in 2015-wir schaffen esled towards an uncontrolled flood of refugees which destroyed the perception of order and stability. in june 2018, there was a great turn in the attitudes of the rulers regarding immigration, with a broad consensus at the european council around much more restrictive. this practical agreement intended to hand over the decision-making capacity over who enters and who does not in the "fortress europe", strengthening the policies of controlling the external borders; fighting against traffickers; and more aid in the countries of origin instead of endless aid in europe. there is a need to strengthen collaboration with transit countries. it is necessary to prevent ships from leaving their points of origin. in cases where this is not possible, the practice should be implemented that those rescued at sea should be assisted and returned to the point of origin or departure of navigation. this is the specific task of frontex, the european border and coast guard agency: provide technical assistance and support to the countries of origin and transit to help strengthen border controls, even if it cannot replace national competence; it is converted into an authentic border police, but not in charge of rescuing. i will to come back to this point later. according to the ngo african center for strategic studies, there is a migratory flows that move 3.5 million people from one place to another from and within africa in the hands of traffickers; 50% of them are minors, and only 1% of those 3.5 million, will try to reach europe; the remaining 99% travel between african countries. 8 in this context, i point out at a report by the department for human rights at the un, marking the horror of criminal smuggling networks which lead to humanitarian scandals such as: enslavement; imprisonment; rape; prostitution; the sale of organs; and camps, whose living conditions are beyond imagination. what alternative do citizens of many african countries have to come to europe? if the european states renounce their ethical convictions, delegating their responsibility, mafias and some connected "heroic" ngos will occupy the scene doing the dirty work. those still determined to reach europe may have to pay large sums to people-trafficking gangs and risk their lives in the sea (we may say the same about america, substituting the word "sea" by "desert"). the more borders, bureaucratic obstacles, closed routes and prohibitions the immigrant finds, the more profitable for the trafficker. no one moves as many people on the planet as immigration traffickers, nobody determines human flows as much as their implementation in a given territory, nobody has their flexibility to change plans and adapt to changing circumstances and nobody gets so many benefits as they do. their criminal business is more lucrative nowadays than drug or arms trafficking. some of those traffickers have changed tactics. before, they put hundreds of immigrants in old overloaded wooden boats with the aim of trying to reach europe. nowadays, after cashing from them, the immigrants are taken in safe boats from african territorial waters, until they know that the ship of some ngo is a few miles away. then, once in international waters, they put on life jackets, crammed them in zodiacs, which can barely sail a few hours and warn by radio that there are shipwrecked people in the area. the more rescue boats they have, the more immigrants will try to cross the mediterranean…, and the more deaths, drowning in the sea, those claimed heroes of the goodism will provoke. a ngo director denounced on television that although he had managed to rescue 60 people from a zodiac, another 340 had perished. what nobody asked was if he did not realize that by telling those who leave libya that there are boats a few miles away they are contributing to the death of hundreds of people who, for one reason or another, cannot be picked up. 9 trafficking in human beings to the european destination is more profitable than drug trafficking: it moves around the mediterranean, according to the latest un report published last year, about 7 billion dollars. just take the account: boats for 30 people are used for 120, crammed, standing, and almost unable to move for hours. at 4,000 e per head, 10 it gives 480,000 e per trip. it is paid in two parts: the first 2,000 e to take them from their country of origin to the ports of libya and the other 2,000 to move them to european port, in an offshore mothership, and then in small boats that launch into the sea in a point located by gps where they can be picked up by the rescue boats of the ngos, or by merchants, fishing or recreational. if they do not find this type of boats in the area, they make a distress call with a satellite telephone with the coordinates. if the trip is frustrated and they are returned to their countries, they try again when they have collected the money. and several thousand have not even had that opportunity because they have lost their lives. with that turnover, there is no problem in paying the corresponding bribes in each place (fernández arribas 2019). "the good trafficker tries not to lose the immigrants who have been his clients. his goal is to get them to europe and earn money. if they lose, e.g., a truck with 40 immigrants between agadez and algeria or a boat that sinks with 100 people, is not a problem, because they have already paid; but if they lose 500 kg of cocaine or two boxes of kalashnikov, then they do have a serious problem. that is the difference". and how are these people's traffickers? "these gangsters are criminal entrepreneurs, but entrepreneurs. they must have many contacts, be credible, creative, charismatic, with the power of conviction, knowledge of the routes, the laws, the latest news… which make them very fast, elastic and flexible. they also participate in other businesses; f. inst., when the vehicles that bring immigrants back through the sahara return, they never make them empty: they carry weapons or drugs back to take advantage of the trip" (musumeci and di nicola 2016) . fernández arribas (2019) offers a very detailed description of how tens of thousands of human beings are stranded in territories dominated by mafias, in their expected way towards europe. although every corner of the world retains its specificities, the human traffic mafias analyzed by the un reflect some common patterns. all of them have recruitment agents from the main groups that are victims of extortion. a second level is that of the local mafias, who know the land and generally pay the collectors. one more step is that of small-scale service providers: trucks, boats and other means of transport. the most dangerous level is that of the big international mafias, who control the entire process and also add links to large international crime groups and use immigrants as a way to earn money quickly and easily. infrastructures built for the exploitation of the mineral resources of the desert, oil in libya and uranium in niger, facilitate trips through the desert. according to reports from the spanish police, nigeria and libya are the most active and most established bases of immigration mafias in central africa, with ramifications in other countries, where sudanese mercenaries act unscrupulously. in the waiting time, they live in abysmal conditions, suffering very serious violations of the human rights, such as abuse, harassment, violence, robbery, kidnapping, extortion, common torture and rape. in north africa they have their point of convergence in agadez, a town north of niger, or in sehba, south of libya, where control is exercised by heavily armed tribal groups. from that point of confluence, they are transferred to the coastal cities of the tripolitana region, where trips are negotiated and where part of the population collaborates with their garages as a temporary shelter at an abusive but obligatory price for those who see the end of your nightmare construction, agriculture or any job in order to get the money. the boats used are manufactured in libya and the fishermen always have on board some drum of gasoline, pure gold for the weak boats of the new slaves of the 21st century. in libya, each link in the chain receives its commission, especially those who seek protection and security, from militias to corrupt authorities. this action-paying poorer ones to set up vast holding-pens for humans in unhuman conditions-is a big business for a few behind the misery of many others, and involves something which would not be tolerated at home, but it seems somehow acceptable in these situations because it is out of sight. stopping these traffickers, which is the solution that many politicians in europe offer to regulate immigration, is almost impossible; they are always ahead of a european immigration policy, without the necessary coordination. a clear example has been the failure of the military operation eunavfor med sophia (from 2015 to 2019), which ambitious goal of dismantling the mafias that traffic with people from the libyan coasts to europe has not been fulfilled, partially because the closing of the italian ports to illegal immigrants has left it out of play. due to the fact that operation sophia no longer uses ships but only unmanned aerial vehicles, it cannot continue rescuing people at sea. federica mogherini, at that time high representative of the union for foreign affairs, explored a new mission, with more modest goals: to train the libyan coast guard to control their own waters and avoid the departure of irregular immigrants; but there were also no practical results. this shows the external and humanitarian action of the eu, as it really is: "lack of criteria, commitment and agreement on immigration issues…. public opinion will continue to show ships coming from the libyan coasts and criminal organizations will increase their profits" (de ramón-laca 2019; see also espaliu 2018 , espaliú berdud 2019 . as accurately pinpointed by bitzewski (personal communication), though, it is not the eu administration to blame but the heads of states not being willing to take the action. they point their fingers out towards the eu but, when the eu puts proposals on the table, they get reluctant to contribute to the common effort. it starts with the frontier countries, crying but doing very little to protect their own borders, and goes to the rest of europe raising any reason not to commit themselves to the program. the eu should be tougher on the north african governments, corrupted and ineffective. a carrot and stick should be one of the ways to start discussion with them. it's their obligation to control migrants movement within their territories but they make money on it! turkey and egypt are perfect examples of the game. when they want they can stop trafficking! but, obviously, the money is the main reason for action. the north african countries are interested in this business and it is up to us to give them a signal "do not be too smart". we deal with state controlled trafficking and we are very naïve not forcing these governments to take the responsibility. we can help them but we cannot work for them. a key move to avoid the "calling effect" is to guarantee security and economic agreements -migration control has to be paid with money-, with those countries migrants transit through in their way to europe, preventing them from leaving its coasts and returning to their country of origin those people whose asylum in the eu has been denied. in november 2015 the eu established the emergency trust fund for africa (eutf for africa) with an allocation of e 647.7 million covering algeria, tunisia, morocco and egypt, aimed "to contribute to safe, secure, legal and orderly migration from, to and within the region and support an effective management of migration flows that protects human rights" turkey is the main starting point for the arrival of potential refugees from middle east to europe. there are more than 3 millions syrian refugees, and almost another one in lebanon. the repatriation agreement signed by brussels and ankara in march 2016 -entering 6,000 million euros annually in the turkish coffers 11 + visa free travel for some turkish citizens-has been a quite good example of efficacy, convincing them to keep refugees from europe's shores: more than 900,000 migrants-three fifths of the detainees came from afghanistan and pakistan-have been detained in turkish territory since the document entered into force (turkish directorate general of migration management 2019). according to gerald knaus, leader of european stability initiative (esi), the entry of refugees into greece was reduced "by 96% and even higher in the number of deaths". and, in a more global view, the more than one million irregular migrants (mainly refugees) who arrived in europe in 2015 have fallen to 171.635 in 2017. turkey thus has played a leading role as a dam to contain migration outside europe. in the future, eu will have to invest more in integration and public awareness programmes in turkey. erdogan himself has proposed resettling at least some of the refugees in a safe zone he wants set up in northern syria. all of this is legally possible. syrians in turkey do not enjoy formal refugee status, which would protect them from deportation, but "temporary protection", which does not. according to the high commissaire of united nations for refugees (acnur, in french), a turkish meltdown would send economic shockwaves or new surges of migrants onto the european mainland. erdogan has encouraged such fears (july 22nd, 2019), threatening the suspension of the migration deal over the eu's sanctions. 12 another point for the arrival of potential refugees from africa is the maghreb. those eu southern members with close ties to it have an special interest in encouraging the reform of state structures, as well as working to reduce the socioeconomic disparities and lack of opportunities that remain the public's most pressing problems in those countries. two successful cases have been the attempts of cooperation of the eu with morocco and tunisia, as well as a. very important job in the control of migratory flows and the fight against mafias, terrorism and drug trafficking is due to the creation of a coordination authority for the gibraltar strait. by way of example, there is a positive counter-terrorism cooperation carried out by several eu countries working closely with northern africa on security, providing training and equipment for counter-terrorism and conducting some joint operations. morocco might be a capable security partner as the authorities closely monitor its population and controls its religious sphere. it has been successful in preventing attacks and obtaining information that can benefit its european partners, but its counter-terrorism efforts fit within a framework of conserving rather than transforming the state's unaccountable relationship with its subjects, which relies on a repressive political system and resists outside calls for reform. 11 nato has also awarded us$ 5 billion to turkey. 12 four years later, just when this book is going to press, the crisis has returned. turkey does not seem proactive anymore. tayyip erdogan has called for more european support for ending the war in syria and for receiving millions of refugees. and as a pression measure, on february 28, 2020, turkey decided to open its borders for migrants to move to the european union. this has brought together more than 35,000 migrants along the border with greece. three weeks later, though, following the strategies of the other countries to avoid a further spread of covid-19, ankara has announced just the opposite: the closure of the eu's borders. the spanish authorities have observed with relief a downward trend in arrivals in mid-january 2019, with a significant reduction of a 39% of the figures of irregular immigration: the entries, an average of about 1.200 a month, confirm that the flows have been considerably reduced since then and that they have fallen to levels below those registered the previous year, when spain became the main european gateway for irregular immigration. this proactivity of morocco, deploying agents to reinforce the fight against the mafias, stop the exits by sea and employed its coastguard in the rescues on the high seas, has been highlighted both by spain and by an internal report of the european commission as the most effective tool to contain migrants. this change of attitude coincided with the announcement of the visit of king philip vi to rabat, which was finally held on february 13, 2019. on that trip, the spanish monarch asked mohamed vi to go "beyond" in the control of irregular immigration. later, the fisheries and agriculture agreements, signed by eu and rabat with an injection of 140 million euros to contain migratory flows, have also been key to boost moroccan collaboration. besides of that, spain has approved to add the almost 60 million that rabat asked last year to contain the exit of immigrants; that is to purchase surveillance equipment "to combat irregular immigration, immigrant trafficking and trafficking in human beings", as well as for fuel, maintenance of patrols, diets and salaries (palacio 2019b) . the moroccan and sub-saharan return agreements are also praised as a "deterrent factor" to avoid the "call effect". morocco moves many sub-saharan people to the south, leaving them lying in the middle of the desert, or locked in small cells inside an illegal detention center in arekmane (20 km from melilla) and then deported to their countries. tunisia has also made significant advances in its security policies, but it has yet to find balanced ways to deal with its porous borders and the disproportionately large number of radicalized people. unfortunately, the attempts to solve the problem of migration with libya have been rather frustrating. libya is a too fragile state, a territory without government since a few years ago, which is key in the irregular migratory flows towards italy and, in the late times, increasingly diverting the flow of west african migrants to spain, via new algerian routes (fernández-sebastián 2018). nowadays it is the largest and more serious migration corridor, due to the use of mafia "facilitators", as we had previously commented. in this context, some libyan militias behind much of the people-smuggling migrants across the mediterranean claim that eu and, more specifically, italy have given them money and equipment to improve the coastguard stopping migrant boats from setting sail. this may explain the falling of the number of migrants crossing the sea. finally, the european leaders seem delighted with the cooperation with egypt, where immigrants no longer arrive due to the decision of this country to prevent them from leaving its coasts. if all the countries of the south did like egypt, there would be no immigrants at sea. a punctual example of joint collaboration of countries of both sides of the mediterranean sea is the cross-border military exercise neptune, with the strategic objectives of unifying efforts and coordinating action plans among the mediterranean countries, 13 especially in terms of detention and combating the movement of foreign terrorists through ports on both sides of the mediterranean. thus, passenger and freight transport vessels were included in the controls and the use of interpol databases could be activated participation. this activity has been developed between several ports such as tangier med, tangier city and bni-ansar (nador). in sum, the eu should remain committed to encouraging and supporting the most significant pressing remaining security challenges faced by those countries, such as: (1) the reduction of the social frustrations, economic inequality, lack of opportunities, and governance problems that increase the likelihood that people will join extremist groups and recruit radicalized individuals; and (2) the reform of state structures, especially in relation to: (a) improving security governance based in an adequate culture and professionalism of the security forces (f. ins., training of police officers, courts judges and staff, customs and coast guard officials); and (b) developing systematic approaches to prevent further radicalization and addressing conditions that facilitate it, such as: exploring better ways to handle radicalized individuals than large-scale incarceration; distinguishing between committed jihadists and those who are more open to reintegration into society; and developing programmes to promote religious education and awareness, gearing them towards pupils and their families from an early age, so relevant to the treatment of radicalized individuals and the prevention of further radicalization (dworkin and el malki 2018). although the priority has to be focused on the countries of origin and transit, the fact is that we have to face a massive amount of irregular migrants who are arriving to our borders, because a chaotic, uncontrolled immigration cannot be allowed. the main objective of eu policy in this topic should be to encourage legal and orderly immigration and deter illegal flows. what should be the european criteria for who is welcome to europe and who is not, to avoid an uncontrolled migration into our continent? how could be accomplished the aims to become a historic leap in the consolidation of a european area of freedom of movement without internal borders? a spanish writer, de prada (2019), has recently reminded the clairvoyant solutions offered by thomas aquinas already in the middle age on the obligations and limits of hospitality, making clear that the help demanded by those who suffer should not be confused with their unconditional reception. he refers to several possible types of peaceful immigrant: who passes through our land in transit to another place; who comes to settle in it as an outsider; and who wants to fully join the nation that receives it "embracing their religion" (their culture, we would say nowadays). he always puts the notion of common good, which requires a desire to integrate into the life of the host country; and he is inclined not to admit them until examining their degree of "affinity" with the nation that receives them. and, as a measure of legitimate defense, we should reject those immigrants considered hostile, understanding as such not only those who have the purpose of perpetrating crimes or violence, but in general those who harbor intentions contrary to the common good of the nation that receives them (see also : ramirez 2019) . the decision on who is welcome and who is not does not belong to the humanitarian people, even less to the people-smugglers, but to each state. security and protection of the borders is competence of each state member. without borders there are no states and no one else can supplant a state's right to manage and protect them, treating migrants humanely but also firmly, swiftly returning those who arrived illegally or whose claims to asylum have failed. 14 even if the eu lacks competence over it, it does not preclude the convenience of an europeanization of the migration management, through a joint cooperation for specific purposes, even if it means losing part of the national authority over a very sensitive area of the territory. the political leaders of the eu must improve their coordination and develop common legislation on borders and immigration, creating systematic and controlled arrival and integration programs, focused on the new scenarios, such as the solution of the migratory crisis, with a common, effective, and decisive security policy, finding a balance between the implementation of measures that guarantee the security of the states, while respecting the rights of those migrants who no longer enjoy their protection in their respective countries of origin. the eu not only lacks competence over the management of the flow of refugees, but also lack of homogeneous response, as it is shown by of the dublin regulation (eu european parliament 2013), which has resulted an absolute failure, inept to establish a coordinated strategy with minimal effectiveness. the eu foreign policy remains hopelessly underpowered, limited to coaxing national capitals towards agreement and supporting their ad hoc initiatives (the economist economist 2019a, b; niño 2019). it is good to remind again that it is not eu to blame but the states not taking actions. the dublin regulation (2013) determines the eu member state responsible for the examination of an application for asylum seekers of international protection under the geneva convention relating to the status of refugees of 28 july 1951, as supplemented by the new york protocol of 31 january 1967 (eu 2013). according to this legislation, the first member state in which the asylum application is submitted will be responsible for the examination of the request for international protection and the asylum seekers have to stay there. this, the so-called "one stop one shop", burden the countries situated at the entry to europe, notably those in the south, and the individual preferences -that is, where people arriving into europe actually want to go to and where do they wish to live-are bound to not be properly taken into account. consequently, if they move later to another european country -known as secondary movements-, this second receptor may return them to the first state. this secondary migration penalizes those southern countries, because most refugees arrive to the coasts just as a transit towards other northern european countries, where many of the newcomers had linguistic and cultural or family ties. or with better job opportunities and welfare provision. as a matter of fact, most of them live already in germany. 15 in front of this, the different eu member states have rather antagonistic approaches: (a) northern countries, preferential asylum for most of the refugees, are in favour of a quotes policy imposed by brussels' "eurocrats" for the reubication of refugees, 16 and suggest an eu budget with more funds for those regions with higher number of asylum seekers. (b) mediterranean countries, plus portugal and france, suffering a heavy migratory pressure in their borders, have the feeling of being left alone to cope with immigrants, and reject the responsibility of attending by themselves everybody who arrives to their borders, because it would mean establishing a sort of sanitarian cordon with the rest of the communitarian block. their aim is a reform of the dublin regulation and the help of the other eu countries in the sharing of the irregular immigration arriving to the outer borders. for instance, the greek government and aid agencies argue that the eu must overhaul the dublin regulation, so that asylum-seekers are distributed more evenly. the current system, they say, is unfair. five countries-greece, italy, spain, france, and germanyreceived over three-quarters of europe's asylum applications in the first half of 2018. greece has had to deal with 70 times as many claims as hungary, a country of comparable size and wealth. the rules are also ineffective: eu money is not an adequate replacement for relocation. southern countries are also reluctant to expand frontex because this affects their rights to the sovereignty of control of the territory, but also concerns related to better registration of migrants…. this is the key problem! (c) the visegrad countries (v4) -poland, hungary, czech republic and slovakiaplus baltics (latvia and lithuania) and some recent addings (at least, austria, and partially italy), call for reform, and refuse to consider any binding sharing 15 in 2017, germany received 222.560 applications, almost double that of any other eu country, requesting the return of 64.267 refugees to other eu countries, but only managed to execute 15% of the returns of asylum seekers requesting from the eu. based on that, the german home minister, horst seehofer, wants to send tens of thousands of migrants to italy, and, on the contrary, italian home minister, feels legitimized to send those who arrive to the northern european countries; f.ins.,"france was to welcome 9,816 immigrants, but in reality accommodated only 640" (france has returned to italy 10,949 people in 2018). 16 following the principle of solidarity, which is included in the lisbon treaty (2007), jean-claude juncker called on the member states of the eu to share refugee quotas according to the wealth of each country and population size, but it shattered and the european policy of immigration and asylum was marked by increased sovereignism in the states of europe. out of asylum-seekers. 17 based on their right to security, they insist that their priorities are more about controlling europe's outer borders, in order to preserve the free movement of persons within the schengen space, than about managing the burden of refugees who cross them. what should be a reasonable attitude to avoid an uncontrolled moving of illegal migrants within the schengen area? the intended distribution of the burden of refugees imposing a quota system -i.e. every eu state had to admit a fixed amount of people-has not worked: only a 28% of the quota has been achieved by the different members. this system of quotes was firmly opposed by the central europe defence cooperation (cedc), 18 arguing that the structures of their countries are not "ready" for supporting the social weight of the newcomers: it would be highly detrimental to the national security and sovereignty. 19 they felt marginalized by angela merkel decision to keep germany's borders open to refugees at the peak of the crisis in 2015, without any previous consultation; it seemed to them, the chancellor had turned them into transit corridors for undesirable migrants drawn by the promise of a cushy life there. they suggest as alternative to accept the free choice of country. following this rationale, the polish minister of foreign affairs in years 2015-2018, witold waszczykowski, was backing the disagreement of his president, andrzej duda, to force the entrance of immigrants against the wishes of the polish people, asserts that "the security of poland is more important than the unjustified decisions of the european institutions on the issue of the refugees". viktor orban even dares to declare central europe a "migrant-free zone". the central european countries are pushing for the eu to get involved in the custody of the external borders and accuse the southern countries of letting irregular migrants pass unchecked through their territory to the rest of the eu, and ending up circulating in europe at will. for instance, sebastian kurz, at that time austrian kanzler and rotatory president of the council of the eu, told in a local newspaper "i am afraid that many are trying to avoid the high number of migrant records that they would have to do" (referred in abc, 9/9, 2018) . his words suggested that national authorities sometimes turn a blind eye to not registering migrants and that, on the other hand, a community official who did not work directly for any state would not allow those distractions. the eu summit in brussels on june 28th 2018, following a suggestion of angela merkel and horst seehofer, reached a transitory agreement based in two points: (a) bilateral agreements between different states, stopping secondary movements in their inner borders, i.e. sending the refugees back to the state in which their asylum application was first submitted, obviously with an economical compensation; and (b) more resources for setting up centres of transit (internment) or "landing regional platforms" with the task of reviewing asylum applications, "distinguishing between economic migrants and those needed of international protection". this move would speed up the deportations, disincentives dangerous adventures and reduce drownings at sea. this seems to partially accept sebastian kurz's proposal of a "copernican revolution" in asylum policy migratory model, as a new possible alternative similar to the one applied in australia: to implement the number of naval patrols for intercepting boats with refugees and confine them in islands like nauru o papua-new guinea": control first; then generosity. following this model means two things: first, taking tough action along borders, at sea and "upstream" (inside africa) to slash the number of asylum-seekers smuggled to europe; thwarting smuggling, the argument goes, would reduce drownings at sea, and reassure voters who might otherwise be tempted by the far right. second, striking deals with poorer countries to establish camps, run with un agencies, to receive, detain and, eventually, return migrants. it is a laudable but ill-defined goal, because it is unclear where to establish those camps. it was mentioned "in safe countries outside the eu". but where? some members want deals with north african countries to reduce departures, 20 but it still unknown which non-european countries would be willing or able to host such centres. 21 in front of this north african rejection, the danish prime minister at that time, lars lokke rasmussen, revealed that some communitarian countries are 20 austria, which occupied the eu presidency that semester, hoped for a quick agreement to equip frontex with a supranational force of up to 10,000 members and to establish a landing platform for irregular migrants in north africa. 21 algeria: just the day after the summit, algerian foreign minister abdelkader messahel said in an interview with the french broadcaster rfi: "i believe that europeans have enough capacity, means and imagination to manage these situations." "it is excluded that algeria opens any retention zone. "morocco: the next day, the moroccan foreign minister, naser burita, emphatically stressed that this country has always "rejected and rejected" in its territory the detention centers for foreign migrants. tunisia: for logistical and political reasons, it could be the ideal candidate to host this type of centers: its coasts are the closest to the maritime zone where the majority of migrants sailing from the western strip of libya are rescued; and, its democratic transition seems to be quite consolidated, being the country in the region that receives the highest volume of eu aid funds per capita. however, the tunisian ambassador to the eu, tahar cherif. abounded in categorical rejection by his political class and public opinion. "for tunisia, the creation of reception centers is a red line," says valentin bonnefoy, a researcher at the tunisian ftdes, a ngo specialized in migration. more than seven years after the revolution, this maghreb country does not have an asylum law, something that many observers attribute to a veiled strategy to avoid becoming a host country. egypt also rejected the possibility, although in a not-so-sharp way: "the eu migrant reception facilities in egypt would violate the laws and the constitution of our country," said parliament president ali abdel seeking to establish camps for failed asylum-seekers in a continental country, but out of ue, more specifically in the balkans. there is even a third possibility to consider: within the own eu border. jean-claude juncker, in his 2018 speech on the state of the eu, proposed to establish a more efficient control of the eu's external border, converting frontex, created in 2004 and reinforced in 2016 as a european guard of coasts and borders, into an authentic border police, but not in charge of rescuing. although still subject to the control of the national authorities, it is provided with broad competences in areas such as the control of irregular migratory flows from outside the eu, the return of irregular migrants to their countries of origin, the detection of illegal steps between countries of the club and the fight against the channels of transit in third countries. on november 8th 2019, the eu decided to grow it from 1,300 s to a standing corps of 10,000, with a 26% jump in funding next year, to 421 m. e, for the first time, the eu will be able to dispatch gun-toting men and women clad in eu uniforms to patrol its fringes, without asking member-states to cough up guards. in this way, the surveillance capacity in european territory will be reinforced. this necessary hard-headed policy of tough border controls, swift return of illegal immigrants and encouraging would-be migrants to stay home obliges governments to work with others in the control of its migratory flows. europe cannot maintain the schengen system of internal free migration if it does not control its external borders. and, we have to admit it, it does not. the eu has so far failed in all its attempts to establish a common policy to address the problem; it has become impossible to have a level-headed conversation about managing migration in europe. the malta agreement (september 23rd, 2019) is a tentative deal, signed by a group of five eu interior ministers (germany and france, as well as finland, italy and malta), on a temporary scheme for a rapid relocation in other countries of asylum seekers, who are rescued from the mediterranean sea. it could open the way to a comprehensive overhaul of the dublin regulation by which the migrant's country of arrival is responsible for verifying the right to asylum of each person. 22 it states that "the relocation member state will assume responsibility for the relocated person" and contemplates a quick procedure to say in advance the number of potential refugees each state is willing to host, setting a period of only four weeks to relocate rescued refugees in the mediterranean in other member states. this would allow the frontline first-arrival countries (the mediterranean), to be discharged from the responsibility of participating in their reception, quite heavy in periods of strong migratory pressure. in return, berlin and paris hope to achieve a reduction in the socalled "secondary movements" or movements of irregular migrants from the country of entry to other eu states. aal in welt am sonntag. in addition, aal said that his country already has millions of refugees from nearby countries, such as syria, yemen, iraq or sudan, so its reception capacity is at the limit. 22 the eu ministers discussed on 8-10-19, in luxembourg this proposal to relocate asylum seekers rescued at sea, but they got a lack of solidarity of the whole european bloc, and the sole support of portugal, luxembourg and ireland. the agreement also speaks of a return protocol "immediately after landing", redoubling diplomatic pressure on migrant countries of origin, using "appropriate incentives to ensure full cooperation, including consular cooperation, from countries of origin", although at least it includes everyone passing a "medical and safety exam". it also underlines the need to "commit to improving the capabilities of the coastguards of mediterranean third countries". it is hoped that the deal will put an end to the game of pass-the-migrant spectacle of some countries squabbling over which should accept responsibility for small numbers of asylum-seekers, breaching in what until now has been a guiding principle: that irregular migrants must be dealt with by their country of first arrival. since participation in the system will be voluntary, much will now depend on how many countries will take part, how many asylum-seekers each will accept and whether penalties are to be imposed on those countries that refuse to co-operate (this last seems unlikely, given that such an idea would have to be approved by all the eu's members, including the countries liable to be affected (economist 2019). summarizing, there is a widespread perception that a series of instruments to control its external borders are not working well -the dublin asylum agreements, refugee quotas, frontex, return and development policies…-and that a lack of trust has grown not only between the member states, but also between the states and the european institutions, especially after the refugee reception crisis in 2015. in few words, there is a deficient management of migration and a weak european solidarity on this issue (de la cámara 2019; de wenden 2019). the call thus is now for a joint cooperation towards a true common policy on asylum and immigration with a complete and efficient control of the eu's external border, reinforcing the role of frontex. everybody accepts this priority as the only possibility left for preventing a reinstatement of inner borders controls which would lead to the end of one of the most valued achievements of the eu, the schengen space. a positive step in this direction has just being announced, after the starting of their new mandate, by margaritis schinas, vice president of the european commission in charge of completing a new architecture that guarantees solidarity to the countries of the external border: the eu is going to make sure that there is a sufficient dimension of responsibility in terms of border control and returns. and as tangible measures in that direction, they promise an improvement of the management of external borders with 10,000 permanent staff; moving towards a federalization model of border management, this coming spring there will be the first community corps with their own boats and carry weapons, with the deploying the first 700 european coastguards. the responsibility concerning the immigrants does not finish at the border. once accepted as our guests, we cannot forget about them. and, among our humanitarian obligations, we have to help properly integrating newcomers into our own society, avoiding their eventual fondness towards a multiculturalism, which only produces ghettos of their own culture, or wrongly thinking that the mere acceptance as migrants give them the right to have a claim to social welfare. and, on the contrary, who arrive without being invited cannot impose the host other people's rules. once they find a home in a new country, they have to accept the laws, rules, traditions and culture of the adopted society that welcomes them, learn the local language, mix with the natives, and be aware of the specific needs and priorities of their new home. in few words, they come to european territory with equal rights and obligations, but no more. whoever is not able to assimilate to their new society, should better return to their origin (ramirez 2017 (ramirez , 2019 . according to the dublin regulation, asylum-seekers are the responsibility of the first country to record their presence and, if they move later to another european country, this second receptor may return them to the first state, most of them arrive to the southern coasts heading north, trying to slip there unnoticed, as illegal paperless "invisible migrants", to avoid being picked up and returned to their first country of arrival. officials in the country of arrival can also use bureaucracy to slow the process of registration. and so, after six months, the new host state becomes responsible. this gives a strong incentive for foot-dragging. the recent malta tentative deal (2019) tries to partially solve this problem, allowing the frontline states to be discharged from the responsibility of participating in the relocation of the newcomers. once accepted as our guests, what to do with them? let us focus on the policy towards them in sweden and germany, preferential asylum of most migrants. strange enough, they are far from coincident at all. in sweden, immigrants received ample food and shelter, a generous welfare benefits, 1.5 times higher than the ones received by host taxpayers, as well as many facilities for family reunification, without any special focus on their social integration. even more, most of them are not allowed to work. this almost open bar policy, paying migrants to do nothing, has produced (a) an increment of the social expenses on the foreign population, with the consequent reduction of the benefits for the natives -the newcomers have priority to the swedish people; 23 (b) a call effect on other tentative immigrants; and (c) increase of criminality and insecurity, which triggers the anti-immigrant feelings of host taxpayers who feel swamped. in my opinion, migrants should be encouraged to work, getting them language classes and education and offering job training, and introducing them into the labor market, meeting the main demands of the host country: f. ex, in nordic countries, anticipating a shortfall of geriatric nurses. in germany, the arrival of nearly one and a half million asylum seekers since 2015 polarized the country, with a consequent rise of a climate of political anxiety. it seems they have finally realized that the solution of the problem is to integrate into the labor market those who are already in the country, and relax the requirements to allow the entry of more workers. with this purpose, in december 2018, the german government approved the fachkräfteeinwanderungsgesetz ("skilled workers immigration law"), an ambitious legislative package to attract qualified labor from non-eu countries and alleviate the pressing lack of workers in some sectors and regions of the country. this will extend the rules covering foreign graduates to vocationally trained workers, cautiously opening the door for rejected applicants for asylum, but who are already integrated into the labor market, and recruit more workers from outside the eu with medium and high education to find qualified work under certain conditions. germany economy enjoys enviable health, registering an unemployment rate of 4.8%, the lowest since the reunification of the country. figures from the institute for employment research (iab), under the ministry of labor, estimate that there are about 1.2 million jobs vacancies, while posts actually registered in employment offices in november 2018 amounted to 807,000 (35,000 more than the same month of the previous year). however, one of the biggest concerns of the german businessmen, the so-called mittelstand, the motor of the exporting power and the backbone of the german economy, is the lack of skilled workers. unlike in other european countries, small and medium-sized german companies are distributed throughout the country, not necessarily concentrated in industrial centers. this often hinders the recruitment of workers who prefer to live in urban areas. there is a shortage mostly of workers with a level of professional training, such as plumbers, or drivers, and diploma courses, for example, of children's educators. elderly care and tourism, are also crying out for workers. this legislative text allows non-eu citizens to go to germany to seek work for six months provided they have the necessary training, know the language and have the means to survive during that time. in the case of persons with temporary permits, such as rejected asylum seekers, they must show that they have been working in germany for at least 18 months and that they do not have a criminal record. the head of the employers' association, ingo kramer, recently indicated that 400,000 of the asylum seekers who arrived in 2015 are working or receiving some vocational training. in addition to the labour shortages, there are also demographic forecasts, which warn of a marked aging of the population. these projections will also affect eastern europe, where a good part of foreign workers in germany come from and whose arrival is expected to decrease in the coming years. according to thomas liebig, expert on migration issues at the oecd, "these countries are becoming places of immigration. we have to look for workers outside the eu". although the labor integration of immigrants advances, experts warn that it will take time. "it's a slow process; sometimes they are people who do not speak a word of german, and many of them come from afghanistan or somalia, where they have not had schooling" explains liebig (2018) . tangible achievements, indeed! milanovic and branco (2018) proposes an intermediate position between open to all or closed borders, under the name of "circular migration": to admit workers who cover specific positions, having salaries and work conditions similar to those of the locals, but with not vote rights, nor social benefits for children, retirement or free education; and at the end of their contracts, they will have to return to their countries. in few words, they will be partial citizens for a limited time, like it is already happening elsewhere: in gulf, singapore, iraq, usa, canada. perhaps one country may need extra workers and be in position of offering them stable working conditions; but this may not occur in other eu members. this is also suggested by alejandro portes, princess of asturias of social sciences award 2019: offering a temporary, flexible and comprehensive program of visas to allow access to young people who want to come to work or study for a while, allowing a fruitful flow between countries. come in that way would also be much more economical, and would do a lot of damage to the traffickers, because those who come in that way would not have to pay them (17 october 2019). psychological experiences of refugees and the response of the community in the lake chad region summa theologica (fathers of the english dominican province translation, prima secundae, question 105 letter to the editor, the economist de la cámara m (2019) the eu migration challenge inmigración y cuestión religiosa, abc, 17 ago de ramón-laca j (2019) operación sophia: paradojas de la acción exterior europea. análisis en 3 minutos | nº 228 a new european pact on immigration and asylum in response to the "migration challenge the southern frontline: eu counter-terrorism cooperation with tunisia and morocco the problem with eu foreign policy. too much historical baggage, the economist a migrant move in malta. the eu reaches a tentative deal to share out migrants rescued at sea. the economist taking european defence seriously: the naval operations of the european union as a model for a security and defence union, cuadernos europeos de deusto los buques de la operación sophia en el dique seco: elementos de un revés para la política común de seguridad y defensa regulation (eu) no 604/2013 of the european parliament and of the council of 26 maritime dimension in the fight against illegal migration on the western mediterranean route sbarchi? un nuovo schiavismo leguina joaquín (2019) migraciones sin respuestas alemania busca extranjeros para 1, 2 millones de empleos, el país, 20 dic how to stop migration towards big cities? research gate la inevitable migración hacia europa, el pais confessioni di un trafficante di uomini. reverse niño elena (2019) terrorismo e inmigración: cambiando el foco lazos y nudos con marruecos, el mundo europe's partnership with morocco. proyect syndicate apostolic constitution exsul familia nazarethana, castel gandolfo portes a (2019) princess of asturias of social sciences award buenismo ante el problema de los refugiados, migraciones en el siglo xxi: riesgos y oportunidades el terrorismo como desafío a la seguridad global the refugees issue in the frame of the european security: a realistic approach bondad y buenismo, abc, 14 ago sarah r (2019) le soir approche et déjà le jour baisse turkish directorate general of migration management (turkish: göçi̇daresi genel müdürlügü) (2019) migration management global compact for safe, orderly and regular migration. marraquesh global trends: forced displacement in 2017 he is member of the advisory board of the society for terrorism research and of the professors world peace academy. he has also chaired the complutense research group on sociopsychobiology of aggression and the departments of psychobiology at the seville and complutense universities, as well as being director of the rector office at the autonomous university of madrid. dr. martin ramirez was a humboldt and fullbright fellow but, let us close here our considerations, stressing that a revision of national and eu legislation is required, focused towards a cooperation with the countries of origin and transit; and that, instead of dreaming naively in a chimeric -non-existing-european eldorado, we have to promote the great possibilities that african continent has, knowing that, as the journalist lucia mbimio says, "we must not stop dreaming, but change the compass of dreams! returning from europe to africa is not a failure." (2019, 66). key: cord-298685-qxkxjxsz authors: pensaert, maurice b.; martelli, paolo title: porcine epidemic diarrhea: a retrospect from europe and matters of debate date: 2016-12-02 journal: virus research doi: 10.1016/j.virusres.2016.05.030 sha: doc_id: 298685 cord_uid: qxkxjxsz abstract a retrospect is given on the emergence of porcine epidemic diarrhea (ped) during the early seventies in europe. while, at first, it appeared as a disease affecting feeder pigs, fatteningand adult swine, it later also became pathogenic for neonatal and suckling pigs hereby drastically increasing its economic impact. isolation of the causative virus revealed a new porcine coronavirus, the origin of which has never been clarified. pathogenesis studies with the prototype strain cv777 showed severe villous atrophy in neonatal pigs and the virus-animal interactions showed many similarities with transmissible gastro-enteritis virus (tgev), another porcine coronavirus. disease patterns in field outbreaks showed muchvariation but, while farm related factors played a role, possible genetic variations of virus strains in europe have not been examined and are thus unknown. cv777 in experimental pigs caused diarrheal disease and mortality rates similar to those later encountered in asia and more recently with the “original” us strains even though genomic typing of the prototype european strain have shown that it belongs to the s-indel strains. in europe, ped has become endemic during the eighties and nineties and subsequently regressed so that, after 2000, swine populations in many countries have largely become seronegative. sporadic outbreaks have recently reappeared showing a large variety of clinical outcomes. one" or also "tge2" and both these denominations referred to its clinical similarity to tge, a common cause of viral diarrhea in pigs in europe at that time. an important difference with tge was, however, that neonatal pigs were not affected. since these denominations were considered unsatisfactory from a scientific point of view, the name of the new syndrome was quickly changed to "epidemic diarrhea-ed". the first ed outbreak occurred on a farm in the spring of 1971 and the second 6 months later, at a distance of 2 miles from the http://dx.doi.org/10.1016/j.virusres.2016.05.030 0168-1702/© 2016 elsevier b.v. all rights reserved. former. suckling piglets were not affected but pigs of 10 weeks and older and also adults showed an acute diarrhea lasting one week. the outbreak lasted 3-4 weeks on the farm. during the autumn of 1971 and also the following winter, several new outbreaks were reported. a clinical diagnosis and possibility for differentiation from tge was thus based on the high morbidity in fatteners and adult animals in the absence of disease in neonatal and freshly weaned pigs. in most of these diarrheal cases, tgev was excluded by laboratory examination. the fact that ed was observed on farms with a recent history of a tge outbreak, and thus in tgev immune animals, increased the conviction that tgev was not involved. during 1972, ed spread rapidly between pig farms, particulary fattening herds. mortality was rare and the effect of an outbreak was estimated at about 2 weeks feed cost. a similar disease pattern was observed during the early seventies in belgium and a rapid spread occurred to neighbouring countries in western europe. here also, suckling pigs were not affected and remained free of diarrhea even when their mothers suffered from a watery diarrhea during several days. some neonatal pig mortality could occur by starvation because the sick mothers often suffered from agalactia. an additional sign observed in belgium and later also reported in gemany, but not mentioned in england, was that some fatteners were found dead, particularly towards the end of the fattening period, and this occurred repeatedly in some farms but not in others. a mortality rate as high as 3% could be encountered. this was not due to dehydration accompanying the diarrhea but animals suddenly died from acute back muscle necrosis. while the clinical link with an ed infection was clear, the pathogenetic background has never been revealed. belgian pigs were highly stress positive at that time and a severe belly ache often observed in adult animals during an outbreak of ed may have been a trigger. in general, as no baby pig mortality occurred due to the ed agent, not very much attention was given to this new diarrheal syndrome and the etiology was not intensively investigated. however, it was assumed that a viral agent was involved since bacteriological examination of faecal material did not reveal a specific bacterial cause. none of the known porcine viruses could be associated and a new virus was, therefore, suspected. much changed in 1976 when wood (1977) from the veterinary investigation centre in norwich (england) described a new diarrheic syndrome. it differed from ed in that it now affected pigs of all ages, including neonatal and suckling pigs. mortality was variable, restricted to young piglets and averaged around 30%. this new disease now resembled tge more closely than ed did, but tgev was again excluded using direct immunofluorescence on intestines and applying established serological techniques available for detection of anti-tgev antibodies. now, a differentiation with tge on a clinical basis only became difficult, often impossible. this new syndrome was called ed2 to differentiate it from the 1971 ed1 where no baby pigs were involved. ed2 was economically much more important than ed1. ed2 also quickly spread to the european continent and was recognised in belgium in 1977. reports from other countries including the netherlands, germany, france, bulgaria, hungary and switzerland, followed soon. in belgium, mortality rates in neonates on breeding farms varied considerably. they could be as high as 80% (large variation from 30 to 80%) and the average was 50%. variation in mortality in neonatal pigs was litter bound, not explained at that time, but also farm bound where it appeared to be associated with farm size (still many small family farms at that time), farm struc-ture (one or several farrowing units), number of neonatal pig litters present at the start of the outbreak, number of pregnant sows due to farrow within one week of the appearance of disease signs and possibly other factors. differences in virulence of virus isolates was not given any attention. this new evolution to ed2 with the involvement of baby pigs and its larger economic impact yielded better opportunities for collecting material for etiological studies, for experimental reproduction of the disease and for the development of virological and serological techniques. in 1978, chasey and cartwright (1978) reported the detection of virus like particles, and pensaert and debouck (1978) described the isolation of a new coronavirus-like agent (cvla) from diarrheic pigs, with both research groups succeeding in reproducing diarrhea in experimental pigs. soon after the isolation of this new coronavirus, extensive pathogenesis studies were performed in colostrum deprived pigs with one of the belgian isolates, designated coronavirus cv777, (isolated in month 7 of 1977) which became the prototype strain for pedv in europe (debouck and pensaert, 1980; debouck et al., 1981) . ed2 was soon named "porcine epidemic diarrhea" (ped) caused by ped virus (pedv) a denomination which still stands at present. from the early studies with pedv in neonates (debouck and pensaert, 1980; debouck et al., 1981) it was soon clear that the pathogenesis resembled very much that of tgev. experience gathered from research with tgev helped much in the approach to study this new enteric disease. lack of success to cultivate the virus in cell cultures forced to produce clean virus stocks by oral inoculation of colostrum deprived pigs, performing surgery 18 h later and rinsing the in vivo produced virus from the lumen of the infected small intestines during 12 h while keeping the pig in the incubator (debouck and pensaert, 1980) . such "clean" pig adapted virus stocks served for experimental pig inoculation experiments and to produce an hyperimmune serum for the preparation of a conjugate for an immunofluorescence (if) conjugate to detect the virus in tissues. serological tests were developed to detect antibodies by elisa and to study possible relationship with other coronaviruses by immuno-electron microscopy . genome analysis of the ped isolate(s) was not available at that time. by immuno-electron microscopy and if, pedv was not related to any of the known porcine coronaviruses (tgev, haemagglutinating encephalo-myelitis virus) . some discrete relationship with members of the genus alpha-coronavirus was later demonstrated using other and more sensitive tests. the origin of pedv was thus unknown and no potential parent coronavirus could be indicated. an elisa test was soon used for routine serology . a crucial question was whether or not the ed1 agent and ed2/pedv were related or whether ed2/pedv was totally new. infectious material containing the ed1 agent from earlier outbreaks was not available. a retrospective serological survey was carried out on sow sera that had been collected in slaughterhouses in belgium starting in 1969 and thus prior to the emergence of ed1 in 1972 on the european continent. antibodies to pedv were not found in sera collected in 1969 but were present in 7% of the sows collected in 1971, in 42% of the sows in 1975 and in 32% of the sows in 1980. these results indicated that the coronavirus ped had been responsible for first ed1 outbreaks, for the ed2 outbreaks and thus it can be accepted that pedv emerged in 1971 but later widened its host tropism from growing and adult swine towards neonatal pigs. this finding was interesting from an evolutionary point of view. thus, pedv that presumably started as a cause of diarrhea in 1971 in feeders, fatteners and adult swine, had suddenly acquired tropism for neonatal pigs and now became a rather devastating disease. but even after the emergence of ed2/pedv, some outbreaks on breeding-finishing farms still did not involve neonatal pigs. while it was assumed that both ed1 and pedv were co-circulating in the swine population, it is also possible that some farms had experienced an earlier ed1 infection and that immune sows protected their offspring against pedv by lactogenic immunity while groups of fattening pigs had become susceptible. it must, however, be mentioned that cross-protection between ed1 and pedv has never been studied. also, after a first epidemic phase of the new pedv, the virus often persisted on breeding-finishing farms in weaned and feeder pigs (endemic ped). the sow population was immune, protecting its offspring, while feeder pigs became susceptible after loosing their maternal protection. the highly variable and mixed clinical picture was, at that time, ascribed to the possible co-circulation of the original ed1 agent and its presumed variant pedv in the population. genome analysis was not available and ed1 infectious material is also now no longer available to retrospectively examine this issue. ed2/pedv is likely a variant of ed1. that variants of pedv relatively easy emerge is not unusual as animal coronaviruses are known to easily undergo genetic alterations. recombination and insertions and deletions have repeatedly been demonstrated in pedv by genome analyses of isolates during more recent outbreaks in asia and in the usa (fan et al., 2012; li et al., 2016; jarvis et al., 2016; vlasova et al., 2014; oka et al., 2014) . even now (2016) in recent cases of ped in europe, varying types of clinical manifestations, either with or without affection of neonatal pigs, are observed (see later). the question on the origin of pedv (and thus of its presumed ancestor ed1 agent) in 1971 is unanswered. there are no indications for a possible evolution from another known so called "parental" coronavirus, even after comparative studies with the known coronaviruses using detailed genome analyses of different genes including the s gene. so far, only discrete antigenic relationship involving the n protein but without any cross protection was detected with some of the other animal members of the genus alphacoronavirus such as feline infectious peritonitis virus (fipv), tgev, porcine respiratory coronavirus (prcv), canine coronavirus (ccov) and mink coronavirus (mcv). by the use of monoclonal antibodies to the n proteins of the human alphacoronaviruses nl63 and 229e, no cross reactivity was detected with pedv (sastre et al., 2011) . the only alphacoronavirus in which also the m proteins cross reacts with pedv is mcv (have et al., 1992) . the nucleotide sequence of the pedv nucleocapsid gene and of typical coronavirus motifs show that pedv, within the region of the genome sequenced, shows indeed greatest homology to the human 229e, tgev, prcv, fipv, ccov and feline enteric coronavirus (fecv) (bridgen et al., 1993) . it is interesting to mention that, similar to pedv, several of the other alphacoronaviruses, including the human 229e, tgev, prcv, ccov, fecv and fipv use the cellular receptor aminopeptidase n (apn) for virus entry into cells in their host (weiss and navas-martin., 2005) and this seems to be a common evolutionary characteristic. still, the genetic and antigenic diversity between pedv and the other alphacoronaviruses is very largealso, no cross-reactivity has been reported between pedv and the coronaviruses belonging to the beta, gamma or delta genera.the genomic data presented above and the use of the same cellular receptor suggest a common origin of some of some of these alphacoronaviruses. a carrier-wild animal species as source of the virus, as often described with other coronaviruses, cannot be excluded. soon after its detection, experimental studies in neonatal pigs revealed that target cells of pedv were limited to the epithelium covering the intestinal villi and the pathogenesis was thus highly similar to that of tgev (debouck and pensaert, 1980; debouck et al., 1981) . cv777 virus infection in the villous enterocytes in neonatal pigs caused rapid cell desquamation throughout the small intestine within 24-36 h after inoculation which was somewhat slower than observed with tgev. still, the villous atrophy induced by pedv was so abrupt and extensive that rapid and severe dehydration occurred leading to death in neonatal pigs. due to this similarity in pathogenesis with tgev, much of the scientific knowledge acquired on tge diagnosis, −immunity, −prevention could be almost invariably applied to ped. an apparent difference with tgev, probably of minor importance from a clinical point of view, was that epithelial cells on colonic villi were also infected but desquamation was not observed. still now, it is a question if this colonic site of replication contributes to disease severity. ped diarrhea in fatteners and sows is often accompanied by an apparent belly ache, a clinical sign not seen with tge, and the question arises if the colon infection may contribute to this clinical manifestation. results of pathogenesis studies obtained in caesarean derived, colostrum deprived neonatal pigs upon inoculation with the european prototype strain cv777 of the seventies, were practically identical to those observed more recently in asia and in the usa epidemics with the so-called "original us pedv strains" stevenson et al., 2013; kim and chae, 2003) . a point of debate in the pedv evolution, particularly since its occurrence in asia and its emergence the usa, is the arising of pedv genetic variants influencing virulence. the history in europe, here presented, allows to assume that ed2/pedv was a variant of ed1 which had acquired tropism for intestinal enterocytes in neonatal pigs. this new tropism expanded and increased the virus virulence since a vulnerable age became affected and piglets mortality became an important economic aspect of the disease. currently, two major pedv variants are described in the usa upon routine genome analyses of usa isolates. the first, also called "original us pedv ", appears to be "highly virulent" while the second, the so called s-indel strains, standing for insertions and deletions in the s gene of the virus, are associated with mild(er) clinical outbreaks. similar genotypic variants have been detected in asia, the s-indels already before 2010 and the highly virulent since 2010. when adopting this genomic identification, it appears that cv777 is classified as a s-indel isolate apparently belonging to a different cluster compared to the us indels (carvajal et al., 2015) . considering the pathogenesis and virulence of the european prototype strain cv777 of the seventies as evaluated by the sites and degree of replication and the degree of villous atrophy, no real difference exists with the more recent highly virulent (original us pedv) isolates from the usa. for example, the pig adapted c777 when experimentally inoculated in neonatal piglets, caused villous atrophy with villous length reduction from the normal value of 700-900 m to as low as 200-300 m throughout the small intestine and within 6-36 h after the start of the diarrhea coussement et al., 1982) . much depends on how virulence of pedv is determined. if virulence of a pedv isolate is considered merely from the point of view of virus-neonatal pig interaction with parameters such as duration of incubation period, rapidity and severity of enterocyte desquamation, degree and extent of atrophy of villi, production of virulent virus quantities and severity of diarrhea, then cv777 can be classified as highly virulent despite its identification with s-indel isolates. that s-indels isolates do not systematically mean low virulence was recently shown in a us study (chun-ming et al., 2015) in which 4 litters of 3-4 days old suckling pigs were inoculated with the s-indel iowa 106 strain in the presence of their ped negative mothers. the severity of clinical signs and the mortality of the pigs varied between the 4 liters (from 0% to 75%). severe clinical signs were observed in 2 of the 4 litters. two of the 4 sows developed diarrhea. it was observed that, despite similar background of sows and environment in this experiment, the severity of disease was rather variable. it appeared that the pigs' body weight at birth and the sows health conditions and lactation were influential factors. in the same experiment mentioned above (chun-ming et al., 2015) , one litter was also inoculated with an original us pedv strain of high virulence. it was concluded that virulence of the s-indel isolate was generally lower based on the longer incubation period, the shorter duration of diarrhea, more limited regions of virus infection, overall lower pig mortality (18% vs 55% for "original") and some other additional parameters. the sites and extent of the deletions or insertions and the seqence differences in the s gene may play an important role. in a recent publication (chen et al., 2016 ) the pathogenicity differences between 3 u.s.pedv prototype strains and a s-indel-variant stain were compared in conventional neonatal pigs under experimental infections and enteric disease, as evidenced by clinical signs,fecal virus shedding, gross and histopathological intestinal lesions, were significantly lower for the s-indel strain.however,the molecular basis for the virulence differences were not elucidated. since the early beginning in europe, it was clear that ped disease can show much variability even in different litters of pigs particularly when suckling their mother. such differences and the high variation in pig mortality in different litters (from 30 to 80%) was an observation also made in the seventies in europe when the first epidemic occurred and the reason was never unravelled. even more variability is experienced when virulence and severity of ped disease is related to the interaction virus-farm population and thus in field outbreaks. the result of a ped outbreak will be much more difficult to predict, to evaluate and to define since, next to possible virulence differences of the isolates and next to variation among litters in suckling pigs, many additional factors play a role in determining the clinical outcome of the infection. they include immune status of sows, dose of virus exposure on the farm, herd size and pig farming management and others, all of which may be interacting in a different way. moreover, the procedures applied for intentional infection (feed back) of the sow population to speed up the induction of immunity to be passively transfered to the litter could be considered as a potential cause of worsening of the clinical status of the suckling pigs. in fact, that practice can also be a source of other pathogens for gilts/sows and/or for newborn piglets. it is thus possible that, particularly in a fully susceptible pig population and even with pedv strains of similar virulence, the mortality rates and losses are much higher in some continents or regions or farms with extensive and highly industrialised pig farming. the overall health status of the population apparently also plays an important role. while genomic changes surely will occur in ped virus isolates, it is advised to be careful when associating them with virulence changes. when a different clinical picture is observed on farms, it is often too hastily concluded that variants with varying virulence have arisen based on genome analysis only and without testing for virulence factors in experimental pigs. while genome analysis is certainly useful and may be directional, repeated comparative animal inoculation experiments with so called new isolates, clinically denominated as candidate "virulence-variants", need to be carried out in a standardized way before solid conclusions about virulence are made. this is indicated by the large variations very often observed with one and the same isolate. the neonatal, non suckling pig, preferably colostrum deprived, is reliable and even essential for this purpose. parameters as duration of incubation period, a timewise follow up of site and degree of villous affection in the small intestine are needed and must be repeated before calling a pedv isolate a variant with impact on virulence. it should be stressed that pig adapted virus strains should be used as it is known that major genomic modifications can arise when pedv is cell culture passaged, as well in porcine as in non-porcine cells, such as in vero cells. the epidemiology of ped in europe has been and still is quite puzzling. pedv outbreaks in the late seventies and early eighties occurred both on breeding and fattening swine farms. acute outbreaks with neonatal pig mortality were encountered in the breeding-fattening farms which became infected for the first time. pedv often became endemic. in farrowing-finishing farms, successive groups of pigs became infected upon weaning and after losing their lactogenic protection from their immune mothers, so that the virus could persist. whether the virus persisted or not after the original outbreak was somewhat unpredictable, as it could also disappear from the farm. the farm size (number of sows) and its structure (number of units) played a role. also ped persistence regularly occurred in fattening farms using the system of continuous introduction of feeder pigs originating from numerous and different breeders. a typical case of persistent diarrhea caused by pedv lasting 10 months on a breeding-finishing farm was described in the netherlands (pijpers et al.,1993) and this was a feature regularly observed in europe in the eighties. recent experience in the usa (2013) (2014) (2015) , has shown that management practices adopted in the epidemic phase of the infection can turn ped to a endemic/enzootic and long lasting form (jung and saif, 2015) . pedv infections were a regular cause associated with viral diarrheal picture in weaned and feeder pigs. in a serological study in belgium in 1986, pedv was associated with diarrhea in 13 out of 16 groups of feeder pigs after arrival in fattening farms (callebaut et al., 1986) but, the virus remained prevalent in the swine populations of western europe during the eighties. a serosurvey in belgian sows using sera collected in slaughterhouses, and thus mostly originating from different farms, showed pedv antibodies 32% in 1980 and 19% in 1984 . similar percentages of sows were positive in germany (on 3 regional locations), france, spain, the netherlands and bulgaria while no antibodies were found in scandinavia, northern ireland, usa or australia . in 1982, antibodies were detected in sera received from taiwan (the first evidence of the presence of pedv in asia). as the eighties advanced, fewer outbreaks on breeding farms were seen even though the virus was still detected but the general economic impact of ped had become lower. in belgium in 1992, 17 groups of feeder pigs from 15 commercial finishing herds, using the all in-all out production system, were examined for serocoversion to pedv and tgev. none of the groups seroconverted to tgev while 7 seroconverted to pedv with diarrhea observed in all 7 (van reeth and pensaert, 1994) . in an hungarian study published in 1996, 5.5% of 92 faecal samples from weaned pigs with diarrhea tested positively for pedv (nagy et al., 1996) . during the nineties, an acute ped outbreak which was described in spain involving a fattening unit of 5000 pigs with diarrhea starting in 7-9 weeks old pigs in one barn affecting pigs from 20 to 90 kg and subsequently spreading to the other barns (carvajal et al., 1995) . an isolated outbreak was described, in 1998 in england, in a large finishing herd where weaners were brought in over a 2 month period and positive sows were found in the breeding herds supply-ing the weaners (pritchard et al., 1999) . but, no further epidemic of ped occurred despite a very low pedv seroprevalence as only 1.9% of fatteners from 64 different finishing units were positive for antibodies to pedv(may 1996 -january 1997 . interest from a disease and economic point of view became very low in europe and no further research was performed on ped. practically no serosurveys were carried out. a serological survey in sows from farrow to finish herds carried out in belgium in 1996 revealed that gilts were positive for pedv antibodies in only 2 of the 144 considered farms, and in 1997, 72 fattening farms were examined for pev antibodies and none were positive (pensaert, unpublished) . it appeared that pedv, except for a focal case, was disappearing from the european swine population towards the turn of the century. for this reason, no attention or follow up was given anymore to this viral infection while its field of interest had fully moved to asia. however, a somewhat atypical ped outbreak occurred unexpectedly in the po valley in northern italy in 2006, (martelli et al., 2008) . it occurred between may 2005 and june 2006 in an area densely populated with pigs. the outbreak started with four cases occurring in fattening farms from may to july. no clinical cases were detected during august and september. in october, two new cases appeared: the first in a fattening unit and the second in the nursery of a three-site production unit. the disease spread during the winter of 2005-2006, affecting more than 60 farms including fattening units as well as farrow-to-finish or farrow-to-weaner farms. some pedv positive farms were still detected between mid-2006 and the end of 2007, but the disease progressively disappeared (sozzi et al., 2014) . from 2008-2014, only sporadic outbreaks were observed in grower and finisher herds (efsa, 2014) . this epidemic in italy in 2006-2007 inclined us to forecast a new episode of ped epidemics in europe but it did not occur. recently and due to an increased attention following the 2013 epidemic in the usa, single or limited ped outbreaks have sporadically been diagnosed in europe. one case in ukraine, (dastjerdi et al., 2015) occurred in a 5000-sow farm (240 farrowings a week) and mortality in pigs less than 10 days old approached 100%. the virus was closely related to "original us" strains reported form north america (sequence identity of 99.8%). isolates from other cases reported from belgium (theuns et al., 2015) , holland (van der wolf et al., 2015) , france (grasland et al., 2015) , germany hanke et al., 2015) and portugal (mesquita et al., 2015) and italy were, on the basis of genetic sequence, closely related to each other. when sequenced, they were classified as s-indel strains, and the german isolate showed 99.4% identity to the oh851 strain isolated in the usa in january 2014 . the size and clinical disease in these outbreaks were very variable. the outbreak involved in belgium: 1 fattening farm (no mortality), in france: 1 farrow to finish farm (mortality 12% in pigs at one week and 25% at weaning), in germany: 4 farms (2 fattening with 1.5% and 2% mortality, 2 breeding with 70% and no mortality, respectively) and in portugal where it started in one farm (with pig mortality, but not further defined) and where the virus spread to 43 other pig farms during a period of 3 months. from these data, it can be seen that, again, there was much and unexplained variation in ped clinical disease and outcome. except for the possibility of the outbreak in ukraine, it is very doubtful that the other european isolates have anything to do with those involved in the us epidemic. similar focal cases must have occurred in europe before the us outbreak but were, most likely, neither recognized nor diagnosed nor reported as ped. s-indel strains have been present in europe as cv777 appears to be the earliest known representative (carvajal et al., 2015) . it is remarkable that, in many european countries, no large epidemic occurred despite several indications that the breeding population in their densely populated swine raising regions is negative for antibodies to pedv and thus presumably fully susceptible. it is difficult to understand why a virus such as pedv has gradually regressed in the swine population in europe in the absence of any special control measures. vaccination has not been applied and no control programmes have been installed. the puzzling aspect is that, during the last decennia, pedv was and still is focally present in europe and did not cause an epidemic despite the high numbers of susceptible-seronegative farms and despite the very dense swine populations in some regions. one would expect that a virus such as pedv, which replicates to very high titers in swine and which can easily and rapidly spread from one swine farm to another, would be able to maintain itself in the swine population. as previously explained, once an outbreak has occurred on a breeding farm, pedv virus could persist easily when successive litters of pigs, after losing their lactogenic protection at weaning, become a susceptible target for infection. in fact, persistence for a virus such as pedv would be almost as a "natural" feature similar to the endemic character observed with other porcine enzootic enteric viruses such as swine rotaviruses, swine enteroviruses and others. tgev cannot serve as an example here because, in europe, it has largely been eliminated from the swine population due to the emergence, in the early eighties, of the closely related porcine respiratory coronavirus (prcv). prcv is a tgev deletion mutant which has acquired respiratory tropism and shows an epidemiological advantage of rapid aerogenic spreading while causing a protective immunity to tgev. endemic prcv has thus "replaced" tgev in europe. it would be interesting to study the mechanisms behind the regression/waning of pedv in europe. could it be that the virus has a non swine ancestor which has temporarily become adapted to swine but which is not really swine-borne? such evolution would not be unique for animal coronaviruses. could it be that the virus can maintain itself in the population only when present at a sufficient high dose allowing it to continue the infection chain but once reaching a low level quantity,e.g on a farm basis, is not longer able to do so? the waning of pedv has apparently not occurred in parts of asia within its 2-3 decennia of presence on that continent to the same degree as it did in europe, and it will be intriguing to closely follow the epidemiological course and evolution of pedv in the usa, once the epidemic phase has passed. surveillance and control of ped coronavirus in pig in italy seqence determination of the nucleocapsid protein gene of the porceni epidemic diarhoea viris confirms that this virusis a coronavirus relatyed to human coronavirus 229 e and porcine transmissible gastroenteritis virus enzyme-linked immunosorbent assay for the detection of the coronaviruslike agent and its antibodies in pigs with porcine epidemic diarrhea prevalence of influenza-, aujeszky, transmissible gastroenteritis and procine epizootic diarrhea virus in feeder pigs evaluation of a blocking elisa using monoclonal antibodies for the detection of porcine epidemic diarrhea virus and its antibodies porcine epidemic diarrhoea: new insights into an old disease virus-like particles associated with porcine epidemic diarrhoea pathogenesis comparison between the united states porcine epidemic diarrhoea virus prototype and s-indel-variant strains in conventional neonatal piglets experimental infection of a us spike-insertion deletion porcine epidemic diarrhea virus in conventional nursing piglets and cross-protection to the original us pedv infection pathology of experimental cv777 coronavirus enteritis in piglets porcine epidemic diarrhea virus among farmed pigs prevalence of porcine epidemic diarrhea (ped) virus in the pig population of different countries the pathogenesis of an enteric infection in pigs experimentally induced by the coronavirus-like agent cv 777 experimental infection of pigs with a new porcine enteric coronavirus cv777 scientific opinion on porcine epidemic diarrhea and emerging deltacoronavirus complete genome sequence of a novel porcine epidemic diarrhea virus in south china complete genome sequence of a porcine epidemic diarrhea s gene indel strain isolated in france comparison of porcine epidemic diarrhoea viruses from germany and the united states serological evidence of infection with a coronavirus related to transmissible gastroenteritis virus and porcine epidemic diarrhea virus genomic and evolutionary inferences between american and global strains of porcine epidemic diarrhea virus pathology of us porcine epidemic diarrhea virus strain pc21a in gnotobiotic pigs porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis experimental infection of piglets with a korean strain of porcine epidemic diarrhoea virus genome sequencing and analysis of a novelrecombinant porcine epidemic diarrhea virus strain from henan epidemic of diarrhoea caused by porcine epidemic diarrhoea virus in italy outbreak of porcine epidemic diarreha virus in portugal enterotoxigenic eschirichia coli, rotavirus, porcine epidemic diarrhoea virus, adenovirus and calici-like virus in porcine postweaning diarrohea in hungary cell culture isolation and sequence analysis of genetically diverse us porcine epidemic diarrhea virus strains including a novel strain with a large deletion in the spike gene letter to the editor. pig farm a new coronaviruslike particle associated with diarrhea in swine an immunoelectron and immunofluorescent study on the antigenic relationship between the coronavirus-like agent cv777 and several coronaviruses porcine epidemic diarrhoea virus as a cause of persistent diarrhoea in a herd of breeding and finishing pigs transmissible gastroenteritis and porcine epidemic diarrhoea in britain diagnosis and investigations on ped in northern italy differentiation betyween human coronaviruses nl63 and 229 e using a novel double-antibody sandwich enzyme-linked immunosorbent assay based on specific monoclonal antibodies emergence of porcine epidemic diarrhea virus in southern germany emergence of porcine epidemic diarrhea virus in the united states: clinical signs, lesions, and viral genomic sequences complete genome sequence of a porcine epidemic diarrhea virus from a novel outbreak in belgium first case of porcine epidemic diarrhea (ped) caused by a new variant of ped virus in the netherlands prevalence of infections with enzootic respiratory and enteric viruses in feeder pigs entering fattening units distinct characteristics and complex evolution of pedv strains, north america coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. microbiol an apparent new syndrome of porcine epidemic diarrhea key: cord-269124-oreg7rnj authors: spyrou, maria a.; bos, kirsten i.; herbig, alexander; krause, johannes title: ancient pathogen genomics as an emerging tool for infectious disease research date: 2019-04-05 journal: nat rev genet doi: 10.1038/s41576-019-0119-1 sha: doc_id: 269124 cord_uid: oreg7rnj over the past decade, a genomics revolution, made possible through the development of high-throughput sequencing, has triggered considerable progress in the study of ancient dna, enabling complete genomes of past organisms to be reconstructed. a newly established branch of this field, ancient pathogen genomics, affords an in-depth view of microbial evolution by providing a molecular fossil record for a number of human-associated pathogens. recent accomplishments include the confident identification of causative agents from past pandemics, the discovery of microbial lineages that are now extinct, the extrapolation of past emergence events on a chronological scale and the characterization of long-term evolutionary history of microorganisms that remain relevant to public health today. in this review, we discuss methodological advancements, persistent challenges and novel revelations gained through the study of ancient pathogen genomes. the long shared history between humans and infectious disease places ancient pathogen genomics within the inter est of several fields such as microbiology, evolutionary biology, history and anthropology. research on this topic aims to better understand the interactions between pathogens and their hosts on an evolutionary timescale, to uncover the origins of pathogens and to disentangle the genetic processes involved in their epidemic emer gence among human populations. over the past 10,000 years, major transitions in human subsistence strategies, such as those that accompanied the neolithic revolution 1 , likely exposed our species to a novel range of infectious agents 2 . closer contact with domesticated animals would have increased the frequency of zoonotic transmission events, and higher human population densities would have enhanced the potential of pathogens to propagate within and between groups. throughout human his tory, a number of epidemics and pandemics have been recorded or are hypothesized to have occurred (fig. 1) . although most of their causative agents still remain speculative, robust molecular methods coupled with archaeological and historical data can confidently demonstrate the involvement of certain pathogens in these episodes. the investigation of past infectious diseases has tra ditionally been conducted through palaeopathological assessment of ancient skeletal assemblages 3, 4 , although this approach is limited by the fact that most acute infec tions do not leave visible traces on bone. since the 1990s, the field of ancient dna (adna) has brought molecular techniques to this study, providing a diachronic genetic perspective to infectious disease research. initial attempts relied on pcr technology [5] [6] [7] [8] [9] , which restricted the study of ancient microbial dna to targeted, short genomic fragments that were amplified from ancient human remains. this method made infectious disease detection possible but gave limited information on the evolution ary history of the patho gen. in addition, complications associated with the study of adna, which is typically present at low quantities, is heavily fragmented and har bours chemical modifications [10] [11] [12] , hampered efforts to reproduce and authenticate early findings [13] [14] [15] . over the past decade, major advancements in geno mics, in particular, the development of high throughput sequencing, also called next generation sequencing (ngs) 16 , radically increased the amount of data that can be retrieved from ancient remains. this techno logy has assisted the development of quantitative meth ods for adna authentication 11, 12, [17] [18] [19] and has enabled the retrieval of whole ancient pathogen genomes from archaeological specimens. the first such genome, pub lished in 2011 (ref. 20 ), was that of the notorious bacterial pathogen yersinia pestis, the causative agent of plague. since then, the field has expanded its directions to the in depth study of infectious disease evolution, providing a unique resource for understanding human history. here, we review the latest methodological innovations that have aided the whole genome retrieval and evolu tionary analysis of various ancient pathogens (table 1) , most of which are still relevant to public health today. a scientific field focused on the study of whole pathogen genomes retrieved from ancient human, animal or plant remains. the cultural transition associated with the adoption of farming, animal husbandry and domestication as well as the practice of a sedentary lifestyle among human populations. the infectious disease transmission from animals to humans. in the second half of this review, we highlight the util ity of this approach by discussing evolutionary events in the history of y. pestis that have been uniquely revealed through the study of ancient genomes. methods for isolating ancient microbial dna the sweet spot for ancient pathogen dna. the retrieval of dna from ancient human, animal or plant remains carries with it a number of challenges, namely, its limited preservation and hence low abundance, its highly fragmented and damaged state and the perva sive modern dna contamination that necessitates a confident evaluation of its authenticity 21, 22 . efficient adna recovery is best accomplished via sampling of the anatomical element that contains the highest quantity of dna from the target organism. for human adna analysis, bone and teeth have been the preferred study material, given their abundance in the archaeological record. recent studies suggest that the inner ear por tion of the petrous bone 23 and the cementum layer of teeth 24 have the greatest potential for successful human dna retrieval. however, petrous bone sampling and shotgun ngs sequencing of adna from five bronze age skeletons previously shown to be carrying y. pestis failed to detect the bacterium in this source material, suggesting that its preservation potential for pathogen dna is low 25 . direct sampling from skeletal lesions, where present, has proved a rich source of adna for some chronic disease causing bacteria, such as mycobacterium tuberculosis, which was isolated from vertebrae 26 ; mycobacterium leprae, which could be isolated from portions of the maxilla and various long bones 27, 28 ; and treponema pallidum subsp. pallidum and t. pallidum subsp. pertenue, which have been isolated from long bones 29 . of note, the sampling methods for recovering pathogen dna do not generally follow a standardized procedure, in part because of the great diversity in tissue tropism and resulting disease progression. in addition, acute blood borne infections do not typically produce diagnostic bone changes as opposed to those that affect their hosts chronically 3 . therefore, if infections have caused mortal ity in the acute phase, as is the case for individuals from epidemic contexts who do not display skeletal evidence of infection, the preferred study material has been the inner cavities of teeth. pathogen adna is thought to be preserved within the remnants of the pulp chamber, likely as part of desiccated blood 8, 17 . consequently, tooth sampling has proved successful in the retrieval of whole genomes or genome wide data (that is, low coverage genomes that have provided limited analytical resolution) from ancient bacteria such as y. pestis 20, [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] , borrelia recurrentis 40 and salmonella enterica 41 ; ancient eukaryotic pathogens such as plasmodium falciparum 42 ; and ancient viruses such as hepatitis b virus (hbv) 43, 44 and human parvovirus b19 (b19v) 45 . even m. leprae, which commonly manifests in the chronic form, has been retrieved from ancient teeth 27, 28 . other types of specimen have also shown potential for adna retrieval. examples are dental calculus as a source of oral pathogens, such as tannerella forsythia 46 pandemics refers to increased, often sudden, disease occurrence within populations across more than one region or continent, whereas epidemics refers to increased disease occurrences within a confined region or country. the evaluation of the health status of ancient individuals or populations, usually through the analysis of disease marker presence on skeletal assemblages. (adna). the dna that has been retrieved from historical, archaeological or palaeontological remains. tropism refers to the type of tissue or cell in which infection is established and supported. segregating the metagenomic soup: methods for pathogen detection. regardless of the source of genetic material, most ancient specimens yield complex metagenomic data sets. poorly preserved adna usually makes up a miniscule fraction of the total genetic mate rial extracted from a sample (<1%), and the majority of dna usually stems from organisms residing in the envi ronment 41 . hence, specialized protocols are necessary for the detection and isolation of ancient pathogen dna and its confident segregation from a rich environmental dna background (fig. 2) . in this context, laboratory based techniques are sep arated into those that target a specific microorganism and those that screen for several pathogenic micro organisms simultaneously (fig. 2 ). methods that screen for a single microorganism have used species specific assays of conventional or quantitative pcr (also known as real time pcr) 17,61-64 , as well as hybridization based enrichment techniques 17, 26, 28 (fig. 2 ). these methods are particularly useful when the target microorganism is known, for example, in the presence of diagnostic skeletal lesions among the studied individuals 26, 28 , or when a hypothesis exists for the causative agent of an epidemic 17 . by contrast, broad laboratory based patho gen screening in adna research has used microarrays for both targeted enrichment 65 57 and hbv 54 that were sequenced using capillary sequencing (sanger method). a term used to describe a specimen or data set that includes nucleic acid sequences from all organisms within the sampled proportion. the diagram provides an overview of techniques used for pathogen dna detection in ancient remains by distinguishing between laboratory and computational methods. in both cases, processing begins with the extraction of dna from ancient specimens 183 . as part of the laboratory pipeline, direct screening of extracts can be performed by pcr (quantitative (qpcr) or conventional) against species-specific genes, as done previously 17, 61, 63, 64 . pcr techniques alone, however, can suffer from frequent false-positive results and should therefore always be coupled with further verification methods such as downstream genome enrichment and/or next-generation sequencing (ngs) in order to ensure ancient dna (adna) authentication of putatively positive samples. alternatively , construction of ngs libraries 184, 185 has enabled pathogen screening via fluorescence-based detection on microarrays 66 and via dna enrichment approaches 17 . the latter has been achieved, through single locus in-solution capture 26, 28 or through simultaneous screening for multiple pathogens using microarray-based enrichment of species-specific loci 65 and enables post-ngs adna authentication. in addition, data produced by direct (shotgun) sequencing of ngs libraries before enrichment can also be used for pathogen screening using computational tools. after pre-processing, reads can be directly mapped against a target reference genome (in cases for which contextual information is suggestive of a causative organism) or against a multigenome reference composed of closely related species to achieve increased mapping specificity of ancient reads. alternatively , ancient pathogen dna can also be detected using metagenomic profiling methods, as presented elsewhere 41, 71, 72 , through taxonomic assignment of shotgun ngs reads. both approaches allow for subsequent assessment of adna authenticity and can be followed by whole pathogen genome retrieval through targeted enrichment or direct sequencing of positive sample libraries. detection 66 , whereby probes are designed to represent unique or conserved regions from a range of pathogenic bacteria, parasites or viruses. although amplification based or fluorescence based approaches can be fast and cost effective for screening large sample collections 17, 38 , enrichment based techniques are usually coupled with ngs and therefore provide data that can be used to assess adna authenticity. when shotgun sequencing data are generated, com putational screening approaches can be used to detect the presence of pathogen dna as well as for meta genomic profiling of ancient specimens (fig. 2 ). in cases for which a causative agent is suspected, ngs reads can be directly mapped (for example, using the read align ment software burrows-wheeler aligner 67 ) against a specific reference genome or against a multigenome reference that includes several species of a certain genus with the purpose of achieving a higher mapping speci ficity to the target organism 34 (fig. 2 ). in addition, broad approaches involve the use of metagenomic techniques for pathogen screening. examples of tools that have shown their effectiveness with ancient metagenomic dna include the widely used basic local alignment search tool (blast) 68 ; the megan alignment tool (malt) 41 , which involves a taxonomic binning algorithm that can use whole genome databases (such as the national center for biotechnical information (ncbi) reference sequence (refseq) database 69 ); metagenomic phylogenetic analysis (metaphlan) 70 , which is also integrated into the metagenomic pipeline metabit 71 and uses thousands (or millions) of marker genes for the distinction of specific microbial clades; or kraken 72 , an alignment free sequence classifier that is based on k-mer matching of a query to a constructed database. taxonomic sequence assignments from the above methods, however, should be interpreted with caution, mainly because some pathogenic microorganisms have close environmental relatives that are often insuffi ciently represented in public databases. for example, a >97% sequence identity was shown between environ mental taxa and human associated pathogens such as m. tuberculosis and y. pestis according to an analysis of 16s ribosomal rna genes 73 . as such, given that envi ronmental dna often dominates ancient remains that stem from burial contexts 74 , analyses should always ensure a qualitative assessment of assigned reads, that is, an evaluation of their mapping specificity and their genetic distance (also called edit distance) to the puta tively detected organism. in addition, one should con sider the known adna damage characteristics as criteria for data authenticity. although several types of chemical damage can affect post mortem dna survival, certain characteristics have been more extensively quantified. the first, termed depurination, is a hydrolytic mecha nism under which purine bases become excised from dna strands. this process results in the formation of abasic sites and is a known contributor to the fragmen tation patterns observed in adna. as such, an increased base frequency of a and g compared with c and t immediately preceding the 5ʹ ends of adna fragments is often considered a criterion for authenticity 12 . a sec ond type of damage commonly identified among adna data sets is the hydrolytic deamination of c, whereby a c base is converted into u (and detected as its dna analogue, t) 12, 75 . this base modification usually occurs at single stranded dna overhangs that are most acces sible to environmental insults, resulting in an increased frequency of miscoding lesions at the terminal ends of adna fragments 11, 12 . consequently, the evaluation of dna damage profiles (for instance, by using map damage2.0 (ref. 76 )) is a prerequisite for authenticating ancient pathogen dna and is necessary for ensuring adna data integrity in general. more detailed overviews of authentication criteria in ancient pathogen research have been reviewed elsewhere 19, 73 . targeted enrichment approaches to isolate whole ancient pathogen genomes. evolutionary relationships between past and present infectious agents are best determined through the use of whole genome sequences of pathogens. however, the recovery of high quality data is often challenging owing to the aforementioned char acteristics of adna and therefore requires specialized sample processing. for example, in cases in which adna authenticity has already been achieved in the detection step, u residues resulting from post mortem c deami nation can be entirely 77 or partially 78 excised from adna molecules using the enzyme uracil dna glycosylase (udg) to avoid their interference with downstream read mapping and variant calling. in addition, given the low proportion of patho gen dna in ancient remains, a common and cost effective approach for whole genome retrieval involves microarray based or in solutionbased hybridization capture. both methods constitute a form of genomic selec tion of continuous or discontinuous genomic regions through the design and use of single stranded dna or rna probes that are complementary to the desired tar get. microarray based capture utilizes densely packed probes that are immobilized on a glass slide 79 . it is cost effective in that it permits the parallel enrichment of molecules from several libraries that can be subsequently recovered through deep sequencing, although competi tion over the probes can impair enrichment efficiencies in specimens with comparatively lower target dna con tents. nevertheless, this type of capture has shown its effectiveness in the recovery of both ancient pathogen and human dna 20, 26, 28, 41, 55, 80 . more recently, in solutionbased capture approaches have gained popularity owing to their capacity for greater sample throughput without compromising capture effi ciency [81] [82] [83] ; every sample library can be captured indi vidually, thus providing, in principle, an equal probe density per specimen. this technique has contributed to the increased number of specimens from which human genome wide single nucleotide polymorphism (snp) data could be retrieved 84, 85 , even from climate zones that pose challenges to adna preservation (pre sented elsewhere [86] [87] [88] ). in addition, in solutionbased capture has recently become the preferred method for microbial pathogen genome recovery for both bacteria and dna viruses (for examples, see refs 34, 37, 41, 43, 45, 49, 50 ). nevertheless, deep shotgun sequencing alone has also been used for human [89] [90] [91] and pathogen 28,33,48 high quality an algorithm that assigns metagenomic dna reads to a species or a higher taxonomic rank (for example, genus or family) based on the sequence specificity. the matching, for each read, of multiple subsequences of length k without mismatches to a database. a hydrolytic reaction in which the β-n-glycosidic bond of a purine (adenine or guanine) is cleaved, causing its excision from a dna strand. the hydrolytic removal of an amine group (nh 2 ) from a molecule. in ancient dna studies, the term deamination most often refers to the deamination of cytosine residues into uracils. the identification of polymorphisms (nucleotide differences) in sequenced data by comparison to a reference. www.nature.com/nrg 328 | june 2019 | volume 20 genome reconstruction, especially for specimens with fairly high endogenous dna yields, although this frequently carries with it a greater production cost. in the absence of ancient pathogen genomes, the tim ings of infectious disease emergence and early spread are inferred mainly through comparative genomics of modern pathogen diversity 92, 93 , palaeopathological eval uation of ancient skeletal remains 94 or analysis of his torical records 95, 96 . such approaches are highly valuable and, when combined, can be used to build an inter disciplinary picture of infectious disease history; however, limitations also exist. for example, the analysis of con temporary pathogen genetic diversity considers only a short time depth of available data and cannot predict evolutionary scenarios that derive from lineages that are now extinct. in addition, skeletal markers of specific infections in past populations only exist for a few con ditions and, when present, can rarely be considered as definitive, as numerous differential diagnoses can exist for a given skeletal pathology 97 . similarly, historically recorded symptoms can often be misinterpreted given that past descriptions may be unspecific and do not always conform to modern medical terminology 98 . in the past decade, the reconstruction of ancient pathogen genomes has complemented such analyses with direct molecular evidence, often revealing aspects of past infections that were unexpected on the basis of existing data. the recent identification of hbv dna in a mummified individual showing a vesicopustular rash 53 , which is usually considered characteristic of infection with varv, highlights the importance of molecular methods in evaluating differential diagnoses. the oldest recovered genomic evidence of hbv to date was from a 7,000year old individual from present day germany 44 , which shows that this pathogen has affected human populations since the neolithic period. in addition, the virus was identified recently in human remains from the bronze age, iron age and up until the 16th century of the current era (ce) in eurasia 43, 44, 53, 54 . regarding bacterial pathogens, the identification of b. recurrentis in a 15th century individual from norway 40 showed that -aside from y. pestis -other vector borne pathogens were also circulating in medieval europe. furthermore, the causative agents of syphilis and yaws, t. pallidum subsp. pallidum and t. pallidum subsp. pertenue, respectively, were recently identified in different individuals from colonial mexico 29 who exhib ited similar skeletal lesions. this study demonstrates the power of ancient pathogen genomics in distinguishing past infectious disease agents that are genetically and phenotypically similar but that differ greatly in their public health significance. finally, the identification of g. vaginalis and s. saprophyticus in calcified nodules from a woman's remains (13th century troy) 48 directly implicates these bacteria in pregnancy related com plications in the past. these findings, as well as other insights gained from analyses of ancient pathogen genomes (table 1) , demonstrate the ability of adna to contribute aspects of infectious disease history beyond those accessible by the palaeopathological, historical and modern genetic records. the reconstruction of whole pathogen genomes has not only been a tool for demonstrating infectious disease presence in the past but also aided in the robust infer ence of microbial phylogeography, which is important for understanding the processes that influence pathogen distribution and diversity over time. the evaluation of genetic relationships between ancient and modern pathogens is often conducted by direct whole genome or genome wide snp compari sons of bacteria 20, 27, 29, 36, 48 , viruses 43, 44, 50, 53 or mito chondrial genomes and nuclear genome data from eukaryotic microorganisms 56, 59, 60 . hence, accurate variant calling is critical for drawing reliable evolutionary inferences, although this process is often a challenge when handling data sets derived from samples with high rates of dna fragmentation (resulting in ultrashort read data), low endogenous dna content and high levels of dna dam age. in these cases, increased accuracy is best achieved through stringent ngs read mapping parameters and through visual inspection of the sequences overlap ping the studied snps 35 . in addition, histograms of snp allele frequencies -used to estimate the frequency of heterozygous calls in haploid organisms 26,52 -can often demonstrate the effects of environmental contamination on ancient microbial data sets 41 . once variant calls are authenticated, one of the most common types of evolutionary inference in patho gen research is through phylogenetic analysis, which is a powerful means of resolving the genetic history of clonal microorganisms (fig. 3) . among the most commonly used tools in ancient microbial genomics are mega 99 , which comprises several phylogenetic methods; phyml 100 , raxml 101 and iq tree 102 , which implement maximum likelihood approaches; mrbayes 103 , which uses a bayesian approach; and programs used for phylo genetic network inference, such as splitstree 104 . two notable studies that examined phylogenetic relationships among ancient m. leprae genomes revealed a high strain diversity in europe between the 5th and 14th centuries ce 27, 105 . considered alongside the oldest palaeopatholog ical cases of leprosy dating to as early as the copper and bronze age in eurasia 106,107 and the high frequency of protective immune variants against the disease identi fied in modern day europeans 108 , these results may sug gest a long history of m. leprae presence in this region. moreover, the phylogenetic analysis of a 12th century s. enterica subsp. enterica genome from europe showed its placement within the paratyphi c lineage 109 . further identification of the bacterium in 16th century colonial mexico 41 revealed it as a previously unknown candidate pathogen that was likely introduced to the americas through european contact. given the low frequency of paratyphi c today, these results may be indicative of a higher prevalence in past populations. finally, an example from viral genomics is the recovery of hiv rna from degraded serum specimens 57 , which high lighted the importance of archival collections in reconcil ing the expansion of recent pandemics. specifically, these data were able to dispute a long standing hypothesis regarding the initiation of hiv spread in the usa. when the evolutionary histories of pathogens are influenced equally by mutation and recombination, additional tools have been used to identify recombining loci and to determine genetic relationships within and between microbial populations (fig. 3) . for example, the programs clonalframeml 110 and recombination detection program 4 (rdp4) 111 have been used to infer potential recombination regions within ancient 43, 44, 53 , respectively. in addition, principal component analysis (pca) and ancient admix ture component estimation using the bayesian modelling frameworks structure 112 and finestructure 113 on both multilocus sequence typing (mlst) and whole genome data were recently used for population assignment of a 5,300year old h. pylori genome 49 . these analyses revealed key information on changes of the bacterial population structure that occurred in europe over time. furthermore, the recent study of ancient t. pallidum subsp. pallidum and t. pallidum subsp. pertenue 29 used the program tree puzzle 114 , a maximum likelihoodbased phylogenetic algorithm, to gain a more robust phylogenetic resolution of ambiguous branching patterns among bacterial lineages. such whole genome analyses of both clonal and recombining pathogens have helped to elucidate not only past infectious disease phylogeography but also possible zoonotic or anthroponotic transmission events that reveal disease interaction networks through time. among others (table 1) , a notable example is that of 1,000year old pre columbian m. tuberculosis genomes isolated from human remains, which showed a phylo genetic placement among animal adapted lineages, being most closely related to a strain circulating in modern day seals and sea lions 26 . although the extent to which these strains were capable of human to human transmission is unclear, this study supports the existence of tuberculosis in pre columbian south america and is helping to delineate the genomic and adaptive history of m. tuberculosis in the region before european contact 26 . another example of intriguing evolutionary relationships revealed uniquely through the study of ancient pathogen genomes includes analy ses of neolithic and bronze age hbv. these genomes grouped in extinct lineages that are most closely related to modern strains identified exclusively among african non human p ri ma te s 4 3 ,44 , a result that raises further questions regarding past transmission events in hbv history. finally, the phylogenetic analysis of medieval m. leprae genomes suggested a european source for lep rosy in the americas 28 , reinforcing the hypothesis that humans passed the disease to the nine banded arma dillo, the most common reservoir for this disease in the new world 115 . importantly, the resolution of evolutionary analyses will depend on the quality, size and evenness of spatial sampling in the comparative data set. therefore, the incomplete and often biased sampling of ancient and modern microbial strains can introduce challenges for discerning true biological relationships and past evo lutionary events. nevertheless, in recent years, marked reductions in ngs costs 116 have aided the increased pro duction of large whole genome microbial data sets from present day strains. current efforts for centralized data repositories that are continuously curated (such as the pathosystems resource integration center (patric) database 117 and the recently introduced enterobase 118 ) and the development of robust phylogenetic frameworks that can accommodate genome wide data from >100,000 strains (for example, grapetree 119 ) are becoming valua ble for integrating large sample sizes into microbial evo lutionary analyses. in combination with the increasing number of ancient microbial data sets, these tools will aid in the evaluation of genetic relationships by offering higher resolution. inferring divergence times through molecular dating. apart from providing a molecular fossil record and revealing diachronic evolutionary relationships, a third analytical advantage gained from the retrieval of ancient pathogen genomes is that their ages can be directly used for calibration of a molecular clock. the ages of ancient specimens can be determined through contextual information, through archaeological artefacts or directly through radiocarbon dating, predominantly of bone or tooth collagen. such temporal calibrations are required for high accuracy estimations of micro bial nucleotide substitution rates and in turn lineage divergence dates (fig. 3) , particularly because both esti mations seem to be highly influenced by the time depth covered by the genomic data set 120 . for such analyses, the most widely used program is the bayesian statistical framework beast 121, 122 . a characteristic example of how ancient calibration points can considerably affect divergence date estimates is that of m. tuberculosis. according to modern genetic data and human demographic events, the m. tuberculosis complex (mtbc) evolution was suggested to have fol lowed human migrations out of africa, with its emer gence estimated at more than 70,000 years ago 93 . recently, its emergence was re estimated to a maximum of 6,000 years ago on the basis of the 1,000year old myco bacterial genomes from peru 26 , a result that was further the diagram is an overview of whole-genome analysis applied to date for ancient microbial data sets and distinguishes the methods used for clonal and recombining pathogens; of note, the depicted summary is not meant to represent an exhaustive pipeline of all possible analyses that could be undertaken. ancient genome reconstruction is usually initiated through reference-based mapping or through de novo assembly of the data, although the latter has only been possible in exceptional cases of ancient dna (adna) preservation 28, 44 . subsequently , the genomes are assessed for their coverage depth and gene content for evaluation of their quality , which is also relevant for the comparative identification of virulence genes over their evolutionary time frames. here, we show an example of virulence factor presence-or-absence analysis in the form of a heat map, as done previously 33, 34, 37, 41 . in addition, a comparison of the ancient genome or genomes with modern genomes can be carried out for single-nucleotide polymorphism (snp) identification and for assessment of snp effects (using snpeff 186 ), which is particularly relevant for variants that seem to be unique to the ancient genome or genomes. initial evolutionary inference can often be carried out through phylogenetic analysis and by testing for possible evidence of recombination in the analysed data set, for example, by comparing the support of different phylogenetic topologies 114 and by identifying potential recombination regions and homoplasies 110, 111 . if the data support clonal evolution, robust phylogenetic inference (for example, through a maximumlikelihood approach) is followed by assessment of the temporal signal in the data 124, 125 . if the data set shows a sufficient phylogenetic signal, molecular dating analysis and demographic modelling are considered possible, although the size of the data set will determine whether such analyses will be feasible and meaningful. alternatively , if recombination is confirmed, genetic relationships between microbial clades or populations can be determined through phylogenetic network analysis 104 or through the use of population genetic methods such as principal component analysis (pca) and identification of ancestral admixture components 112, 113 . in this case, the assessment of the temporal signal and proceeding with molecular dating analysis is cautioned and likely best performed after exclusion of recombination regions from all genomes in the data set. mrca , most recent common ancestor. ngs, next-generation sequencing. a term used to describe that genome evolution occurs as a function of time and, therefore, the genetic distance between two living forms is proportional to the time of their divergence. a technique to estimate the age of a specimen on the basis of the amount of incorporated radiocarbon ( 14 c) that after the death of an organism gradually becomes lost over time. denotes the frequency of substitution accumulation in an organism within a given time; usually represented as substitutions per site per year. the dates of separation between two phylogenetic lineages, for example, the split between two species. corroborated by the incorporation of 18th century european mtbc genomes in the dating analysis 26, 52, 123 . in molecular phylogenies, the length of each individ ual branch usually reflects the number of substitutions acquired by an organism within a given period of time and, as such, varying branch lengths should represent heterochronous sequences. therefore, an important pre requisite for a robust dating analysis is that the nucleo tide substitution rate of the species whose phylogeny is to be dated behaves in a 'clock like' manner, meaning that phylogenetic branch lengths correlate with archaeological dates or sampling times. such relationships can be assessed through date randomization and root-to-tip regression tests (fig. 3) . the former is used to assess the effect of arbi trary exchange of phylogenetic tip dates on the nucleo tide substitution rate and divergence date estimates 124 , whereas the latter is used for estimation of a correlation coefficient (r) and coefficient of determination (r 2 ) by relating the tip date of each taxon to its snp distance from the tree root (using, for example, the program temp est 125 ). the resulting values determine whether there is a temporal signal in the data and suggest whether branches within a phylogeny evolve at a constant rate, in which case a strict molecular clock 126 can be statistically tested, for example, using mega 99 or marginal likelihood estimations 127, 128 , and applied. if branches are affected by differences in their evolutionary rates, a relaxed clock 129 would be more appropriate. in general, a constant mole cular clock will rarely reliably describe the history of a microbial species, even more so for infectious pathogens whose replication rates vary between active and latent or between epidemic and dormant phases 120, 130 . in certain cases, neither of the two models may fit the data, such as when extensive rate variation weakens the temporal signal. this challenge was encountered in initial attempts to date the y. pestis phylogeny using too few ancient cali bration points 36, 130 . similar limitations can arise when the evolutionary history of a microorganism is vastly affected by recombination, as observed for hbv 44, 53 , although hbv molecular dating was recently attempted using a different genomic data set and suggested that the currently explored diversity of old and new world pri mate lineages (including all human genotypes) may have emerged within the last 20,000 years 43 . molecular dating analysis requires the use of an appro priate demographic model for the available data, which can be determined through model testing approaches (for example, through marginal likelihood estimations 127, 128 ). currently, the most widely used models for estimating dates of divergence are the coalescent constant size 131 , which assumes a continuous population size history -and is unrealistic for epidemic pathogens -and the coalescent skyline 132 , which can estimate effective population size (n e ) changes over time. moreover, the birth-death demographic model 133, 134 , which is cur rently unexplored within adna frameworks, may prove an insightful analysis tool in the future. this model has shown its applicability on comprehensive pathogen data sets from modern day epidemic contexts 133 . it has the ability to incorporate prior knowledge on incom plete sampling proportions and sampling biases within a data set, a frequent caveat of adna studies that is currently unaccounted for within molecular dating analy ses. finally, recently developed fast dating algorithms should also be noted, for example, the least squared dating (lsd) program, which does not use constrained demographic models but can handle uncorrelated rate variation among phylogenetic branches and has shown potential for analysing large genomic data sets 135 . the pathogen best studied using adna analysis so far is y. pestis, the causative agent of plague. to date, 38 ancient genomes of this bacterium have been published 20,30-39 (fig. 4) , and their analyses have yielded valuable infor mation on past pandemic emergence as well as in depth microbial evolution. integration of such knowledge into human population frameworks has provided key insights into the association of human migrations and infectious disease transmission in the past 31, 34 . this sec tion describes the evolutionary history of y. pestis with the aim of demonstrating aspects of its emergence and spread as revealed through adna research. plague is a well defined infectious disease caused by the gram negative bacterium y. pestis, which belongs to the fam ily enterobacteriaceae. it evolved from a close relative, yersinia pseudotuberculosis, which is an environmental enteric diseasecausing bacterium 136 . although the two species are clearly distinguishable in terms of their vir ulence potential and transmission mechanisms, their nucleotide genomic identity reaches 97% among chromo somal protein coding genes 137 . in addition, they share the virulence plasmid pcd1, which encodes a type iii secretion system common to three known pathogenic yersinia: y. pestis, y. pseudotuberculosis and yersinia enterocolitica. the distinct transmission mechanism and pathogenicity of y. pestis are conferred by the unique acquisition of two plasmids, ppcp1, which contributes to the invasive potential of the bacterium 138 , and pmt1, which is involved in flea colonization 139, 140 , as well as by chromosomal gene pseudogenization or loss throughout its evolutionary history 141 . y. pestis is not human adapted. its primary hosts are sylvatic rodents such as marmots, mice, great gerbils, voles and prairie dogs, among others, in which it is continuously or intermittently maintained in so called reservoirs or foci [142] [143] [144] . its global distribution includes numerous rodent species 144, 145 and encompasses regions in eastern europe, asia, africa and the americas (fig. 4) , where the bacterium persists in active foci, some of which have existed for centuries or even millennia 31, 33, 34, 37, 130 . y. pestis transmission among hosts is facilitated by a flea vector (fig. 5) . the best yet characterized is the oriental rat flea, xenopsylla cheopis, although others are also known to play important roles in y. pestis transmission 142, 144, 146 . notably, recent modelling infer ences suggest important roles for ectoparasites such as body lice and human fleas in its propagation during human epidemics 147 . landmark studies investigating the classical model of transmission have shown that y. pestis has the unique ability to colonize and form a biofilm within the flea, which blocks a portion of its a test that involves random shuffling of calibration points (tip dates) across a molecular phylogeny to evaluate the effect of randomizations compared to true data on the nucleotide substitution rate estimates. a test that uses a linear correlation to determine the relationship between branch lengths and sampling times within a time-dependent phylogeny. a mathematical model that aims to explain the size and density of a population over time. www.nature.com/nrg 332 | june 2019 | volume 20 foregut, the proventriculus (fig. 5 ). this phenotype is determined by the unique acquisition and activity of certain genomic loci in y. pestis, namely, the yersinia murine toxin (ymt) gene, which is present on the pmt1 plasmid 140, 141 and facilitates colonization of the arthropod midgut 141 . in addition, it is dependent on the pseudogenization of certain genes, namely, the biofilm downregulators rcsa, pde2 (also known as rtn), pde3 (also known as y3389) 141 and the ure ase gene ured 148, 149 , which are, by contrast, active in y. pseudotuberculosis. the biofilm prevents a blood meal from entering the flea's digestive tract, leaving it starving; as a result, the insect intensifies its feeding behaviour and promotes bacterial transmission to un infected hosts [150] [151] [152] . this continuous transmission cycle among fleas and rodents, also called the enzootic phase of maintenance (fig. 5) , is thought to drive the preser vation of plague foci around the world and is depen dent on environmental and climatic factors as well as on host population densities 142, [153] [154] [155] . disruption of this equilibrium for reasons that are not well understood can cause disease eruption among susceptible rodent species, leading to so called plague epizootics 142 (fig. 5) . during that time, marked reductions in the rodent pop ulations force fleas to seek alternative hosts, which can lead to infections in humans and, as a result, trigger the initiation of epidemics or pandemics. plague manifestation in humans has three disease forms, namely, bubonic, pneumonic and septicaemic 156 . bubonic plague is the most common form of the disease and can cause up to 60% mortality when left untreated 157 . subsequent to the bite of an infected flea, bacteria travel to the closest lymph node, where excessive replica tion occurs, giving rise to large swellings, the so called buboes. in addition, following primary bubonic plague, bacteria can disseminate into the bloodstream to cause septicaemia (secondary septicaemic plague) and to the lungs, causing secondary pneumonic disease. both forms are highly lethal disease presentations and cause nearly 100% mortality when left untreated. only the pneumonic form can result in direct human tohuman transmission. early evolution: plague in prehistory. the time of divergence between y. pestis and y. pseudotuberculosis has been difficult to determine given the wide temporal interval produced by recent molecular dating attempts 92, 130, [169] [170] [171] [172] [173] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] 200 , are shown as grey circles within their geographical country or region of isolation, and the size of each circle is proportional to the number of strains sequenced from each location (number indicated when more than one genome is shown). the areas highlighted in brown are regions that contain active plague foci as determined by contemporary or historical data. ybp, years before present. adapted with permission from the 'global distribution of natural plague foci as of march 2016' from https://www.who.int/csr/disease/plague/plague-map-2016.pdf. based on adna data (13,000-79,000 years before present (ybp)) 33, 34 . nevertheless, y. pestis identification in human remains from neolithic and bronze age eurasia suggests that it caused human infections during these periods and originated more than 5,000 years ago 31, 33, 34 . these data have revealed important details about the early evolution of the bacterium. genomic and phylogenetic analyses have shown that strains from the late neolithic and bronze age (lnba) occupy a basal lineage in the y. pestis phylogeny, and a recent study suggests the presence of even more basal variants in neolithic europe 31 (fig. 6 ). such analyses have demonstrated that, during its early evolution, the bacterium had not yet acquired impor tant virulence factors consistent with the complex trans mission cycle common to historical and extant strains. one of these genes is ymt, whose absence has been asso ciated with an inability for flea midgut colonization in y. pestis 141 . in addition, these strains possess the active forms of the rcsa, pde3, pde2 and ured genes, which suggests an impaired ability towards biofilm formation and blockage of the flea's proventriculus 141, 149 . finally, they possess an active flagellin gene (flhd), which is pres ent as a pseudogene in all other y. pestis, as it is a potent inducer of the innate immune response of the host 158 . as a result, during its initial evolutionary stages, y. pestis may have been unable to efficiently transmit via a flea vector. flea borne transmission of y. pestis is a known prerequisite for bubonic plague development 141 ; hence, it has been suggested that this disease phenotype was not present during prehistoric times 33, 159 . in addition, these results have raised uncertainty regarding the pos sible vector and host mammalian species of the bacte rium. the bronze age in eurasia was a period of intense human migrations, which shaped the genomic landscape of modern day europe 85, 160 . remarkably, the y. pestis lnba lineage was shown to mirror human movements during that time 34 and was found in regions that do not host wild reservoir populations today (fig. 4) . the wide geographical distribution of these strains, their supposed limited bubonic disease potential and their relationship with human migration routes might together be indica tive of a different reservoir host species compared to wild rodents that have a central role in plague transmission in areas such as central and east asia, where the disease is endemic today. nevertheless, an alternative mode of flea transmis sion, termed the early phase transmission, which occurs during the initial phases of infection and was suggested to be biofilm independent 161 , should also be considered as a possible way of y. pestis propagation during its early evolution 34 . although this transmission mechanism is currently not well understood, its comparative mode and efficiency in different rodent species have recently started to be assessed 162 evidence showing the full capacity for flea colonization similar to modern and historic strains was identified in two 3,800year old skeletons from the samara region of modern day russia 37 . although this strain was shown to occupy a phylogenetic position among modern y. pestis lineages (fig. 6) , molecular dating analysis indicated that it originated ~4,000 years ago, suggesting that it over lapped temporally with the other bronze age strains that lacked the genetic prerequisites for arthropod transmis sion. similar characteristics were previously identified in a low coverage 3,000year old isolate from modern day armenia 33 , which suggests that multiple forms of the bacterium were circulating in eurasia between 5,000 and 3,000 years ago that may have had different transmission cycles and produced different disease phenotypes. as the propagation mechanisms of those strains are still uncer tain, and the exact timing of flea adaptation in y. pestis is unknown, additional metagenomic screening from human and animal remains may provide relevant infor mation on disease reservoirs and hosts across neolithic and bronze age eurasia. it is becoming increasingly apparent that, aside from plague, other infectious diseases, such as those caused by hbv 43,44 and b19v 45 (table 1) , were circulating dur ing the same time periods. further pathogen screening coupled with a temporal assessment of human immune associated genomic variants 84 may reveal key aspects of disease prevalence and susceptibility during this pivotal period of human history. after the bronze age, bubonic plague has been associated with three historically recorded pandem ics. the earliest accounts of the so called first plague pandemic, which began with the plague of justinian (541 ce), suggest that it erupted in northern africa in the mid6th century ce 163, 164 and subsequently spread through europe and the vicinity until ~750 ce. the sec ond historically recorded plague pandemic began with the infamous black death (1346-1353 ce) 96 and con tinued with outbreaks in europe until the 18th century ce. the most recent third plague pandemic began in the mid19th century in the yunnan province of china, and it was during that time that alexandre e. j. yersin first described the bacterium in hong kong, in 1894 (fig. 1) and has persisted until today in active foci in africa, asia and the americas. although the majority of mod ern plague cases derive from strains disseminated in this global dispersal, the pandemic is considered to have largely subsided since the 1950s 165 . the association of y. pestis with the two earlier pan demics has, until recent years, been contentious. on the basis of their serological characterization, modern strains were traditionally grouped into three distinct biovars, namely, 'antiqua' , 'medievalis' and 'orientalis' , according to their ability to ferment glycerol and reduce nitrate 165, 166 . in addition, historical accounts of the dis ease seemed to correlate with the supposed distinct geographical distributions of these biovars 166 , and their phylogenetic relationships, as inferred from mlst data, reinforced the hypothesis that each was responsible for a single pandemic 136 . by contrast, later studies identified additional, atypical biovars 167 , and more robust phylo genetic analysis suggested that phylogeography does not correlate clearly with the phenotypic distinctions described between these bacterial populations 92, 130, 168 . recent genomic analyses have revealed high genetic diversity of the bacterium in east asia, which invaria bly led to the assumption that y. pestis emerged there 130 . however, a strong research focus on the diversity of the bacterium in these endemic regions, mainly china, has contributed to a profound sampling bias in the available modern data (fig. 4) . more recent investigations have revealed previously uncharacterized genetic diversity in the caucasus region and in the central asian steppe that ought to be further explored [169] [170] [171] [172] (fig. 4) . currently, the evolutionary tree of the bacterium is characterized by five main phylogenetic branches (fig. 6) . the most ances tral, branch 0, includes strains distributed across china, mongolia and the areas encompassing the former soviet union. the more phylogenetically derived branches 1-4 were formed through a rapid population expan sion event and are today found in asia, africa and the americas 130 . their wide distribution mainly reflects the geographical breadth of branch 1, which is associated with the third plague pandemic that spread worldwide during the 19th and 20th centuries 92 and is still respon sible for more confined epidemics such as those reported in madagascar 173 . the analysis of adna from historical epidemic contexts has generated important information regard ing the evolutionary history of plague. the recovery of y. pestis dna via pcr from remnants of human den tal pulp suggested the involvement of the bacterium in both the first and second pandemics; however, these results were difficult to authenticate 8, 174, 175 . subsequent pcr based snp typing of ancient specimens offered some phylogenetic resolution and revealed an expected ancestral placement of medieval strains in the y. pestis phylogeny [62] [63] [64] . more recently, full characterization and authentication of the bacterium were achieved using plasmid and whole genome enrichment coupled with ngs 17, 20, 35, 36 . historical accounts of the first plague pandemic (6th to 8th centuries ce) suggest that the disease expanded mainly across the mediterranean basin; however, its exact breadth and impact have been difficult to assess given the limited availability of historical and archaeo logical data, with the latter being currently under revision 176 . two recent studies have reconstructed 6th century y. pestis genomes from southern germany 35,36 (fig. 4) , a region that lacked historical documentation of the pandemic. phylogenetic analysis showed that both genomes belong to a lineage that is today extinct and is closely related to strains from modern day china 35, 36 , which suggests the possibility of an east asian origin of the first pandemic. this hypothesis was recently reinforced by the publication of a 2nd century to 3rd century y. pestis genome from the tian shan mountains of modern day kyrgyzstan 39 , which shares a common ancestor with the justinianic plague lineage (figs 4,6) . however, given the >300year age difference between these strains 35, 36, 39 , as well as the aforementioned east asian sampling bias of modern y. pestis data 130 , the geographical origin of the pandemic remains hypothet ical. retrieval of additional y. pestis strain diversity from that time period, particularly from areas known to have played an important role in the entry of this bacterium into europe, that is, the eastern mediterranean region, may hold clues about its putative source. the beginning of the second plague pandemic, 600 years later, was marked by the notorious black death of europe (1346-1353 ce), estimated to have caused an up to 60% reduction of the continental pop ulation in only 5 years 96 . historical records suggest that the first outbreaks occurred in the lower volga region of russia, and the disease then spread into southern europe through the crimean peninsula 96 . initial analy sis of y. pestis via pcr from victims of the black death revealed a distinct phylogenetic positioning of two mid tolate14th century strains and led to the proposal that the disease entered the continent through independent pulses 64 . by contrast, whole genome analysis of ancient strains from western, northern and southern europe demonstrated a lack of y. pestis diversity during the black death, which suggests its fast spread through the continent and favours a single wave entry model of the bacterium into europe 20,30,38 , although the possible presence of additional strain diversity during that time has recently been explored 30 . intriguingly, the phylo genetic positioning of the black death y. pestis genomes places them on branch 1, only two nucleotide substitu tions away from the 'star like' diversification of branches 1-4 (fig. 6) , which gave rise to most of the strain diversity identified around the world today 38, 130 . after the black death, plague epidemics continued to affect europe until the 18th century 177, 178 . inferred climatic data from tree ring records in central asia and europe have recently suggested that such epidem ics were likely caused by multiple introductions of the bacterium into europe as a result of climate driven disruptions of pre existing asian reservoirs 179 . by con trast, ancient genetic and genomic evidence supports the persistence of the disease in europe for 400 years after the black death 32, 38, 62 . analysis of y. pestis strains spanning from the late 14th to the 18th century ce has revealed the formation of at least two european lin eages that were responsible for the ensuing medieval epidemics (fig. 6 ). both lineages derive from the black death y. pestis strain identified in 14th century west ern, northern and southern europe 30, 32, 38 , suggesting that they likely arose locally. the first lineage survives today and gave rise to modern branch 1 strains 30, 38 (which are associated with the third plague pandemic), suggesting the european black death as a source for modern day epidemics 38 . the second lineage has not been identified among present day diversity and currently encompasses strains from 16th century germany 38 and 18th century france (great plague of marseille, 1720-1722 ce) (fig. 6) . these phylogenetic patterns are consistent with a con tinuous persistence of the bacterium in europe dur ing the second plague pandemic. in addition, they are supported by analyses of historical records that suggest the existence of plague reservoirs in the continent until the 18th century ce 180 . y. pestis is absent from most of europe today; specif ically, no active foci exist west of the black sea. plague is thought to have disappeared from most of europe at the end of the second pandemic (18th century ce). this finding is striking given the thousands of outbreaks that were recorded in the continent until that time 177, 178 . the reasons for its disappearance are unknown, although numerous hypotheses have been put forward 181 , includ ing a change in domestic rodent populations in europe, namely, the replacement of the black rat, rattus rattus, by the brown rat, rattus norvegicus 181 ; an acquired plague immunity among humans and/or rodents 181 (although this hypothesis requires an update to accommodate the recent identification of y. pestis in europe 5,000 years ago 31, 33, 34 and the involvement of the bacterium in the first plague pandemic 35, 36 ); the increased living standards such as the better nutrition and hygienic conditions at the beginning of the early modern era, which may have contributed to improved overall health conditions in europe and likely decreased the number of rats and ecto parasites in human environments 181, 182 ; and the poten tial disruption of the european wild rodent ecological niche owing to habitat loss and industrialization start ing in 1700 ce 180 . given the contribution that molecular data can offer in these discussions, future research on ancient sources of y. pestis dna will be instrumental in further revealing the history of one of humankind's most devastating pathogens. the analysis of ancient pathogen genomes has afforded promising views into past infectious disease history. for y. pestis, adna exploration of its evolutionary past has revealed how a predominantly environmental bac terium and opportunistic gastroenteric pathogen deve loped into an extremely virulent form by acquisition of only a few virulence factors. we eagerly await revelations on a similar scale for other important pathogens that are expected to arise from deep temporal sampling and genomic reconstruction, as made possible through the recent advancements discussed here. integration of ancient pathogen genomes into disease modelling and human population genetic frameworks, as well as their analysis alongside the information offered by the archaeological, historical and palaeopathological records, will help build a more interdisciplinary and com plete picture of host-pathogen interactions and human evolutionary history over time. published online 5 april 2019 the origins of agriculture: population growth during a period of declining health emerging and re-emerging infectious diseases: the third epidemiologic transition identification of pathological conditions in human skeletal remains 2nd edn the global history of paleopathology: pioneers and prospects pre-columbian tuberculosis in northern chile: molecular and skeletal evidence identification of mycobacterium tuberculosis dna in a pre-columbian peruvian mummy molecular analysis of skeletal tuberculosis in an ancient egyptian population detection of 400-year-old yersinia pestis dna in human dental pulp: an approach to the diagnosis of ancient septicemia the use of the polymerase chain reaction (pcr) to detect mycobacterium tuberculosis in ancient skeletons ancient dna: extraction, characterization, molecular cloning, and enzymatic amplification temporal patterns of nucleotide misincorporations and dna fragmentation in ancient dna the study provides a quantitative description of adna-associated patterns of nucleotide misincorporation and fragmentation that are currently used as primary authentication criteria ancient dna: do it right or not at all absence of yersinia pestisspecific dna in human teeth from five european excavations of putative plague victims no proof that typhoid caused the plague of athens (a reply to papagrigorakis et al.) genome sequencing in microfabricated high-density picolitre reactors targeted enrichment of ancient pathogens yielding the ppcp1 plasmid of yersinia pestis from victims of the black death the neandertal genome and ancient dna authenticity mining metagenomic data sets for ancient dna: recommended protocols for authentication the study describes the first whole-genome sequence of an ancient bacterial pathogen through the use of high-throughput sequencing genetic analyses from ancient dna optimal ancient dna yields from the inner ear part of the human petrous bone comparing ancient dna preservation in petrous bone and tooth cementum ancient pathogen dna in human teeth and petrous bones pre-columbian mycobacterial genomes reveal seals as a source of new world human tuberculosis ancient genomes reveal a high diversity of mycobacterium leprae in medieval europe the study presents the first de novo assembled ancient pathogen genome and an analysis of m historic treponema pallidum genomes from colonial mexico retrieved from archaeological remains integrative approach using yersinia pestis genomes to revisit the historical landscape of plague during the medieval period emergence and spread of basal lineages of yersinia pestis during the neolithic decline eighteenth century yersinia pestis genomes reveal the long-term persistence of an historical plague focus early divergent strains of yersinia pestis in eurasia 5,000 years ago the study describes y. pestis genomes from bronze age human remains and provides a chronological timing of virulence determinant acquisition during the early evolution of the bacterium the stone age plague and its persistence in eurasia a high-coverage yersinia pestis genome from a sixth-century justinianic plague victim yersinia pestis and the plague of justinian 541-543 ad: a genomic analysis analysis of 3800-year-old yersinia pestis genomes suggests bronze age origin for bubonic plague historical y. pestis genomes reveal the european black death as the source of ancient and modern plague pandemics 137 ancient human genomes from across the eurasian steppes genomic blueprint of a relapsing fever pathogen in 15th century scandinavia this paper presents the metagenomic tool malt and is the first case study to demonstrate metagenomic detection of ancient pathogens in the absence of prior knowledge on the causative agent of an epidemic plasmodium falciparum malaria in 1st−2nd century ce southern italy ancient hepatitis b viruses from the bronze age to the medieval period the studies by mühlemann (nature, 2018) and krause-kyora (elife, 2018) present a time transect of hbv genomes, spanning from the neolithic period to the medieval period, and provide an overview of the hbv population history across millennia ancient human parvovirus b19 in eurasia reveals its long-term association with humans this study provides an analysis of the composition of human dental calculus from ancient individuals, showing the presence of oral microbiome bacterial dna, periodontal pathogen dna and proteins associated with host immunity recovery of a medieval brucella melitensis genome using shotgun metagenomics a molecular portrait of maternal sepsis from byzantine troy the study provides insights into the genomic history of h. pylori over several millennia through a population genomic analysis of a copper age strain against a worldwide data set 17th century variola virus reveals the recent history of smallpox variola virus in a 300-year-old siberian mummy eighteenth-century genomes show that mixed infections were common at time of peak tuberculosis in europe the paradox of hbv evolution as revealed from a 16th century mummy tracing hepatitis b virus to the 16th century in a korean mummy second-pandemic strain of vibrio cholerae from the philadelphia cholera outbreak of 1849 mitochondrial dna from the eradicated european plasmodium vivax and p. falciparum from 70-year-old slides from the ebro delta in spain and 'patient 0'hiv-1 genomes illuminate early hiv/aids history in north america characterization of the 1918 influenza virus polymerase genes the rise and fall of the phytophthora infestans lineage that triggered the irish potato famine reconstructing genome evolution in historic samples of the irish potato famine pathogen screening ancient tuberculosis with qpcr: challenges and opportunities genotyping yersinia pestis in historical plague: evidence for long-term persistence of y. pestis in europe from the 14th to the 17th century yersinia pestis dna from skeletal remains from the 6th century ad reveals insights into justinianic plague distinct clones of yersinia pestis caused the black death parallel detection of ancient pathogens via array-based dna capture ancient pathogen dna in archaeological samples detected with a microbial detection array fast and accurate long-read alignment with burrows-wheeler transform basic local alignment search tool reference sequence (refseq) database at ncbi: current status, taxonomic expansion, and functional annotation metagenomic microbial community profiling using unique clade-specific marker genes metabit, an integrative and automated metagenomic pipeline for analysing microbial profiles from high-throughput sequencing shotgun data kraken: ultrafast metagenomic sequence classification using exact alignments a robust framework for microbial archaeology complications in the study of ancient tuberculosis: presence of environmental bacteria in human archaeological remains dna sequences from multiple amplifications reveal artifacts induced by cytosine deamination in ancient dna 0: fast approximate bayesian estimates of ancient dna damage parameters removal of deaminated cytosines and detection of in vivo methylation in ancient dna partial uracil-dna-glycosylase treatment for screening of ancient dna hybrid selection of discrete genomic intervals on custom-designed microarrays for massively parallel sequencing targeted investigation of the neandertal genome by array-based sequence capture dna analysis of an early modern human from tianyuan cave application and comparison of large-scale solution-based dna capture-enrichment methods on ancient experimental conditions improving in-solution target enrichment for ancient dna genome-wide patterns of selection in 230 ancient eurasians this study delineates large-scale population migrations into europe during the bronze age by analysis of human genome-wide data of genomic insights into the origin of farming in the ancient near east genetic origins of the minoans and mycenaeans language continuity despite population replacement in remote oceania ancient human genome sequence of an extinct palaeo-eskimo the complete genome sequence of a neanderthal from the altai mountains a high-coverage genome sequence from an archaic denisovan individual yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity the study shows a possible co-expansion of m. tuberculosis among human populations during out-of-africa migrations the bioarchaeology of tuberculosis: a global perspective on a re-emerging disease the black death transformed: disease and culture in early renaissance europe the black death advances in human palaeopathology past human infections mega7: molecular evolutionary genetics analysis version 7.0 for bigger datasets a simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood raxml version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies iq-tree: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies mrbayes 3: bayesian phylogenetic inference under mixed models application of phylogenetic networks in evolutionary studies ancient dna study reveals hla susceptibility locus for leprosy in medieval europeans ancient skeletal evidence for leprosy in india possible cases of leprosy from the late copper age (3780-3650 cal bc) in hungary leprosy and the adaptation of human toll-like receptor 1 the study describes a 12th century salmonella enterica subsp. enterica serovar paratyphi c genome and its analysis alongside a comprehensive data set of thousands of s clonalframeml: efficient inference of recombination in whole bacterial genomes rdp4: detection and analysis of recombination patterns in virus genomes inference of population structure using multilocus genotype data inference of population structure using dense haplotype data tree-puzzle: maximum likelihood phylogenetic analysis using quartets and parallel computing on the origin of leprosy dna sequencing costs: data from the nhgri genome sequencing program (gsp). genome patric, the bacterial bioinformatics database and analysis resource the paper introduces a web-based platform that performs genome assembly and multilocus sequence typing analysis and can be used for the retrieval of large data sets on enteric bacteria grapetree: visualization of core genomic relationships among 100,000 bacterial pathogens genome-scale rates of evolutionary change in bacteria beast: bayesian evolutionary analysis by sampling trees beast 2: a software platform for bayesian evolutionary analysis the study describes the first sequenced ancient m. tuberculosis genome and shows the presence of mixed infections in 18th century europe the performance of the date-randomization test in phylogenetic analyses of time-structured virus data exploring the temporal structure of heterochronous sequences using tempest (formerly path-o-gen) bayesian analysis of elapsed times in continuous-time markov chains model selection and parameter inference in phylogenetics using nested sampling improving the accuracy of demographic and molecular clock model comparison while accommodating phylogenetic uncertainty relaxed phylogenetics and dating with confidence the study presents a comprehensive y. pestis modern genomic data set from east asia and demonstrates extensive clock-rate variations across the y bayesian coalescent inference of past population dynamics from molecular sequences birth-death skyline plot reveals temporal changes of epidemic spread in hiv and hepatitis c virus (hcv) estimating the basic reproductive number from viral sequence data fast dating using least-squares criteria and algorithms yersinia pestis, the cause of plague, is a recently emerged clone of yersinia pseudotuberculosis insights into the evolution of yersinia pestis through whole-genome comparison with yersinia pseudotuberculosis early emergence of yersinia pestis as a severe respiratory pathogen murine toxin of yersinia pestis shows phospholipase d activity but is not required for virulence in mice role of yersinia murine toxin in survival of yersinia pestis in the midgut of the flea vector retracing the evolutionary path that led to flea-borne transmission of yersinia pestis this study presents a functional description of genes associated with flea-dependent colonization and transmission in y. pestis recovery of the black-footed ferret progress and continuing challenges. united states geological survey scientific investigations report natural history of plague: perspectives from more than a century of research intraspecific diversity of yersinia pestis yersinia pestis in small rodents comparative ability of oropsylla montana and xenopsylla cheopis fleas to transmit yersinia pestis by two different mechanisms human ectoparasites and the spread of plague in europe during the second pandemic silencing and reactivation of urease inyersinia pestis is determined by one g residue at a specific position in the ured gene silencing urease: a key evolutionary step that facilitated the adaptation of yersinia pestis to the flea-borne transmission route advances in yersinia research transmission of yersinia pestis from an infectious biofilm in the flea vector observations on the mechanism of the transmission of plague by fleas metapopulation dynamics of bubonic plague plague dynamics are driven by climate variation predictive thresholds for plague in kazakhstan yersinia pestisetiologic agent of plague the genus yersinia: from genomics to function ecological opportunity, evolution, and the emergence of fleaborne plague this study presents human genome-wide data from the bronze age period that was used to delineate large-scale migrations across eurasia. the same data set was later used for pathogen screening and could show the presence of y. pestis, hbv and b19v in those populations the role of early-phase transmission in the spread of yersinia pestis infectious blood source 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program for annotating and predicting the effects of single nucleotide polymorphisms, snpeff: snps in the genome of drosophila melanogaster strain w1118 six whole-genome assemblies of yersinia pestis subsp. microtus bv. ulegeica (phylogroup 0. pe5) strains isolated from mongolian natural plague foci complete genome sequence of yersinia pestis strain 91001, an isolate avirulent to humans whole-genome sequencing and comparative analysis of yersinia pestis, the causative agent of a plague outbreak in northern peru human plague associated with tibetan sheep originates in marmots thirty-two complete genome assemblies of nine yersinia species, including y. pestis, y. pseudotuberculosis, and y. enterocolitica nine whole-genome assemblies of yersinia pestis subsp. microtus bv. altaica strains isolated from the altai mountain natural plague focus (no. 36) in russia the genus yersinia: from genomics to function complete genome sequence of yersinia pestis strains antiqua and nepal516: evidence of gene reduction in an emerging pathogen genome sequence of yersinia pestis, the causative agent of plague draft genome sequences of yersinia pestis strains from the 1994 plague epidemic of surat and 2002 shimla outbreak in india comparative genomics of 2009 seasonal plague (yersinia pestis) in new mexico complete genome sequences of yersinia pestis from natural foci in china a north american yersinia pestis draft genome sequence: snps and phylogenetic analysis yersinia pestis halotolerance illuminates plague reservoirs mycobacterium leprae genomes from a british medieval leprosy hospital: towards understanding an ancient epidemic characterization of the reconstructed 1918 spanish influenza pandemic virus the authors thank c. warinner for her valuable comments to the manuscript and m. keller for his contributions in assembling comprehensive meta-information for the y. pestis modern genomic data set. in addition, the authors thank all members of the molecular paleopathology and computational pathogenomics groups at the max planck institute for the science of human history for insightful discussions during meetings. moreover, they are grateful to m. o'reilly, h. shell and r. barquera for extensive assistance with the graphics. this work was supported by the max planck society. m.a.s. researched the literature and wrote the article. all authors provided substantial contributions to discussions of the content and reviewed and/or edited the manuscript. the authors declare no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. nature reviews genetics thanks e. willerslev and other anonymous reviewer(s) for their contribution to the peer review of this work. key: cord-293365-z1h788sc authors: semenza, jan c; ebi, kristie l title: climate change impact on migration, travel, travel destinations and the tourism industry date: 2019-04-12 journal: j travel med doi: 10.1093/jtm/taz026 sha: doc_id: 293365 cord_uid: z1h788sc background: climate change is not only increasing ambient temperature but also accelerating the frequency, duration and intensity of extreme weather and climate events, such as heavy precipitation and droughts, and causing sea level rise, which can lead to population displacement. climate change-related reductions in land productivity and habitability and in food and water security can also interact with demographic, economic and social factors to increase migration. in addition to migration, climate change has also implications for travel and the risk of disease. this article discusses the impact of climate change on migration and travel with implications for public health practice. methods: literature review. results: migrants may be at increased risk of communicable and non-communicable diseases, due to factors in their country of origin and their country of destination or conditions that they experience during migration. although migration has not been a significant driver of communicable disease outbreaks to date, public health authorities need to ensure that effective screening and vaccination programmes for priority communicable diseases are in place. population growth coupled with socio-economic development is increasing travel and tourism, and advances in technology have increased global connectivity and reduced the time required to cover long distances. at the same time, as a result of climate change, many temperate regions, including high-income countries, are now suitable for vector-borne disease transmission. this is providing opportunities for importation of vectors and pathogens from endemic areas that can lead to cases or outbreaks of communicable diseases with which health professionals may be unfamiliar. conclusion: health systems need to be prepared for the potential population health consequences of migration, travel and tourism and the impact of climate change on these. integrated surveillance, early detection of cases and other public health interventions are critical to protect population health and prevent and control communicabledisease outbreaks. travel medicine will increasingly see the health consequences of significant changes associated with global change, particularly climate change and socioeconomic development. together these changes mean more opportunities for people to travel to pathogen-endemic countries and for pathogens to be imported to new locations, with the potential for unexpected communicable disease cases and outbreaks. moreover, people who migrate or are displaced can also be at increased risk for chronic disease and mental health issues. thus, travel medicine needs to take a broader perspective than just asking patients where they are going or where they have been, considering how the ongoing and projected shifts in the magnitude and pattern of disease could affect the health and well-being of individuals and populations. modifications to the approaches used by health systems to manage adverse health outcomes are needed to ensure health care providers have the most up-to-date information. migration describes the movement of a person away from their usual residence whereas travel describes a person who passes from place to place, for any reason. migration and travel have shaped the history of humanity and enriched societies economically, socially and culturally. multiple and interacting factors drive migration in particular. climate change, including increasing climate variability, can be one of these factors. we discuss the potential impacts of climate change on migration and travel and the implications for travel medicine and public health practice. following a brief review of climate change, we discuss the potential health implications of migration and travel and the way in which they are affected by climate change and provide suggestions for health systems to better manage the potential impact of climate change, migration and travel on population health. the intergovernmental panel on climate change special report on warming of 1.5 • c concluded that human activities have caused ∼1.0 • c of global warming since pre-industrial times and that, if it continues to increase at the current rate, warming is likely to reach 1.5 • c between 2030 and 2052. 1 the special report concluded that climate change is increasing, and will continue to increase, land and ocean temperatures and the frequency, intensity and duration of heat waves in most land regions (high confidence). it also concluded that climate change will continue to increase the frequency and intensity of heavy precipitation events globally and the risk of drought in the mediterranean region specifically (medium confidence). climate change is a long-term process, but the extent to which individual weather events are influenced by climate change can increasingly be estimated. 2, 3 migration the greatest human migration started 60 000 or 70 000 years ago when homo sapiens left africa for other parts of the world 4-7 ; a series of 'mega-droughts' may have contributed to this. [6] [7] [8] migration has continued since and has become a defining characteristic of our times, affecting every inhabited continent. migrants may move internally, settle in neighbouring countries or move to other continents. currently, europe, north america and oceania are the main destinations for migrants although, overall, europe and asia have received the greatest number of migrants in recent decades. 9 migration has political, social, economic, cultural, environmental and public health implications. migrants generally contribute more in taxes and social contributions than they receive in benefits. [10] [11] [12] [13] but migration can also pose chal-lenges, particularly when there is a rapid influx of large numbers of people. the international importance of migration was recognized in 2015 by the united nations general assembly when the 2030 agenda for sustainable development was adopted; 11 of the 17 sustainable development goals (sdgs) directly or indirectly relate to migration 14 (table 1 ). in 2016, the united nations general assembly adopted the new york declaration for refugees and migrants to support a comprehensive approach to migration. these international accords were also thematically linked to other major international agreements, including the sendai framework for disaster risk reduction and the paris agreement under the united nations framework convention on climate change. 15 ,16 the drivers of migration are complex and include political, economic, social, cultural and environmental factors (figure 1 ). these same factors can determine whether migration is permanent or temporary. the drivers of migration can be grouped into five categories 17-19 : 1) push factors that force people to migrate including war, unemployment, food scarcity, over-population or prosecution. 2) pull factors that attract people to a new destination including work and educational opportunities, political or religious freedom. 3) network drivers that facilitate the migration process such family ties, social support, kinship, safety and feasibility of transport. 4) national policies that allow or prohibit migration. 5) personal aspirations and motivations. these drivers are often interconnected and situation specific ( figure 1 ). they can also interact with climate change, which can itself be a trigger for migration ( figure 2 ). 20, 21 although environmental drivers do not appear to have been the most significant contributor to international migration to date, 22, 23 migration in response to the consequences of climate change can be a pragmatic adaption strategy that balances the risks of staying and the risks of moving. 20, [24] [25] [26] [27] for example, for the tonga-speaking people in southern zambia, migration is an adaptation strategy to climate variability when the availability of water affects both agricultural production and livestock survival. 28 additional warming of 0.5 • c is projected to further exacerbate climate-related drivers of migration; studies suggest that an increase in extreme weather and climate events and disasters associated with climate change could trigger an increase in migration. [29] [30] [31] [32] climate change impacts on migration and health. the complex and multiple drivers of migration mean that it is difficult to attribute specific migrations to climate change (figures 1 and 2) . as a result, projections of migration associated with climate change vary widely, ranging from 50 million to 200 million, with these numbers based on extrapolations. 27, 33 in 2018, a world bank report on the impact of climate change on migration estimated that by 2050-in just three regions-climate change could force more than 143 million people to move within their countries. 34 table 2 summarizes the world bank findings from three case studies in sub-saharan africa (ethiopia), south asia (bangladesh) and latin america (mexico). evidence for the possible role of climate change on migration comes from different sources (figure 1 and 2) . these include studies of the extent to which 'temperature and precipitation' are associated with out-migration. for example, in recent decades, temperature had a statistically significant effect on out-migration from agriculture-dependent countries. 35 there is a nexus between climate change and migration in that temperature and precipitation are positively associated with migration: a 1 • c increase in average temperature in the sending country is associated with a 1.9% increase in bilateral migration flows; an additional millimeter of average annual precipitation is associated with an increase in migration of 0.5%. 36 another study suggests that an increase in precipitation anomalies from the long-term mean may also be associated with an increase in out-migration. 37 under a moderate climate change scenario, if global mean temperature rises by 2 • c, tropical populations would have to move considerable distances in order find places where temperatures are similar to those in places they currently live in and to preserve their annual mean temperatures. 38 'extreme weather events' linked to climate change, such as heat waves, droughts, storms, floods and wildfires, cause shortterm population displacement ( figure 2 ). in 2017, disastersmost of which were related to extreme weather-displaced 18.8 million people in 135 countries ( figure 3 ). 9 in 2018, california only low-income countries show marked increases in population under spp4. b the higher number of climate migrants under the more climate-friendly scenario in ethiopia is in part driven by the regional climate models, which project lower water availability by 2050 in general compared with the other two scenarios (pessimistic reference and more inclusive development scenarios), which are coupled with higher emissions. experienced the most destructive wildfire season on record with more than 81,000 people being evacuated from their homes. 39 a number of factors led to these fires, including accumulated natural fuel and compounding atmospheric conditions that were linked to climate change. 40 based on the experience of other events in the usa, some people will eventually return to their communities, but others will permanently relocate. for example, following hurricane katrina, it was estimated that between 37% and 54% of the population returned, 41 with young adults being more likely to have moved further away. 41 ,42 in 1992, after hurricane andrew in florida, 76% of displaced residents relocated within the same county, 18% moved within the state and 6% moved out of state. 43 in some cases, extreme weather events can cause longerterm migration. for example, an increase in the frequency and intensity of droughts in tanzania has killed livestock and forced the maasai people to migrate from rural to urban settings, with documented implications for their mental health. 44 similarly, prior to the syrian migrant crisis in 2015, the fertile crescent was affected by a severe and sustained drought associated with anthropogenic increases in greenhouse gas emissions 45 and this, combined with unsustainable agricultural and environmental practices, contributed to internal migration, political instability and conflict and eventually to an exodus of one million migrants to europe. 46 'river flooding and erosion' has adversely affected agriculture in bangladesh and resulted in population migration to india ( figure 2 ). 47 climate change models project an increased frequency and likelihood of severe storms, with implications for sea level and flooding, in the ganges-brahmaputra-meghna delta, and this is likely to displace a large number of people. 48 in pakistan, the adverse economic impact of heat waves on agricultural and non-agricultural activity has increased outmigration. 49 in contrast, flooding in pakistan was not associated with significantly increased migration, possibly due to the larger scale of the response by relief agencies to floods compared with heat waves. 49 in other regions, food scarcity due to flooding has contributed to internal migration. in 2018 in mali, flooding destroyed fields, damaged grain stores and impeded livestock production and, as a result, an estimated 4.6 million people are food insecure and 77 000 internally displaced. 'gradual changes' due to climate change, such as changing rainfall patterns, rise in sea level, increased salinization and decreased soil fertility, can also be a driver for migration ( figure 2 ). practice. migration has implications for health and public health practice. 50, 51 migrants can be exposed to health risks in their country of origin and country of destination (figure 2) 52 ; they may be particularly at risk during their journey, due to lack of shelter, exposure to harsh climatic conditions, heat and overcrowded, inadequate transit and detention centres. 53 public health interventions need to target migrants in all of these settings, and especially during migration, in order to minimize associated health risks (figure 2) . sudden displacement because of a disaster or other event can be very stressful and manifest in post-traumatic stress disorders, depression or anxiety that can continue for months or even years. 54 other factors that can affect the mental health of migrants include family separation, acculturation, job insecurity, restricted mobility, dangerous border crossings, stigmatization and marginalization. 55 stress is associated with higher rates of depression and anxiety disorders in the short term and with cardiovascular disease in the longer term. [56] [57] [58] epidemic intelligence data from the european centre for disease prevention and control (ecdc) suggests that migration is a relatively infrequent driver of communicable disease threat events in europe, compared with travel and tourism. 59, 60 there was no evidence during the 2015 migrant crisis in europe that migrants posed a risk to european union citizens from communicable diseases, 61 and despite the barriers to accessing immunization that migrants experience, the contribution of migrants to the current measles outbreaks in europe is minimal. 62 however, migrants may be at increased risk of communicable disease due to exposure or conditions during migration and in the country of destination (table 3) . 29, 61, 63, [64] [65] [66] [67] for example, there is evidence that tuberculosis transmission occurs on migration routes to europe, including during long-term stays in refugee camps. 68 overcrowded and inadequate refugee camps, detention centres and housing can spread vectors (e.g. lice and fleas) that transmit diseases such as relapsing fever, trench fever and epidemic or murine typhus. 61 poor and overcrowded living conditions can also increase the risk of respiratory diseases, such as seasonal influenza. 69 migrants living in overcrowded conditions with poor sanitation may also be at risk of cholera outbreaks. 70 overcrowding, poor sanitation and limited access to health services can also facilitate the emergence of antimicrobial resistance (amr) among migrants, particularly refugees and asylum seekers. 71 migrants may be at increased risk of communicable disease in their country of destination due to factors including lack of vaccination, low socioeconomic status and poor living conditions and limited access to health care (table 3) . 69 recent evidence from the european union (eu) and the european economic area (eea), based on cd4 cell counts and hiv-rna trajectories from seroconversion also suggests that migrants may be at risk of hiv transmission in their country of destination; two-thirds of a sample of hiv-positive migrants from sub-saharan africa, latin america and the caribbean acquired their hiv infection in the country of destination. 72 essential public health measures include ensuring adequate living conditions, access to health care in refugee camps, detention centres, screening for communicable diseases and assessment offer serological screening and treatment (for those found to be positive) to all migrants from countries of high endemicity in sub-saharan africa and focal areas of transmission in asia, south america and north africa. offer serological screening and treatment (for those found to be positive) for strongyloidiasis to all migrants from countries of high endemicity in asia, africa, the middle east, oceania and latin america. offer vaccination against mmr to all migrant children and adolescents without immunization records as a priority. offer vaccination to all migrant adults without immunization records with either one dose of mmr or in accordance with the mmr immunization schedule of the host country. offer vaccination against diphtheria, tetanus, pertussis, polio and hib a (dtap-ipv-hib) to all migrant children and adolescents without immunization records as a priority. offer vaccination to all adult migrants without immunization records in accordance with the immunization schedule of the host country. if this is not possible, adult migrants should be given a primary series of diphtheria, tetanus and polio vaccines. see table 5 for details. cxr means chest x-ray; ltbi, latent tb infection; tst, tuberculin skin test; igra, interferon-gamma release assay; mmr, measles/mumps/rubella. source: ecdc. public health guidance on screening and vaccination for infectious diseases in newly arrived migrants within the eu/eea. https://ecdc.europa.eu/sites/portal/files/documents/public%20health%20guidance %20on%20screening%20and%20vaccination%20of%20migrants%20in%20the%20eu%20eea.pdf. vaccination against hib is only recommended to children up to five years of age. of vaccination status on arrival in countries of destination (table 4 ). available evidence shows that it is cost-effective to screen child, adolescent and adult migrants for active and latent tuberculosis, hiv, hepatitis c, hepatitis b, strongyloidiasis and schistosomiasis (table 3) . 73 targeted hiv prevention, testing and treatment programmes are also required in countries where migrants are at risk of hiv acquisition after arrival. there is also a clear benefit from ensuring that migrants are included in vaccination programmes and providing catch-up vaccinations where needed (table 5) . particular attention should be given to vulnerable children, women and the elderly, who might also suffer from non-communicable diseases, such as cardiovascular diseases, diabetes, cancer, chronic lung diseases, mental health 74 and trauma. sudden migration can result in complications from noncommunicable diseases if treatment and care are discontinued or if access to medications is interrupted. these conditions can cause a life-threatening deterioration and acutely exacerbate preexisting conditions in the event of sudden migration (table 6 ). travel, including for business and tourism, has increased dramatically in recent decades. globally, in 2017, commercial airlines carried more than 4 billion passengers; this is projected to have risen to 4.4 billion in 2018 and to continue to increase in the coming years. 75 air travel contributes to greenhouse gas emissions and, hence, to climate change. at the same time, the effects of climate change on tourism assets, such as biodiversity, coral reefs, glaciers and cultural heritage, are leading to an increase in 'last chance' travel to destinations before they are further degraded. [76] [77] [78] for example, in the southern hemisphere, sea level is projected to rise by 30-150 cm by the end of this century, submerging much of the maldives. 79 in northern latitudes, climate change is already having an adverse impact on the winter tourism industry in lapland and may make it impossible to maintain its snowcovered winter wonderland in future. 80 in many ski resorts, artificial snowmaking, which has high energy costs, is increasingly being used to supplement natural snow, to improve reliability and to extend the season. climate change can be a factor in creating conditions suitable for vector-borne disease transmission. importation of pathogens from endemic areas can then result in the subsequent spread of these diseases under suitable climatic conditions. extended seasonal transmission seasons due to climate change can also increase the window of opportunity of pathogen importation. climatic suitability, including lower and upper temperature thresholds, affects the growth, abundance and survival of mosquito vectors such as aedes aegypti and aedes albopictus that can transmit dengue, zika and chikungunya. in europe, a warmer climate appears to be associated with more frequent outbreaks of dengue and chikungunya 81 are projected to become more suitable for onward transmission of the chikungunya pathogen. 82 climate change may have contributed to the explosive spread of zika in brazil. 83 the epidemic was preceded by 'record warmest' climatic conditions, accompanied by a severe drought. 84 the utilization of home water storage containers during the drought might have provided breeding sites for aedes mosquitoes and increased exposure to mosquitoes. virus importation into a susceptible population could then have triggered the epidemic. 83 precipitation, another important environmental factor affected by climate change, also influences the availability of conditions suitable for mosquito vectors. for example, heavy rainfall increases the abundance of a. albopictus and, hence, the risk of transmission of dengue and chikungunya. 85 climate change can increase the risk of other vector-borne diseases, including tick-borne and rodent-borne infections, 85 and can also influence the range, seasonality and incidence of water-borne diseases such as cholera. 86, 87 global air travel may facilitate the spread of 'resistant pathogens'. for example, it is thought to have facilitated the rapid dissemination of methicillin-resistant staphylococcus aureus from the uk and north america across europe and then to asia. 88 vancomycin-resistant enterococci and klebsiella pneumoniae carbapenemase-producing k. pneumoniae followed a similar trajectory. 88 the burden of antibiotic resistance in destination countries can also be exacerbated by climate change, because an increase in ambient temperature is associated with a significant increase in antibiotic resistance for common pathogens, including k. pneumoniae and s. aureus. 89 it is hypothesized that temperature accelerates horizontal transfer of resistance genes or the uptake of genetic material. ambient temperature may also facilitate environmental growth of resistant strains and enhance transmission from food, agriculture and environmental sources. 89 climate change impacts on travel: implications for public health practice. air travel can facilitate the spread of communicable diseases around the globe. passenger volume has been identified as a significant driver of the importation of viremic passengers. 90, 91 flights directly connect millions of passengers between europe and asia, africa, north america and south america, with many of these locations 'hot spots' for the emergence of communicable diseases. 92 a disease outbreak in one part of the world can quickly spread to another part via air travel. 59, 60 for example, in-flight transmission of severe acute respiratory syndrome (sars) in 2003 resulted in the rapid spread of sars-associated coronavirus (sars-cov) around the world. 93 international air travellers departing from mexico in 2009 unknowingly carried and disseminated the novel influenza virus a(h1n1)v around the world. 94 similarly, air transport networks contributed to the spread of middle east respiratory syndrome from saudi arabia in 2012, chikungunya dispersion in the americas in 2013, ebola from west africa in 2014 and zika spread in the americas in 2015. [95] [96] [97] [98] more specifically, air travel can increase the risk of importation of pathogens from endemic areas into regions with competent mosquito vectors and suitable climatic and environmental conditions for vector-borne diseases. 90 dengue, a mosquito-borne viral disease, is a significant public health concern, threatening almost half of the world's population. 99 table 5 . vaccinations to be offered to migrants in the absence of documented evidence of prior vaccination within the eu/eea 64 priority vaccinations mmr administer to individuals ≥9 months of age. two doses of mmr a should be administered at least 1 month apart but preferably longer according to national guidelines. measles vaccine provided before 12 months of age does not induce protection in all and should be repeated after 12 months of age. loss of access to medication or devices, loss of prescriptions, lack of access to health care services leading to prolongation of disruption of treatment degradation of living conditions loss of shelter, shortages of water and regular food supplies and lack of income add to physical and psychological strain interruption of care due to destruction of health infrastructure, disruption of medical supplies and the absence of health care providers who have been killed, injured or are unable to return to work interruption of power supplies or safe water life-threatening consequences, especially for people with end-stage renal failure who require dialysis source: http://www.euro.who.int/en/health-topics/health-determinants/migration-and-health/migrant-health-in-the-european-region/migration-and-health-key-issues#292932 transmission occurs largely in tropical and sub-tropical regions, but outbreaks have occurred in europe around the mediterranean where a. albopictus is present. 100 infected air passengers from endemic areas can arrive in europe during their viremic period, be bitten by local mosquito vectors and transmit the dengue virus locally and trigger an outbreak due to a warming climate. 81 other means of transport are also implicated in the spread of disease-causing pathogens. for example, ballast from cargo ships played a role in moving pathogenic vibrios to new locations that were environmentally and climatically suitable, even in northern latitudes. 101 travel and tourism can also facilitate the importation of pathogens from developed countries with low vaccination coverage, to developing countries with high rates of susceptible individuals due to lack of health care access. 102, 103 responding to the public health challenges associated with travel and climate change requires robust national surveillance systems, including effective tracking of vector location and disease importation. 104 integrated surveillance of invasive and endemic mosquito species is crucial for effective prevention and control of vector-borne diseases. 104 early detection of outbreaks can be aided by seasonal surveillance in areas where competent vectors are active and in close proximity to airports with a large influx of passengers from endemic areas. 90 for example, the risk of dengue importation can be described by a model that relates air travellers from dengue-affected areas to dengue importation. 90 this approach can delineate in space and time where the risk is the highest, and target seasonal surveillance to high-risk areas, for early case detection and intervention. an important consideration when projecting risk of disease transmission associated with climate change and travel is that the timing of risks may be under-estimated, i.e. transmission may occur sooner than models suggest. for example, the modelled future environmental suitability of a. aegypti in the contiguous usa in the period 2061-2080 projects potential suitability in southern areas of mid-western states, such as illinois, indiana and ohio. 105 however, breeding colonies of a. aegypti were found in ontario in southern canada in 2017, indicating that the risk of transmission of diseases such as dengue fever and zika may occur earlier than the projections suggest. 106 the importation and spread of tropical pathogens in temperate regions due to climate change is another aspect to consider for public health practice. it is a potential threat to the safety of the blood supply and, hence, of blood transfusions, particularly with respect to pathogens for which there are no diagnostic tests. [107] [108] [109] [110] [111] expansion of areas with an increased risk of communicable diseases due to climate change also increases the risk of blood bank contamination with communicable pathogens as a higher number of prospective blood donors are exposed to potential infections for a longer period, e.g. if climate change alters the length of the annual mosquito activity season. 107 moreover, the asymptomatic phase of many infections, even if it is relatively short, increases the potential for transmission by transfusion. 112 climate change projections of the probability of infection should therefore be used for preparedness activities. in addition, certain pathogens, such as the west nile virus, can persist in stored blood components and subsequently cause infection through intravenous application. pathogen reduction technology that inactivates pathogens in donated blood is a strategy that could be used for pre-emptive risk reduction. 108 the world is warmer today than in pre-industrial times, and warming is projected to continue. the frequency, duration and intensity of extreme weather events have increased, with implications for migration in particular. global warming is associated with migration from farming communities and from small islands and coastal areas. evidence of climate change impacts on migration in other settings is less clear. the combined impact of travel and climate change can favour the importation, establishment and spread of tropical diseases in temperate regions. these developments require public health action, including targeted and culturally appropriate interventions and novel technologies, to prevent and control emerging health threats associated with the interaction between climate change, migration and travel. it calls for training of health care professionals to provide appropriate health care (prevention, screening, and treatment) for migrants and for risk assessment of diseases among travellers/ tourists. adequate living conditions, screening and vaccination programmes, and medical interventions for migrants can prevent outbreaks of communicable diseases and the spread of resistant pathogens. assessment and interventions also need to encompass chronic conditions, mental health and trauma due to migration. targeted hiv prevention, testing and treatment programmes are also required in countries where migrants are at risk of hiv acquisition after arrival. effective national surveillance systems that include tracking of vector location and disease importation can inform targeted prevention and control interventions. novel approaches including modelling the arrival of air passengers into environmentally and climatically receptive areas, to improve assessment of the risk of importation of pathogens from endemic areas, and assessment of climatic suitability, can inform seasonal surveillance or active case finding. specific measures may be required to ensure blood safety, including pathogen reduction technology, where there is a risk of the importation and spread of tropical pathogens in temperate regions. the authors report no financial interests or connections, direct or indirect or other situations that might raise the question of bias in the work reported or the conclusions, implications or opinions stated-including pertinent commercial or other sources of funding for the individual author(s) or for the associated department(s) or organization(s), personal relationships or direct academic competition. j.c.s. wrote the first draft of the paper. both authors approved the final paper. herein are the authors' own and do not necessarily state or reflect those of ecdc. ecdc is not responsible for the data and information collation and analysis and cannot be held liable for conclusions or opinions drawn. we should like to thank wei-yee leong from the lee kong chian school of medicine, nanyang technological university, singapore for her help with the figures. none declared. an ipcc 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diseases in europe the potential impacts of 21st century climatic and population changes on human exposure to the virus vector mosquito aedes aegypti county health unit. aedes aegypti mosquito climate change projections of west nile virus infections in europe: implications for blood safety practices blood supply under threat emerging infectious threats to the blood supply emerging infectious diseases that threaten the blood supply current perspectives in transfusion-transmitted infectious diseases: emerging and re-emerging infections emerging infectious disease agents and their potential threat to transfusion safety we would like to thank the editor and the three anonymous reviewers for detailed and constructive feedback on the manuscript. we also appreciated the insightful comments and suggestions from teymur noori, pontus naucler and senia rosales-klintz at ecdc. the views and opinions expressed key: cord-353775-ogb56xg9 authors: palomino, juan c.; rodríguez, juan g.; sebastian, raquel title: wage inequality and poverty effects of lockdown and social distancing in europe date: 2020-08-11 journal: eur econ rev doi: 10.1016/j.euroecorev.2020.103564 sha: doc_id: 353775 cord_uid: ogb56xg9 social distancing and lockdown measures taken to contain the spread of covid-19 may have distributional economic costs beyond the contraction of gdp. here we evaluate the capacity of individuals to work under a lockdown based on a lockdown working ability index which considers their teleworking capacity and whether their occupation is essential or closed. our analysis reveals substantial and uneven potential wage losses across the distribution all around europe and we consistently find that both poverty and wage inequality rise in all european countries. under four different scenarios (2 months of lockdown and 2 months of lockdown plus 6 months of partial functioning of closed occupations at 80%, 70% and 60% of full capacity) we estimate for 29 european countries an average increase in the headcount poverty index that goes from 4.9 to 9.4 percentage points and a mean loss rate for poor workers between 10% and 16.2%. the average increase in the gini coefficient ranges between 3.5% to 7.3% depending on the scenario considered. decomposing overall wage inequality in europe, we find that lockdown and social distance measures produce a double process of divergence: both inequality within and between countries increase. the dramatic and unprecedented intensity of the shock due to the covid-19 pandemic has highlighted the importance of measuring the economic consequences of "social distancing". the lockdown measures implemented in many countries around the world will likely have a significant negative impact on their gdp. thus, the global economy is expected to shrink by 3% this year. asia will not have economic growth for the first time in 60 years, the economies of the us and europe are projected to contract between 8% and 13% (imf, 2020) , and the global job losses are estimated to be over 200 million (ilo, 2020) . however, the effect of the pandemic will not only take place at the aggregate level and is likely to have distributional implications (furceri et al., 2020) . the social distancing imposed by governments to limit the spread of the pandemic has caused an asymmetric effect on the labour market: discounting essential occupations like health services and food sales, only the jobs not closed by the lockdown that can be done from home ("teleworkable") will be not impeded. this asymmetry of the supply shock implies that the economic costs of social distancing could be significant, not only in terms of negative gdp growth rates but also in terms of higher wage inequality and poverty rates. in this paper, we analyse the potential effects of social distancing on wage inequality and poverty in absence of any compensating public policy across europe. recent studies have provided estimates of the supply shock caused by the emergency regulation imposed to contain the spread of covid-19 (dingel and neiman, 2020; hicks, 2020) . they have evaluated the possible economic consequences of social distancing -without considering the subsequent effects that may occur on the demand side-by calculating to what extent occupations can be performed from home (teleworking). mongey et al. (2020) find that workers with less ability to work from home have been indeed more unable to follow the 'stay at home advice' -using geolocation data-and that they have suffered higher unemployment increases. studies focused on the demand side have shown that, due to fear of infection, economic activity dropped and individuals changed their consumption habits even before lockdown was formally imposed (goolsbee and syverson, 2020) . in a more comprehensive analysis, del rio-chanona et al. (2020) provide quantitative predictions of supply and demand shocks associated with the covid-19 pandemic. these studies, mainly focused on the u.s. economy, have analysed the consequences of social distancing in the job market, at the occupation and industry levels, without delving into the study of poverty and inequality. we find two exceptions. first, irlacher and koch (2020) obtain a substantial wage premium (higher than 10%) in a mincer regression for german workers performing their job from home, and a lower share of teleworkable occupations in poorer german regions. second, brunori et al. (2020) study the short-term effects that two months of lockdown have had on the italian income distribution. by using a static microsimulation model, they find a non-negligible increase of poverty and inequality in italy. to estimate the impact of social distancing on wage inequality and poverty across europe, we concentrate on the legal restrictions (supply side) due to the closure of non-essential occupations and workers not being able to perform their activities at home during the lockdown period. additionally, we consider a range of scenarios with further partial closures of certain activities, caused by mandatory capacity limitations and by the change in individual consumption habits to prevent contagion. despite its relevance, our analysis does not consider additional indirect effects in supply (as shortages propagate through supply chains) and in demand (when the loss of labour income for some workers further reduces consumption). these effects are difficult to estimate at this early stage, and the legal and voluntary restrictions imposed to prevent the spread of the pandemic already provide a clear framework to study the consequences for inequality and poverty of having a particular productive structure. under a lockdown, the asymmetry of the restrictions may affect economies in a different way just because their productive structure is not the same: countries who are specialised in outdoor and non-essential activities like tourism will, in principle, suffer more from the lockdown and the capacity limitations. we thus restrict ourselves to measuring the potential impact on wage inequality and poverty of enforced and voluntary social distancing. in general, if occupations with higher wages are more teleworkable, we should observe an increase in wage inequality due to lockdown and the implementation of social distance measures within each country analysed. however, whether this happens, and the intensity of this change, will depend on the structure of the economy and the extent of essential and closed occupations under the lockdown. the wide set of european countries in our sample -with a variety of productive structures-will also allow us to test if different productive structures imply different potential effects on wage inequality and poverty under lockdown and social distancing. note that if that is the case, inequality would not only increase within countries, but also between nations, which could exacerbate the problem of cohesion in europe. the first step to measure the changes in wage inequality and poverty across europe due to lockdown is to calculate the index of teleworking at the occupational level. dingel and neiman (2020) found that 37 percent of jobs in the united states can be done entirely from home. what is the share of occupations that allow teleworking in europe? following these authors, we use fifteen questions from the occupational information network (o*net) database such as, 'is the work done outdoors?' or, 'does it require significant physical activity?' to calculate the probability of teleworking for each occupation. we then use the 2018 european union labour force survey (eu-lfs) occupational structure to translate these probabilities into the european context. finally, we match the eu-lfs occupation teleworking index and the 2018 european union statistics on income and living conditions (eu-silc), which provides detailed information on wage at the individual level. after this process, we have for every worker in the eu-silc database the individual index of teleworking (according to her occupation) and the wage. a lockdown implies that some activities -like healthcare or food chain related jobs-will become essential while others will be closed. when the occupation is essential, workers will be not affected by lockdown regardless of their capacity to work from home. when a certain economic activity is closed -like hospitality-working is not at all possible. for the remaining economic activities, only teleworking is allowed. consequently, during the lockdown we need to adjust our index of teleworking for the workers whose occupation is essential or closed, to obtain an individual measure that summarizes the capacity of each worker to keep active under the lockdown. we will call this measure lockdown working ability (lwa) index. the next step is to estimate the wage loss due to the lockdown. because not all workers are able to perform their job at home and some activities are closed or limited (or less demanded to avoid infection), there are potential wage reductions for a significant part of the labour force. to simulate these wage losses, we consider four possible scenarios: two months of lockdown and two months of lockdown plus six months of only partial functioning of the closed activities at 80%, 70% and 60% of capacity. in addition, we consider in appendix e another three scenarios where partial functioning of closed occupations −at 80%, 70% and 60% of full capacity− lasts for nine months. with these proposals we intend to measure not only the effect of the lockdown, but also the impact of the de-escalation period imposed to contain the spread of covid-19. although each european country may have followed slightly different lockdown and deescalation strategies, the core of the social distancing enforcing policies has been similar in most of them. for that reason, and to ensure that in our analysis differences across countries are mainly due to their productive structure, we simulate the same scenarios for all european countries. the last step is to measure the changes in wage inequality and poverty across countries, and the variation of wage inequality between and within-countries due to the lockdown. for this task, we first compute the lockdown incidence curve (lic), which represents the relative change in the wage of individuals ordered by centiles, and the related changes in the mean 'growth' rate of the poor (ravallion and chen, 2003) and headcount poverty index. then, we use the gini coefficient and the mean logarithmic deviation (mld) to calculate the changes in wage inequality. the first measure is a popular index of inequality which is widely used in the literature, while the second measure fulfils some properties which are necessary for our analysis of inequality decomposition. in particular, the mld is the only inequality index that is additively decomposable into a between-group and a within-group component (bourguignon, 1979; shorrocks, 1980) and has a path-independent decomposition (foster and shneyerov, 2000) . our results show that poverty increases for the headcount index and the mean loss rate of the poor in all countries for all simulations, although these changes vary greatly with the country and simulation under consideration. for the four simulated scenarios, we estimate for 29 european countries an average increase in the headcount poverty index that goes from 4.9 to 9.4 percentage points and a mean loss rate for the poor that goes from 10% to 16.2%. likewise, wage inequality increases for the gini coefficient in all countries for all simulations. for example, the average increase in the gini coefficient varies between 3.5% and 7.3% for europe as a whole. we thus find that poverty and inequality changes are sizeable in all countries and they increase with the duration of the lockdown. when we decompose overall inequality in europe, both within countries and between countries inequality increase, producing a double process of divergence in wage inequality in europe. but this increase in wage dispersion is not symmetric, and the within-countries inequality component increases more than the betweencountries inequality component. thus, the increase in the within-countries inequality component ranges from 5.0% to 12.1%, while the change in the between-countries inequality component goes from 2.5% to 4.0%, depending on the scenario under consideration. the observed increases in poverty and inequality are in general greater in eastern and southern countries than central and northern countries and are inversely related to the lwa index. to further understand these differences across european countries we need to analyse separately the three components of the lwa index: teleworking and essentiality (which increase the working ability of occupations during the lockdown), and closure (which implies a lower working ability during the lockdown and subsequent de-escalation periods). we observe that the occupational and industry structure of eastern european countries presents, in general, medium average levels of closure, but low average levels of essentiality and teleworking. on the contrary, northern and central european countries show large values of essentiality and teleworking, and low average levels of closure. meanwhile, workers in southern european countries have medium average levels of essentiality, rather low levels of teleworking and, especially, the highest average levels of closure, due to the large preponderance in their productive sector of activities that imply the agglomeration of large groups of people like recreation or hospitality. the rest of the paper is structured as follows. in section 2 we present the lwa index and the methodology applied to calculate the wage losses and changes in inequality and poverty. in section 3 we highlight the main results obtained for europe. finally, section 4 concludes. to analyse the working ability of individuals during the lockdown, we need first to estimate occupational teleworking. for this task we use three different databases (see appendix a). first, we make use of teleworking information acquired using key attributes and characteristics of occupations from the american o*net database (dingel and neiman 2020) . second, we use the latest 2018 wave of eu-lfs (2020 release) -with detailed employment and occupational information for european countries-to accurately obtain occupational teleworking information for the european occupational categories. finally, this information is combined with the rich socioeconomic data -crucially, salaries-from the 2018 wave of eu-silc (2020 release). this strategy, which is explained in detail in appendix a, allows us to calculate the teleworking capacity of european workers. however, teleworking capacity is not the only determinant of workers ability to effectively work and keep their wage during the lockdown period. we need to consider that some having calculated the teleworking index and identified the essential and closed occupations, we construct the lockdown working ability (lwa) index. this measure summarizes the capacity of individuals to work under a lockdown taking into account not only the value of their occupation's teleworking index, but also if such occupation is essential ( ) or closed ( ). the central idea is that workers in essential occupations can work during the lockdown regardless of whether the occupation can be teleworked or not. on the contrary, workers in closed activities cannot work at all to the extent that their overall activity has been closed. in all remaining cases, working capacity will depend on the share of that occupation that can be teleworked. formally, the first step in constructing the lwa index requires to split the population of workers into three groups according to the occupation of each worker ∈ {1, 2, … , }. if the individual has an occupation that is neither essential nor closed, the value of her index will be equal to the value of her index of teleworking, ∈ [0,1]. if the person has an essential job ( = ), we will compute the lwa index as is the essentiality score given to the occupation of the individual. thus, for partially essential occupations (0 < < 1), the non-essential share of the occupation (1 − ) can work during lockdown only to the extent that it is teleworkable. finally, if the person has a job that is closed ( = ), we will calculate the lwa index as = (1 − ) , where ∈ (0,1] is the close score given to the closed occupation of the individual. in partially closed occupations (0 < < 1), the non-closed share of the occupation (1 − ) can work to the extend that is teleworkable. in summary, the lockdown working ability index is calculated as follows: for all ∈ {1, 2, … , }. as shown in figure 1 , the average lwa index varies significantly across european countries: our lwa index varies significantly not only by countries but also by gender, type of contract −permanent or temporary−, type of work −full or part time−, and level of education (see table 1 ). according to their lwa index, women jobs are less affected by social distancing than men jobs in all european countries. interestingly, the biggest difference between both sexes is found in the nordic countries: norway (23 points), denmark (22 points the next step is to calculate the potential wage loss due to the lockdown for every individual in the population. following the facts observed in europe during the pandemic, we adopt four possible scenarios. as a lower bound, we assume a simple scenario: two months of lockdown (case i). 4 here we suppose that occupations can be developed at full capacity (100%) after the lockdown. next, we assume two months of lockdown and six months of partial functioning of closed occupations at 80% (case ii), 70% (case iii) and 60% (case iv) of full capacity. the rationale for these scenarios is that governments may not allow a fully functioning of closed occupations after the lockdown to avoid a new outbreak of the virus and that individuals may voluntarily choose to stay home, which reduces their consumption, to avoid infection (goolsbee and syverson, 2020) . for example, some activities like arts, entertainment, recreation, restaurant, hotel and transportation are still under a large negative shock in production and consumption. 5 consequently, to be more informative we have adopted a range of capacity constraints that goes from 100% to 60% of full capacity for a period of six months. in addition, given the uncertainty about the duration of legal and voluntary restrictions, in appendix d we have further replicated our results for another three scenarios where partial functioning of closed occupations −at 80%, 70% and 60% of full capacity− lasts for nine months instead of six. we simulate the same scenarios for all countries so that differences across countries are mainly due to their distinct productive structures, isolating our analysis from the influence of particular mitigation measures adopted by each european government. using the lwa index, we calculate the wage loss ( ) experienced by every individual during the lockdown according to the four simulated scenarios described. for the first case (i) the equation we estimate is the following: where −1 is the annual wage of individual in period − 1 (before the lockdown) and represents the duration of the lockdown in annual terms, i.e., = 2 12 . because measures the capacity of individual to work under a lockdown, the term 1 − represents the incapacity of worker to perform their job under a lockdown. consequently, the wage loss 4 the duration of the lockdown in many european countries has been approximately of two months. for example, the lockdown went from the 23rd of february to the 3th of may in italy, from the 15th of march to the 4th of may in spain, and from the 17th of march to the 11th of may in france. 5 for these activities chetty et al. (2020) have found, as of july 08 th 2020, a decrease in spending compared to the pre-lockdown levels in the range of between 32.9% and 48.3% in the us. based on weekly credit card expenditure data, bbva research (2020) has found, as of july 12 th 2020, a negative interannual growth rate for these spending groups ranging between 20% and 40% in spain. experienced by workers under a lockdown is the proportion of annual wage they lose due to their inability to work during the shutdown period. for the cases (ii), (iii) and (iv) we apply the same equation (2) unless the individual has a closed occupation, in which case, we need to additionally consider the wage loss due to the partial closure of 20%, 30% or 40% of their occupation for six (or nine) additional months. for these scenarios the relevant equation is: where 1 = { 1 = 0 ≠ is the indicator function, represents the duration of the partial closure ( 6 12 or 9 12 ), and is the proportion of closure (0.2 for case (ii), 0.3 for case (iii) and 0.4 for case (iv)). to give the intuition of expressions (2) and (3), we provide an example. suppose we are interested in calculating the wage loss for three workers with different occupations under a lockdown of 2 months and a posterior partial closure of some activities of 20% (keeping 80% of capacity) for 6 months. the first worker is a physician, the second works as a clerk and the third one is a waiter. their pre-lockdown ( − 1) annual salaries are 1 −1 , 2 −1 and 3 −1 , respectively. the occupation of the first worker is essential with = 1 so we apply equation (2) to calculate her wage loss: 1 = 1 −1 · 2 12 · 0 = 0, i.e., the doctor does not lose earnings during the pandemic. the second worker has an administrative occupation that in our example is neither essential nor closed so her index is equal to the value of her index of teleworking, for example, 0.7. then, according to equation (2) her wage loss will be 2 = 2 −1 · 2 12 · (1 − 0.7) = 2 −1 · 0.6 12 . finally, the occupation of the third worker is closed with = 1 so the value of her index is 0. in this case, we apply equation (3) closely related to the lic we have the mean loss rate for the poor, a measure that reveals the average wage loss for workers below the poverty line. 8 let ( ) denote the headcount index defined as the proportion of workers whose salary is less than , where is the poverty line (set at 60% of the median wage). then, the mean loss rate for the poor ( ) is defined as the area under the lic up to the headcount index divided by the headcount measure, which can be expressed as: when < 0 for all < ( ) one can conclude that the lockdown was poverty-augmenting. in addition to representing the lics for the set of european countries and compute the above unfortunately, the gini index is not additively decomposable into a between-group and a within-group component. its decomposition includes also a residual term which cannot be assigned to either component. for this reason, we use the mld index in the last part of our analysis, where we decompose the overall estimated change of inequality in europe into its between-countries and within-countries components. the mld belongs to the generalized entropy class, which is the only class of inequality indices that is additively decomposable into a between-group and a within-group component (bourguignon, 1979 and shorrocks, 1980) . moreover, the mld has a path-independent decomposition, so the result of the decomposition is independent of which component (between-group or within-group) is eliminated first (foster and shneyerov, 2000) . the mld ( ) is defined as: where 1 is n-coordinated vector of ones. expression (7) provides a breakdown of overall wage inequality into between-group and within-group terms. the between-group component ( 1 1 1 , 2 1 2 , … , 1 ) is the level of wage inequality that would arise if each worker in a country enjoys the mean wage of the country, and the within-group component ∑ ( ) =1 is the weighted sum of wage inequalities within different countries. how large are the wage losses experienced by workers during the lockdown? are they evenly distributed? a visual approximation to the wage loss across the wage distribution can be achieved by looking at the lic curves. in figure 3 we represent the lics for some european countries under two months of lockdown (case i). 9 we highlight the lic for two extreme cases, romania, and cyprus, where the main wage losses take place at the upper and lower part of the wage distribution ( figure 3 , panel a) and for germany, the uk and france (figure 3, panel b) , where wage losses tend to decrease with the percentile that the worker occupies. in our two-month lockdown scenario, wage losses are already sizeable and can be superior to 10% at some parts of the distribution in some countries, varying significantly with the centile of the workers. also, we find that the shape of the distribution of wage losses is similar for the rest of scenarios and the main difference lies only in the larger size of the wage drops. we formally capture the potential impact of social distancing on poverty with two measures: the mean loss rate for the poor ( ) and the changes in the headcount poverty index ( ). 10 table 2 (columns 2 to 5) shows the values of for the four simulations under consideration, which indicate that the lockdown is poverty-augmenting in the four scenarios for all european countries. under the most conservative scenario, a two-month lockdown, we find a mean loss rate for the poor of 10% for europe on average. if we consider an additional 6-month period of partial functioning of closed activities at 60% of full capacity (scenario iv), the mean loss rate for poor workers in europe increases up to 16% (19% if the period of partial functioning lasts for nine months). by countries, the highest loss rate for the poor is found in cyprus (between 12.3% and 22.4%), while the smallest one happens in romania (between 3.1% and 4.0%). the share of workers under the poverty line also increases significantly for the four simulated cases in all european countries (see table 2 , columns 6-14). 11 for europe on average, this increase varies between 4.9 percentage points under two months of lockdown and 9.4 percentage points if we consider an additional six months during which closed activities are partially functioning at 60%. these values imply that −in absence of compensating policies− the percentage of poor people in europe (those with earnings below 60% of the pre-lockdown median in the country) may substantially increase even if lockdown does not last long. if closed 10 the contribution of growth and redistribution to poverty reduction over the period 1981 to 2010 in 124 countries, including europe, is estimated in bluhm et al. (2018) . the relationship between the components of social mobility (growth, dispersion and exchange mobility) and inequality is estimated for 15 countries of the european union in prieto et al. (2008) . 11 the headcount poverty index gives additional relevant information about the consequences of the pandemic for poverty since this index is not necessarily consistent with the lic (essama-nssah and lambert, 2009). eastern and southern countries than central and northern countries. thus, we find that the highest increase in poverty according to the headcount poverty index is in croatia (between 8.5 and 15.3 points). on the contrary, the smallest percentage increase in poverty according to the headcount index happens in switzerland for case i (2.6 points) and denmark for cases ii (3.7 points), iii (4.1 points) and iv (4.7 points). if we look at the relationship between these changes in the headcount poverty index and the average lwa we find a negative correlation with 2 = 0.35 for the first scenario ( figure 4 , panel a) and 2 = 0.51 for the fourth scenario ( figure c1 , panel a, in appendix c). when we consider the gini of lwa within countries instead of the average lwa the correlation becomes positive with 2 = 0.34 for the first scenario (figure 4 panel b) and 2 = 0.56 for the fourth scenario ( figure c1 , panel b, in appendix c). the uneven distribution of potential wage losses across the distribution is prone to have an impact on wage inequality as well. european countries already have important differences in pre-lockdown inequality (table 3, pre-lockdown wage inequality ( = 25.4) . other countries with low levels of inequality before the lockdown are sweden, czechia, belgium and norway, all of them with a gini index slightly below 0.30. on the other extreme of the spectrum, we find the countries with the highest level of pre-lockdown wage inequality: bulgaria, ireland, the uk and spain, all of them with a gini index above 0.40. when comparing wage inequality after the lockdown with the baseline, it is observed that absolute and relative changes in inequality are sizeable and increase in all countries with the duration of the partial closure of some activities (table 3) . for example, the relative increase of the gini coefficient, at scenario (i), ranges from 2.2% (the netherlands) to 4.9% (cyprus). at the more severe scenario (iv), relative increases in inequality range from 4.9% in france to 10.9% in cyprus (if the period of partial functioning lasts nine months these rates become 7% in france and 15% in cyprus). a scrutiny of the absolute changes in the gini coefficient −which makes the change scale independent of the previous level of inequality− reveals that cyprus is again the european country where inequality increases the most for the four simulation cases (between 1.9 and 4.2 gini points) followed by ireland (between 1.7 and 3.4 points). on the other hand, the smallest absolute change in inequality is found in norway (0.7 points) for scenario (i), in norway and france for scenarios (ii) (1.2 points) and (iii) (1.5 points), and in france and denmark for scenario (iv) (1.8 points). these variations in inequality also tend to be related with the lwa index. in figure 4 given the link between the values of the lwa index and the increases in wage inequality (and poverty), it is not surprising that the observed changes are in general greater in eastern and southern countries than central and northern countries. as mentioned before, northern and central europe present large average levels of essentiality and teleworking, and low average levels of closure. meanwhile, eastern europe shows the opposite pattern, i.e., low average levels of essentiality and teleworking, and medium-high average levels of closure. the partial closure of activities that imply the agglomeration of large groups of people like tourism significantly penalises southern europe, whose countries tend to have the highest average closure scores. while some tertiary jobs like administrative, programmers and accountants are not affected by partial closures, others are strongly impacted by the measures to fight covid-19 and the fears to table 3 . wage inequality changes in europe. note: cl1, cl2 and cl3 refer to partial closure for 6 months at 80%, 70% and 60% of full capacity, 2m is 2 months, and ∆ a g and ∆ r g are the absolute and relative changes in the gini index. bootstrapped standard errors are in parenthesis. be infected: hospitality, restaurants, arts and entertainment. for this reason, the impact on inequality and poverty is also related to the share of these specific tertiary occupations. 12 our findings show an increase in inequality for all european countries but, would inequality changes be different enough to increase inequality between countries? the answer is yes, although they are smaller than the inequality changes occurring within countries. in table 4 we show the results of the decomposition of wage inequality for all european workers. our simulations show an increase in overall inequality in workers' salary of 4.26% in europe (0.423 to 0.441) according to the mld index under a lockdown of two months. for the same scenario, the changes in the between-and within-countries inequality components are 2.46% (from 0.125 to 0.128) and 5.01% (from 0.298 to 0.313), respectively. for two months of lockdown and six months of partial functioning of closed activities at 60% of capacity (scenario iv) we find the following increases in inequality for europe on average: 9.68% in overall inequality, 3.98% in between-countries inequality and 12.07% in within-countries inequality. when the period of partial functioning of closed activities at 60% of capacity lasts nine months the corresponding increases are: 14.00% in total inequality, 4.81% in between-countries inequality and 17.85% in within-countries inequality. both components of overall inequality increase, but the within-countries inequality component increases significantly more than the between-countries inequality component in all scenarios. 13 that is, cohesion between european countries decreases with the lockdown, though the main change in wage inequality happens within european countries. with the partial closure of some activities, changes get larger and the double process of wage divergence (between and within countries) deepens. the emergency measures adopted to contain the spread of covid-19 all around the world are largely based on social distancing and closure of high-risk productive activities. the paralysis of production imposed by the contention measures during the lockdown and the capacity limitations driven by official restrictions and by consumers precautionary behaviour will thus have an uneven impact on workers from different occupations and industries. our analysis reveals a sizable potential increase in poverty and inequality across europe. table 4 . the between-and within-countries inequality components in europe. note: ∆ a is the absolute change in wage inequality and ∆ r (%) is the relative change in wage inequality. standard errors are in parenthesis. poverty will increase under our simulations in all countries. under the most conservative scenario, a lockdown of two months, we estimate a mean loss rate for the poor of 10% and an increase in the headcount index of 4.9 percentage points on average in europe, with the change ranging from 2.6 points (switzerland) to 8.5 points (croatia). likewise, wage inequality increases under a lockdown of two months, being the change in the gini coefficient equal to 3.5% for europe on average, with changes ranging between 2.2% (netherlands) and 4.9% (cyprus). considering a more severe scenario with 6 months of partial closure at 60% of full capacity after a two-month lockdown, we estimate a mean loss rate of 16.2% for the poor workers in overall europe, a rise of 9.4 percentage points in the headcount poverty index and a gini increase of 7.3% on average for europe. our results also highlight that lockdown measures are likely to worsen cohesion in europe both between countries and, especially, within countries. our simulations show that between-countries inequality will increase in europe between 2.46% and 3.98%, while within-countries inequality will increase between 5.01% and 12.07%. in general, we find a greater increase of both poverty and inequality in eastern and southern europe than in northern and central europe. workers tend to have a lower and more unequally distributed ability to work under the shutdown and social distancing in the economies of eastern and southern europe than in the northern and central european countries. these differences across european areas get larger with the severity of the measures to fight and prevent covid-19 infection. impacto de la covid-19 sobre el consumo en españa en tiempo real y alta definición poverty accounting decomposable income inequality measures distant and unequal. lockdown and inequalities in italy how did covid-19 stabilization policies affect spending and employment? a new realtime economic tracker based on private sector data supply and demand shocks in the 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inequality measures an economic definition of poverty an axiomatic characterization of the watts index key: cord-321340-hwds5rja authors: sun, h.; dickens, b. l.; cook, a. r.; clapham, h. e. title: importations of covid-19 into african countries and risk of onward spread date: 2020-05-24 journal: nan doi: 10.1101/2020.05.22.20110304 sha: doc_id: 321340 cord_uid: hwds5rja background the emergence of a novel coronavirus (sars-cov-2) in wuhan, china, at the end of 2019 has caused widespread transmission around the world. as new epicentres in europe and america have arisen, of particular concern is the increased number of imported coronavirus disease 2019 (covid-19) cases in africa, where the impact of the pandemic could be more severe. we aim to estimate the number of covid-19 cases imported from 12 major epicentres in europe and america to each african country, as well as the probability of reaching 10,000 infections in total by the end of march, april, and may following viral introduction. methods we used the reported number of cases imported from the 12 major epicentres in europe and america to singapore, as well as flight data, to estimate the number of imported cases in each african country. under the assumption that singapore has detected all the imported cases, the estimates for africa were thus conservative. we then propagated the uncertainty in the imported case count estimates to simulate the onward spread of the virus, until 10,000 infections are reached or the end of may, whichever is earlier. specifically, 1,000 simulations were run separately under two scenarios, where the reproduction number under the stay-at-home order was assumed to be 1.5 and 1.0 respectively. findings we estimated morocco, algeria, south africa, egypt, tunisia, and nigeria as having the largest number of covid-19 cases imported from the 12 major epicentres. based on our 1,000 simulation runs, morocco and algeria's estimated probability of reaching 10,000 infections by end of march was close to 100% under both scenarios. in particular, we identified countries with less than 100 cases in total reported by end of april whilst the estimated probability of reaching 10,000 infections by then was higher than 50% even under the more optimistic scenario. conclusion our study highlights particular countries that are likely to reach (or have reached) 10,000 infections far earlier than the reported data suggest, calling for the prioritization of resources to mitigate the further spread of the epidemic. abstract 10 11 background 12 the emergence of a novel coronavirus in wuhan, china, at the end of 2019 has caused 13 widespread transmission around the world. as new epicentres in europe and america have arisen, of 14 particular concern is the increased number of imported coronavirus disease 2019 (covid-19) cases 15 in africa, where the impact of the pandemic could be more severe. we aim to estimate the number 16 of covid-19 cases imported from 12 major epicentres in europe and america to each african 17 country, as well as the probability of reaching 10,000 infections in total by the end of march, april, 18 and may following viral introduction. 19 20 we used the reported number of cases imported from the 12 major epicentres in europe and 22 america to singapore, as well as flight data, to estimate the number of imported cases in each 23 african country. under the assumption that singapore has detected all the imported cases, the 24 estimates for africa were thus conservative. we then propagated the uncertainty in the imported 25 case count estimates to simulate the onward spread of the virus, until 10,000 infections are reached 26 or the end of may, whichever is earlier. specifically, 1,000 simulations were run separately under 27 two scenarios, where the reproduction number under the stay-at-home order was assumed to be 28 1.5 and 1.0 respectively. 29 30 findings 31 we estimated morocco, algeria, south africa, egypt, tunisia, and nigeria as having the largest 32 number of covid-19 cases imported from the 12 major epicentres. based on our 1,000 simulation 33 runs, morocco and algeria's estimated probability of reaching 10,000 infections by end of march was 34 close to 100% under both scenarios. in particular, we identified countries with less than 100 cases in 35 total reported by end of april whilst the estimated probability of reaching 10,000 infections by then 36 was higher than 50% even under the more optimistic scenario. 37 38 conclusion 39 our study highlights particular countries that are likely to reach (or have reached) 10,000 infections 40 far earlier than the reported data suggest, calling for the prioritization of resources to mitigate the 41 further spread of the epidemic. 3 background 46 47 in late december 2019, a novel coronavirus (sars-cov-2) was identified among patients presenting 48 with viral pneumonia in wuhan city, china 1 . since then the number of coronavirus disease 2019 49 cases and deaths increased rapidly 2,3 , and the city was locked down by the chinese 50 government on 23 rd january 2020. by late february, there had only been limited importations from 51 and to places outside china 4 . however, new epicentres in europe and america emerged shortly 52 thereafter, causing a second wave of importations that further accelerated the spread of the 53 pandemic 4 . most countries have since then imposed travel restrictions to prevent further 54 importation of covid-19 cases 5 . by 30 th april 2020, over three million cases and 200,000 deaths had 55 been confirmed worldwide 4 . 56 a particular area of focus has been on countries in africa, with worries about missed imported cases 57 and what the impact will be of widespread transmission given the other heavy health burdens in 58 these countries. the first confirmed case in africa was reported in egypt on 14 th february 2020, and 59 two weeks later, the virus was found in sub-saharan africa with a reported case in nigeria 4 . by the 60 end of april, over 37,000 cases had been reported in the whole of africa, with substantial variation in 61 the reported cumulative incidence across different countries 4 . this inter-country heterogeneity can 62 be due to a wide range of factors, such as the number of imported infections, the capacity to 63 conduct tests for covid-19, surveillance efforts, as well as travel and movement restrictions which 64 vary widely from country to country depending on the local context 5 . the reported data alone thus 65 do not provide a clear depiction of the outbreak situation especially in countries with very limited 66 surveillance capacities, and additional studies are needed to narrow the knowledge gap between the 67 reported data and the real disease burdens. 68 previous work has estimated the risk of importation from china at the early stage of the pandemic 6 , 69 assessed each african country's capacity to respond to outbreaks 6 , systematically collated 70 information on the importation events reported by the sub-saharan countries 7 , and projected the 71 spread of the epidemic seeded by the early cases represented in the world health organization 72 situation reports 8 . it is still unclear how many infections may have been introduced to africa from 73 the new epicentres in europe and america, although the reported case data do suggest that the size 74 of this second wave of importations has been much larger than the first wave of importations from 75 china 7 . in this study, we aim to estimate the number of covid-19 cases imported from the major 76 epicentres in europe and america, and the magnitude of onward spread in each african country. 77 this method is insensitive to the different testing and reporting systems that are in place in different 78 countries. 79 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 24, 2020 . . https://doi.org/10.1101 methods 80 81 data 82 we collated data on the daily number of imported cases in singapore reported by 31 st march from 84 the following 12 epicentres: austria, belgium, france, germany, italy, netherlands, portugal, spain, 85 switzerland, turkey, united kingdom, and united states, which accounted for over 90% of 86 singapore's reported number of imported cases from countries outside of asia 9 . these data will be 87 used later to estimate the number of imported cases in africa. in addition, we obtained the total 88 number of cases (imported and autochthonous combined) reported by each african country by end 89 of march and april from the world health organization's situation reports 4 . 90 for each country, we collated the date on which each of the following policies came into force: (1) 92 banning non-citizens and non-residents from entry (the start date could vary depending on the 93 epicentre country from which a visitor arrived); (2) mandatory (self-) quarantine for travellers 94 arriving from each of the 12 epicentre countries mentioned earlier; (3) stay-at-home order for all 95 non-essential workers (hereinafter referred to as "stay-at-home order"). we reviewed the following 96 sources: (1) country-level internal and international restrictions collated by the international sos 5 , 97 (2) oxford covid-19 government response tracker 10 , (3) international travel restrictions collated by 98 the international air transport association 11 , as well as (4) wikipedia, where a separate page was 99 available for each country containing information regarding the government response. for each 100 wikipedia page, we manually reviewed the online reports listed in the references to exclude data 101 with unconfirmed or unreliable sources. if stay-at-home order came into force in different states of 102 the same country at different times, only the earliest date was recorded. 103 we obtained the total number of air ticket bookings for each origin-destination route allowing for up 105 to two connections during march 2017 from the official airline guide. this will be used later to 106 estimate the ratio of air passenger volumes between pairs of origin and destination countries, which 107 we assumed to be relatively stable over time. 108 109 estimating the number of imported cases 111 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020 . . https://doi.org/10.1101 for each african country , we denote the daily number of air passengers that arrived from an 112 epicentre country by → ( ) ( = , + 1, … , → ), where refers to the start date of the 113 covid-19 epidemic in the epicentre country , and → refers to the last day that non-citizens and 114 non-residents travelling from country were allowed to enter country . each day the probability 115 that an air passenger travelling from country to country was an imported case is denoted by ( ) , 116 which we assume to be dependent on both the origin country and time , but independent from 117 the destination country . hence, the total number of covid-19 cases imported from an epicentre 118 country to an african country by the time the travel ban came into force (denoted by → 119 below) can be approximated using a poisson distribution (refer to the supporting information for 120 the derivation details): 121 . 122 we used the imported covid-19 case data reported by singapore as well as flight data to provide a 123 conservative estimate for → , under the assumption that singapore, being one of the countries 124 with the highest surveillance capacity 12 , has detected all the imported cases. owing to the delay 125 from infection to hospital admission, we considered all cases imported from country to singapore 126 that were reported by date ( → + 9) (hereinafter denoted as , ) based on linton et al.'s 127 estimated mean incubation period and time from illness onset to hospital admission 13 . we assumed 128 that the ratio between the daily number of air travellers from epicentre to country and to 129 here, , refers to the proportionality constant to be estimated using the reported value of , 137 and flight data, and was assigned a uniform prior with support (0, 1). we performed markov chain 138 monte carlo to sample from the posterior distribution of , using the jags software 14 , with 20,000 139 iterations burn-in and 150,000 iterations thinned for a posterior sample of size 5,000. the posterior 140 sample for all the model parameters was then used to estimate the uncertainty distribution of the 141 total number of covid-19 cases imported from the 12 major epicentres to each country. 142 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. . https://doi.org/10. 1101 in march 2020, a spike in the number of cases imported from united kingdom and united states was 143 observed in singapore, which was partly due to the increase in the number of returning singaporean 144 students studying overseas 15 . this change in flight patterns, however, may not be applicable to all 145 african countries. therefore, to be even more conservative, we also derived the imported case count 146 estimates excluding united kingdom and united states from the 12 epicentre countries previously 147 considered. the resulting estimates were subsequently used in the simulations of the onward spread 148 of sars-cov-2 to get our estimates of case numbers over time. stay-at-home order, was assumed to follow a negative binomial distribution with mean 2 and 165 dispersion parameter 0.58 8 . once the stay-at-home order came into force, we created two scenarios 166 for the percentage reduction of the reproduction number: (1) 25% reduction, and (2) 50% reduction. 167 to be conservative, we assumed that the stay-at-home order, once implemented, can be sustained 168 up to the end date of our simulations. we ran the simulation algorithm following churcher et al. 18 , 169 and derived the estimated probability of reaching 10,000 infections by the end of march, april, and 170 may respectively for each country. (refer to the supporting information for the implementation 171 details) 172 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. we estimated morocco, algeria, south africa, egypt, tunisia, and nigeria as having the largest 175 number of covid-19 cases imported from the 12 new epicentres in europe and america (table 1 176 and figure 1 ). all of these countries had their lower bound estimate of the imported case count 177 exceeding 100 (table 1) . by contrast, nine countries (e.g. lesotho, eswatini, and south sudan) were 178 found to have a very low risk of importation, with the upper bound estimate of the imported case 179 count below 10 (table 1 ). in a more conservative scenario where united kingdom and united states 180 were excluded from the list of epicentre countries, the estimated number of imported cases did not 181 change drastically for most countries, albeit with some exceptions such as kenya, whose estimate 182 decreased from 97 (95% ci: 75-120) to 27 (95% ci: 16-41) ( table 1) . 183 based on our 1,000 simulations of the onward sars-cov-2 spread, both morocco and algeria's 184 estimated probability of reaching 10,000 infections by end of march was close to 100% under both 185 scenarios that we considered (figures 2a, 2d) , whilst the reported total number of cases in each 186 country by end of march was ~500 ( figure 2g ). under the assumption that stay-at-home order 187 reduces the reproduction number to 1.5, we found four african countries where the estimated 188 probability of reaching 10,000 infections by end of march was higher than 50% ( figure 2a ). this 189 number quickly rose to 34 countries reaching this number of infections by the end of april, and 47 190 countries by end may (figures 2b, 2c) . for the alternative scenario where the reproduction number 191 is reduced to 1.0 by stay-at-home order, the numbers of african countries with a higher-than-50% 192 estimated probability of reaching 10,000 infections by end of march, april, and may were 3, 23, and 193 32 respectively (figures 2d-2f) . notably, four countries (angola, gambia, mozambique, and sao 194 tome and principe) were found to have reported less than 100 cases by end of april whilst the 195 estimated probability of reaching 10,000 infections by then was higher than 50% even under the 196 more optimistic scenario ( figures 2e, 2h ), suggesting that a very substantial number of cases may 197 have been undetected. the percentiles of the uncertainty distribution for the date by which 10,000 198 infections are reached in each country under the two scenarios were shown in table 2 . 199 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. in the first wave of importations of infections from wuhan, china, to other places outside china we 207 estimated that most places at risk were in asia, europe and usa 19 . though there were links between 208 china and african countries, these were fewer than those between china and the rest of asia, 209 europe and usa 19 . the shut down in china severely curtailed continuing importations out of china 210 and so these importations rapidly stopped. 211 lower initial importations into africa compared to asia and europe certainly tallies with what has 212 been seen. there have been very few reported cases in africa in the first wave of importations, and 213 no reports of onward transmission. there was much discussion at the time whether the lack of 214 reported imported cases in africa was because imported cases were not being picked up. this may 215 be some of the story, but our analysis would suggest that this was not the whole story, and it was 216 more that the early risk of importation into africa was lower than other places 19 . however the 217 results we present in this paper estimate that this risk has dramatically increased with the spread of 218 the virus in europe and the usa. this also tallies with what we have seen, as countries in africa 219 started to report their first imported cases from europe and the usa 4 . as of april 30 th 2020, south 220 africa had reported the highest number of cases at 5350 4 , and we estimated south africa to have 221 had one of the highest numbers of imported cases from the new epi-centres, although it was also 222 rated highest at risk in africa of importations from china in previous analysis 6 . senegal is one of the 223 countries for whom the risk has notably increased from the risk of importation from china as 224 estimated in previous analyses 6, 19 . we only considered importations from the major epicentres in 225 europe and america, and so the number of importations from all countries will be even higher. 226 our study provides countries with information on the estimated timing of reaching 10,000 227 infections, which can be used for planning. under the assumption that stay-at-home order reduces 228 the reproduction number from 2.0 to 1.5, our estimates suggest that a number of african countries 229 will reach (or have reached) 10,000 infections even earlier than the predictions of pearson et al. 8 230 this could be due to a number of imported infections being undetected and hence not reflected in 231 the situation reports, as well as the delay from infection to reporting, both of which were accounted 232 for in our study. notably, we estimated two countries in north africa, namely algeria and morocco, 233 as having the highest probabilities of reaching 10,000 infections by the end of march, which may 234 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. . https://doi.org/10.1101/2020.05.22.20110304 doi: medrxiv preprint have occurred even prior to the lockdown. countries in sub-saharan africa having the earliest 235 estimated timings of reaching 10,000 infections include angola, côte d'ivoire, senegal, and south 236 africa. in countries where stringent social distancing measures have yet to be implemented at the 237 time of writing (e.g. tanzania), the unfolding of the epidemic was estimated to be substantially 238 faster than previous estimates suggest 8 . on the other hand, we projected that countries such as 239 seychelles will reach 10,000 infections later than pearson et al.'s forecasts 8 owing to the stay-at-240 home order. the epidemic was found to be further slowed down in many countries when we 241 assumed the reproduction number to be reduced by 50% due to stay-at-home order. 242 many countries in africa have considerable experience in dealing with other infectious disease 243 outbreaks, most notably ebola, and will be able to call upon that experience for covid-19. countries 244 hit in this third wave of transmission, including those in africa have some advantage as there have 245 been a variety of responses from around the world from which to assess what to do or not to do. 246 however there will need to be consideration of how effective measures can be adapted to different 247 settings 20 . issues such as high hiv prevalence in some countries, and a younger demographic may 248 both affect the cases and deaths observed in different ways. this relationship however is yet to be 249 determined and there will need to be rapid research in countries in africa to determine what the risk 250 of disease is in different populations and how best to respond in light of many other competing 251 health priorities. 252 many countries in africa are on high alert for incoming cases from europe and usa, taking measures 253 such as quarantine of arrivals or shutting down travel from affected countries. this is a sensible 254 response given the vast amount of transmission on-going in these places. however as travel is either 255 maintained or reopened between countries closer by, risk of importations from other countries 256 should continue to be considered. close attention should therefore be paid to where will be the next 257 epicentre, perhaps within africa, and how this could translate into imported cases for each country, 258 particularly for those countries that we estimate to have experienced lower numbers of imported 259 cases previously and therefore lower onward transmission. 260 not accounted for in our study currently is the impact of less stringent interventions on the local 261 sars-cov-2 spread, such as the effect of prohibiting large public gatherings, closure of social venues 262 and schools, and restrictions on inter-district travels. it is still unclear as to whether and to what 263 extent these interventions were effective in their local context, and hence in our simulations we only 264 considered stay-at-home order for all non-essential workers as an effective intervention to reduce 265 local transmission. future modelling work considering the impact of different interventions in 266 different places will be vital for determining how each country can continue to respond. 267 in addition, we have made simplifying assumptions about the change in travel patterns in response 268 to the pandemic in each african country relative to that in singapore, due to the unavailability of 269 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020 . . https://doi.org/10.1101 respectively. reproduction number in the absence of stay-at-home order in each country was 398 assumed to be 2. reported total number of cases (g-h) were extracted from the world health 399 organization's situation reports. 400 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020 . . https://doi.org/10.1101 table 1: estimated number of covid-19 cases (with 95% credible interval) imported from the 12 new epicentres in europe and america (second column), and after excluding united kingdom and united states from the list of epicentre countries (third column) to create a more conservative estimate (refer to methods for more details). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 24, 2020. table 2 : summary statistics for the estimated date by which 10,000 infections are reached in each african country. reproduction numbers used for the simulation were 2.0 before, and 1.5 or 1.0 after stay-at-home order came into force in each country. simulations were performed until 31 st may, or 10,000 infections are reached, whichever is earlier, based on 1,000 model runs. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 24, 2020. . https://doi.org/10. 1101 genomic characterisation and epidemiology of 325 2019 novel coronavirus: implications for virus origins and receptor binding of novel coronavirus-infected pneumonia clinical features of patients infected with 330 2019 novel coronavirus in wuhan 5. international sos. travel restrictions, flight operations and screening covid-19: s'porean students abroad heading home after government 367 advisory but a few plan to stay put a new framework and software to estimate 371 time-varying reproduction numbers during epidemics serial interval of novel coronavirus (covid-19) 375 infections measuring the 378 path toward malaria elimination estimating number of global importations 381 of covid-19 from wuhan, risk of transmission outside mainland china and covid-19 382 introduction index between countries outside mainland china. medrxiv limiting the spread of 385 covid-19 in africa: one size mitigation strategies do not fit all countries estimated imported case count from 12 epicentres estimated imported case count from 10 epicentres key: cord-350104-b99y6n43 authors: de zwart, onno; veldhuijzen, irene k.; elam, gillian; aro, arja r.; abraham, thomas; bishop, george d.; voeten, hélène a. c. m.; richardus, jan hendrik; brug, johannes title: perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey date: 2009-01-06 journal: int j behav med doi: 10.1007/s12529-008-9008-2 sha: doc_id: 350104 cord_uid: b99y6n43 purpose: to study the levels of perceived threat, perceived severity, perceived vulnerability, response efficacy, and self-efficacy for severe acute respiratory syndrome (sars) and eight other diseases in five european and three asian countries. method: a computer-assisted phone survey was conducted among 3,436 respondents. the questionnaire focused on perceived threat, vulnerability, severity, response efficacy, and self-efficacy related to sars and eight other diseases. results: perceived threat of sars in case of an outbreak in the country was higher than that of other diseases. perceived vulnerability of sars was at an intermediate level and perceived severity was high compared to other diseases. perceived threat for sars varied between countries in europe and asia with a higher perceived severity of sars in europe and a higher perceived vulnerability in asia. response efficacy and self-efficacy for sars were higher in asia compared to europe. in multiple linear regression analyses, country was strongly associated with perceived threat. conclusions: the relatively high perceived threat for sars indicates that it is seen as a public health risk and offers a basis for communication in case of an outbreak. the strong association between perceived threat and country and different regional patterns require further research. severe acute respiratory syndrome (sars) and avian influenza are two examples of recent emerging infectious diseases that may cause severe threats to population health, large economic losses, as well as fear and dread [1, 2] . the behavior of the general population or specific risk groups can play an important role in both the spread and control of infectious diseases. the sars epidemic showed the impact of worldwide travel on the rapid spread of an epidemic, as well as the possible merits of strict hygiene and quarantine measures in halting that epidemic [3] . in case of an infectious disease pandemic, public health authorities will be dependent on the willingness and ability of the general public to adhere to recommendations regarding personal hygiene, vaccination and/or prophylaxis, quarantine, travel restrictions, or closing down of public buildings such as schools [4, 5] . compliance with recommended precautionary behaviors is not self-evident [6] . specific attention to factors influencing behavioral change during outbreaks of infectious diseases is, therefore, necessary. one of the factors that may influence willingness and motivation to adopt precautionary behaviors is risk perception [7] [8] [9] [10] , i.e., the perceived personal vulnerability or likelihood of a disease or health threat. perceived vulnerability, combined with perceived severity, can be regarded as perceived threat. people are expected to have the highest perceived threat of sars if they think that an infection with sars is likely and will have serious health consequences. however, risk perception is certainly not the only determinant of protective behavior. protection motivation theory suggests that response efficacy (i.e., the extent to which people believe that available protective actions against sars are effective) and self-efficacy (i.e., the extent to which people believe they have the ability to engage in such protective actions) are two other key predictors of protection motivation [8] . risk perceptions are often biased. unrealistic optimism about risks is often observed toward familiar risks that are perceived to be largely under volitional control. people perceive their relative risk compared to others of the same gender and age as lower. a pessimistic bias, i.e., perceptions of risk that are (much) higher than actual risk, is more likely for new risks that are perceived as uncontrollable. the latter might be the case with new emerging infectious diseases, like sars [9] [10] [11] [12] . while in some fields, such as environmental risks, risk perception has been studied intensively, not much is known about risk perception of recently emerging infectious diseases. related to emerging infections diseases, first, explorative and descriptive studies are needed to increase our insights in perceived threat, risk perception, and efficacy beliefs. such studies can inform more focused and theory-driven investigations. during and in the aftermath of sars, several of such exploration studies have been conducted, but these studies did not include international comparisons across a range of different countries. these studies showed that the risk of sars was perceived differently across the globe and was not directly linked to the proximity of the outbreak. risk perception of sars in some of the asian countries was relatively low compared to risk perception in the usa [13] [14] [15] but similar to levels reported for the netherlands [16] . one study focused on differences in psychosocial factors predicting preventive behavior in four affected regions [17] . ji and colleagues compared optimism related to sars in china and canada and concluded that both groups demonstrated unrealistic optimism, while at the same time they were overly pessimistic about their own chances of getting infected [18] . a limited number of studies have looked at risk perception of avian influenza with different results varying from high perceived risks to low risk perception [19] [20] [21] [22] . a dutch study showed high levels of risk perception of avian influenza in case of an outbreak and indicated that almost 40% of respondents had taken some sort of precautionary measures [23] . there are few international comparative studies that analyze differences in perceived threat, risk perception, and efficacy beliefs between (infectious) diseases and conditions and differences between countries [24] [25] [26] [27] . it is generally unknown whether risk perceptions of emerging infectious diseases are perceived in similar ways across countries. because there was a large difference between how sars has affected southeast asia and europe, one might hypothesize that this would mean a higher risk perception of sars and possibly other infectious diseases in countries in southeast asia. if international differences in risk perceptions of sars exist, the question is whether such differences are specific for sars, whether we see the same for risk perception of avian influenza (as most cases have also occurred in southeast asia), or whether they may indicate a more general trend in risk perceptions. the present study explored perceived threat, risk perception, and efficacy beliefs related to sars in random samples of the population of eight countries in europe and asia. to explore if country differences were specific for sars, perceived threat, risk perception, and efficacy beliefs related to avian influenza and other (infectious) diseases were also investigated. this study had the following specific objectives: -to study levels of perceived threat, vulnerability (or risk perception), severity and comparative vulnerability for sars in denmark, the netherlands, poland, spain, the uk, china, hong kong, and singapore; -to compare perceived severity, vulnerability, and threat of sars with other diseases and conditions, i.e., avian influenza, common cold, diabetes, hiv, high blood pressure, tuberculosis, food poisoning, and a heart attack; -to study differences and associations between these factors across the eight countries and between europe and asia. because data collection for the present study took place in the autumn of 2005, i.e., 2 years after the sars epidemic, it was not possible to collect information on specific precautionary behaviors. furthermore, specific results on risk perception of avian influenza and related efficacy beliefs have been reported elsewhere [23] . data were collected using computer-assisted telephone interviewing in the native languages by native speakers of each country, coordinated by a dutch company that specializes in international telephone survey research, using random digit dialing (rdd). for the asian countries, the dutch company was assisted by an asian agency. if unanswered, numbers were tried again up to five times and, when possible, call back appointments were made. interviews were conducted from 20 september to 22 november 2005 in eight different countries, five in europe representing regions in north, west, south, and east europe (denmark, the netherlands, great britain, spain, and poland) and three regions in east asia (singapore, province of guangdong china, and hong kong). in china, the survey was conducted in the province of guangdong. during the period of data collection, no cases of sars were reported. respondents aged 18 to 75 years were eligible for participation. the questionnaire was based on a previously developed sars risk perception questionnaire [16] and focused on risk perception and severity of sars, avian influenza, and other (infectious) diseases, efficacy beliefs and use of information sources and took, on average, 16 min to complete. the questionnaire was first developed in english, translated into dutch, and subsequently pretested in great britain and the netherlands using cognitive interviewing. further translations were made into danish, spanish, polish, mandarin, and cantonese; all translations were conducted by professional translators and checked by native speakers, including members of the project team. the questionnaire started with basic demographic questions, including urbanization and level of education (see table 1 for categories). respondents were then presented with the following diseases or conditions: diabetes, a common cold, hiv, high blood pressure, sars, tuberculosis, heart attack, flu from a new virus, and food poisoning. these illnesses and conditions were included as these are both infectious and noninfectious diseases, some more common and familiar, and some with more serious consequences, thus giving a range of options for comparisons. for sars and flu, the respondents first received a brief explanation (for sars, "sars is a severe acute breathing related illness caused by a previously unknown virus"; for flu, "a new type of flu virus can arise from avian flu, it causes serious illness and spreads easily in the population"). respondents were then asked about: 1. severity ("how serious (on a scale from 1 to 10) would it be for you if you got [disease] in the next year?"); 2. vulnerability ("how likely do you think it is that you will develop or contract a [disease] in the next year; very unlikely (1) to very likely (5)); 3. comparative vulnerability ("how likely do you think it is that you will develop or contract [disease] in the next year compared to other [women/men] of your age in [own country]; much less likely (1) to much more likely (5)). the questionnaire continued with two questions focusing on knowledge of sars (name symptoms, whether sars is a communicable disease). for sars, flu from a new virus, and common cold, the following additional questions were included: response efficacy ["to what extent do you think people can take effective actions to prevent getting sars/flu from a new virus/common cold in case of an outbreak"; outbreak was included for sars and flu from a new virus; not at all (1) to very much (4)]; self-efficacy ["how confident are you that you can prevent getting sars/flu from a new virus/ common cold in case of an outbreak"; not confident (1) to very confident (4)]. the order of these three diseases was chosen randomly by the computer. the questionnaire continued with questions on use of sources of information during the sars outbreak, trust in these sources, and preferences for ways of communication during future outbreaks. respondents where then presented with scenarios and asked about possible preventive actions. results of this have been reported elsewhere [28] . the questionnaire concluded with some general background questions on perceived general health, perceived happiness, whether respondent had been vaccinated against influenza, and about employment status, education level, and religion. (the questionnaire is available online at http://www2.eur.nl/fgg/ mgz/sarscontrol/questionnaire_risk_perceptions_survey. htm.) respondents indicating they never heard about sars (1.3%) were excluded from the analyses. furthermore, "don't know" answers on the questions about risk percep-tion were treated as missing values and, therefore, also excluded from the analysis. on average, 4.4% of respondents did not know how to rate sars severity and 4.3% could not rate their vulnerability to sars. for the different countries, mean scores and standard deviations (sd) were calculated for severity, risk perception, perceived threat (see below), and comparative vulnerability of eight different diseases or conditions. in line with the protection motivation theory, one measure was defined as "perceived threat"; it was constructed by multiplication of the measures of perceived severity (scale 1-10) and vulnerability (in case of an outbreak in the country for sars and flu from a new flu virus; scale 1-5). to make the scores comparable, the severity score was first divided by two. to normalize the skewed distribution of the new variable, a square root transformation was performed that resulted in a measure of perceived threat on a scale from 1 (low) to 5 (high). a sars knowledge score (scale 0-2) was calculated based on whether the respondent could name a symptom of sars and whether the respondent knew sars was a communicable disease. differences in background characteristics (gender, age group, area, and level of education) and risk perceptions between the samples in europe and asia were explored with chi-square tests or (paired) student's t tests, of which the p value and the effect size r are reported. an r below 0.30 indicates low effect size, 0.30-0.50 indicates medium effect sizes, and higher than 0.50 indicates large effect size. to test for important correlates of sars-related risk perceptions, four multiple linear hierarchical regression models were applied with perceived severity, vulnerability, threat, and comparative vulnerability as dependent variables. the independent variables were included in blocks with country (dummy coded) in the first block, sex, age, highest education, and urbanization in the second block, and the amount of information during the sars outbreak and the sars knowledge score in the last block. as we did not want to choose one country as a reference group, we ran the models by leaving out the intercept. in doing so, the regression coefficients for the countries do not represent the difference in mean compared to the reference group but the actual (corrected) mean value of the respective dependent variable. the r 2 , a measure of the proportion of variance in the dependent variable that is explained by the independent variables in the model, is given for each hierarchical step in the models. the models were applied to the total population and the model for perceived threat was also applied to the separate countries. in the european countries, 16% of the numbers created by rdd were nonexistent and 26% of the numbers could not 463 488 400 401 425 404 396 426 2,177 1,226 3,403 total % 14 14 12 12 12 12 12 13 64 36 100 participation rate 58 81 44 21 34 ---40 13 gender male 40 39 42 41 41 47 44 43 40 45 42 female 60 61 58 59 59 53 56 57 60 55 58 age group 18-30 13 18 10 13 17 43 27 35 14 35 22 31-45 31 31 31 35 34 34 35 31 32 33 table 1 ). for the interviews conducted by the asian agency, no response rates are available. in total, 3,436 respondents were interviewed. data on background variables in the different participating countries are provided in table 1 . most respondents in all countries were female (58% in the total group). european respondents were significantly older than asian respondents (p < 0.001, r = 0.27). substantially more respondents in asia lived in a city, as both hong kong and singapore were included (p<0.001, r=0.56). asian respondents were higher educated than european respondents (p<0.001, r=0.014). sars was rated as the third most severe problem among the diseases and conditions included, hiv as the most serious problem and common cold as the least serious (see table 2 ). compared to flu from a new flu virus, sars was rated more serious in all countries (overall=8.3 versus 7.0 (scale 1-10), p<0.001, r=0.47; country-specific test results not shown). perceived vulnerability, risk perception, for common cold was the highest, 3.8, and for hiv the lowest, 1.4 (scale 1-5). for sars, the risk perception levels differed in case of an outbreak in or outside the country. it was among the highest with 2.7 in case of an outbreak in the country, while in case of an outbreak outside the country it was 2.1 (p<0.001, r=0.44). the vulnerability for an outbreak of flu from a new flu virus was higher than for sars both in case of outbreak inside the country (3.1 versus 2.7, p<0.001, r=0.31) and outside the country (2.9 versus 2.1, p<0.001, r=0.48). this finding was true for all countries (separate test results not shown). perceived threat of sars in case of an outbreak in the country was among the highest of the diseases with a mean score of 3.2 (scale 1-5); perceived threat of hiv (2.4) and a common cold (2.1) were the lowest. perceived threat of sars and flu from a new flu virus in case of an outbreak were similar in most countries, but in denmark, china, and hong kong, sars was perceived more threatening than flu from a new flu virus (p<0.001, r=0.23; p<0.001, r=0.25; and p=0.004, r=0.15, respectively). the level of perceived threat varied across countries. perceived threat of sars was the highest in poland and the lowest in singapore. in fig. 1 , the results of perceived threat of sars, flu from a new virus, high blood pressure, and diabetes are presented. although levels of perceived threat varied between countries, the pattern of perceived threat differences between the different diseases and conditions was the same in all countries with perceived threat of sars and avian flu being the highest and diabetes the lowest. the comparative vulnerability of sars in case of an outbreak outside the country was 2.6 (scale 1-5), indicating that that people thought it slightly less likely that they would contract sars compared to the average other ( table 3 ). for flu from a new flu virus, perceived severity was higher in europe, 7.06 to 6.74 in asia (p<0.0005, r= 0.06) as was perceived vulnerability, 3.16 to 2.97 (p< 0.00005, r=0.08). in comparing europe to asia, there is not one pattern for all diseases, some are perceived more severe in europe (heart attack, hiv), others in asia (food poisoning, common cold) nor is there for perceived vulnerability. of the respondents in the asian countries, more than 80% could name symptoms of sars; this percentage was just over 40% in european countries. the proportion who knew sars was a communicable disease varied between 62% in spain and 88% in denmark. the mean knowledge score was 1.2 (range 0-2) in europe and 1.7 in asia (p<0.001, r=0.69). self-efficacy was lower than response efficacy for both sars and a common cold in all countries, but the difference was larger for sars. both response efficacy and selfefficacy for sars were higher in the asian countries compared to the european countries (p<0.001, r=0.28 and p<0.001, r=0.40, respectively; see fig. 2 ). the regression models for perceived severity, vulnerability, threat, and comparative vulnerability for all countries combined are presented in table 4 . country was significantly associated with perceived threat, vulnerability, severity, and comparative vulnerability. besides country, a higher perceived severity of sars was significantly associated with female gender, lower level of education, and a higher sars knowledge score. a higher perceived vulnerability for sars was significantly associated with lower level of education. all the variables that were significantly associated with severity and vulnerability were also significantly associated with perceived threat. comparative vulnerability was significantly associated with gender and amount of information. comparative vulnerability in women was lower than in men and lower in respondents that received more information about sars. the models for each outcome variable explained less than 10% of the variance ( table 5 ). the proportion of the variance explained by country was higher than that for the other potential correlates in the models. analysis per country (table 6 ) showed that perceived threat of sars was higher in respondents with lower levels of education in poland, great britain, and spain, while it was higher among the higher educated in singapore. singapore was the only country where age was independently associated with perceived threat. level of urbanization was a significant correlate in poland only with living in less urban areas associated with a lower threat. in the netherlands and denmark, perceived threat was higher in respondents who received higher amounts of information about sars, and in great britain, it was higher in respondents with a higher knowledge score. the model for the total population explained 7.5% of variance of which 5.9% was accounted for in a model with only the country variable (table 5 ). in the separate models by country, the explained variance was less than 5% in all countries. the present study shows that perceived threat of sars in case of an outbreak in the country was higher than that of other diseases and conditions included in this study. perceived vulnerability of sars was at an intermediate level compared to other diseases while perceived severity was high. perceived threat for sars varied between countries in europe and asia with perceived severity higher in europe and perceived vulnerability higher in asia. perceptions of vulnerability compared to other people for sars was relatively small and comparable to other diseases. response efficacy and self-efficacy for sars were higher in asia compared to europe. our study has several limitations, especially related to the means of data collection. firstly, the response rate varied substantially between countries from 21.3% to 81.1% with low response rates in the participating asian fig. 1 mean perceived threat of sars and flu from a new flu virus in case of an outbreak, high blood pressure and diabetes by country. the asterisk indicates that the difference in mean perceived threat between sars and flu is statistically significant countries in particular. this may have led to nonrepresentative samples, and the differences in response rates may partly explain the reported differences in risk perceptions and other variables. these differences in response rates and the low rates in some of the participating countries limit the generalizability of our data, and the results should, therefore, be interpreted with caution. secondly, because of the lack of an existing validated questionnaire for perceived threat and risk perception of infectious diseases suitable for telephone administration in large samples, the questionnaire was specifically developed for the project reported in this paper based upon an earlier questionnaire used during the sars outbreak [16] . our study design, aiming to include a large number of respondents from a range of different countries and regions, using telephone surveying as the means of data collection, combined with the financial and time pressure restraints, enabled the inclusion of only a limited number of items per construct. this may have reduced the reliability of our measures, especially toward possible underlying cultural differences in constructs. furthermore, extensive pretesting of the survey questionnaire with cognitive interviewing was restricted to two european countries. we, therefore, do not know whether all concepts used were understood in the same way in all participating countries. on the other hand, we did contextualize our risk perception questions by including a setting (in case of an outbreak), time frame (next 12 months), and focusing on the risk of the individual (instead of population)-all issues known to be important for measuring risk percepthe present study also has its strengths. it is among the first large-scale comparative studies into perceived threat and risk perception of emerging infectious diseases, and in fact, unique in the number of countries represented. perceived threat for sars, as well as avian influenza, were among the highest and at the same level as for, for example, a heart attack. this indicates that these potential problems were taken very seriously by the general public. because few comparative studies into perceived threat of sars and other newly emerging infectious diseases have been conducted, it is difficult to interpret the differences between countries and continents. comparing our results with data from several earlier studies on risk perception of sars in the usa, canada, the netherlands, singapore and hong kong has its limitations, as these studies were done in 2003 during the sars epidemic, whereas in our study, we asked respondents to envisage a new outbreak [13] [14] [15] [16] . for example, in 2003, risk perception of sars in some of the asian countries was relatively low compared to risk perception in the usa. ji et al., in their study on optimism across cultures, have pointed out that unrealistic optimism concerning sars was higher among chinese than among canadians [18] . they interpreted this being in line with the chinese and east asians in general holding a cyclical perception of events, so that a negative event may be seen as antecedent to a positive outcome. the higher level of severity of some diseases in europe (sars, flu from a new virus, hiv, tuberculosis) may indicate that more unfamiliar diseases are perceived more severe. the higher perceived vulnerability for some diseases (sars, tuberculosis, hiv) in asia may be based upon the fact that these are indeed more prevalent in these regions. the observation that, compared to europe, efficacy beliefs for sars were more positive in asia and that people felt more able to control sars, may be explained in the same way. alternatively, it may also be that the more direct and closer experience with the disease in asia and the experience of outliving and overcoming the outbreak have increased self-efficacy and response efficacy beliefs in asia. preventive measures in asia were also more visible and might have been more reassuring to the public [2] . also, efficacy beliefs related to a common cold and flu from a new virus were higher in asian countries where the latter may be explained by the fact that, despite the first cases of avian influenza among humans in asia already reported in 2003, this has not resulted in a larger outbreak [22] . the lower level of risk perception in denmark may reflect part of a scandinavian tendency to perceive risks lower than in other countries [29] . this result is also in line with a lower risk perception of sars among finns compared to dutch [24, 30] . one of the explanations for this tendency is that the media in scandinavia appear to report more about risks abroad with less attention to risk inside the country [29] . however, we need to interpret the differences between countries with care because cognitive constructs such as risk perceptions are not necessarily interpreted in the same way in different cultures [31] . indeed, the data of our study on comparison of risk perceptions for various diseases show that the relative risk perceptions for these diseases, i.e., the order of levels of risk perceptions, are rather consistent across countries. this may indicate that differences between countries in absolute risk perception levels for specific diseases or conditions may reflect cultural differences in the way survey questions are answered rather than real differences in risk perceptions. voeten et al. [32] , in their study on risk perception and efficacy beliefs among chinese communities in the uk and the netherlands, have shown that efficacy beliefs of chinese living in the uk and the netherlands were comparable to those of native uk and dutch respondents. this may indicate that country of residence, perhaps because of country-specific public health systems and media coverage, may be more important than ethnicity or country and culture of origin. because country appears to be a relevant correlate of sars-related risk perceptions in the multivariate analyses, further research is needed to explain these country differences. the results on comparative vulnerability indicate that envisioning an outbreak might make a difference; when respondents were asked to compare their personal risk to that of comparable others, the optimistic bias was lower in case of an outbreak. such a situation is characterized by table 6 correlates of perceived threat for sars; regression coefficients (b) and corresponding 95% confidence intervals (95%ci) derived from linear regression analyses less control, which is associated with less optimism [33, 34] . the notion that, for an outbreak, risks were perceived to be more evenly distributed, and thus they seemed to be less prone to an optimistic bias, may offer starting points for public interventions. such interventions should certainly also focus on increasing self-efficacy, especially in the european countries, because low self-efficacy may lead to lack of protection motivation. perceived threat of sars and flu from a new flu virus in case of an outbreak was similar in most countries. however, the level of severity for sars was higher than for flu from a new virus, while vulnerability for flu from a new virus was higher than for sars in all countries. one explanation might be that sars is a more unfamiliar disease for most people compared to flu. it indicates that people do perceive various aspects of risk perceptions differently for different emerging infectious diseases and that risk communication should thus be disease-and perception-specific. perceived threat for emerging infectious diseases such as sars and avian influenza were amongst the highest rated in the present study, especially in case of an outbreak. from a public health perspective, this offers a good starting point for risk communication and precautionary actions. it also asks for realistic risk communications to put the risks for sars and other emerging infectious diseases into the perspective of global health risks to prevent fuelling unnecessary panic [35] . twenty-first century plague. the story of sars responding to global infectious diseases outbreaks: lessons from sars on the role of risk perception, communication and management world health organization working group on prevention of international and community transmission of sars. public health interventions and sars spread non-pharmaceutical interventions for pandemic influenza, 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the east when the referent group is specified cross-cultural risk perception: a survey of empirical studies precautionary behavior in response to perceived threat of pandemic influenza. emerging infectious diseases september the scandinavian way of perceiving societal risks risk perception, information needs, and risk communication related to sars the general self-efficacy scale: multicultural validation studies sources of information and health beliefs related to sars and avian influenza among chinese communities in the united kingdom and the netherlands, compared to the general population in these countries the social amplification of risk and risk communication the british 2001 food and mouth crisis: a comparative study of public risk perceptions, trust, beliefs about government policy in two communities an iatrogenic pandemic of fear open access this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. key: cord-315576-bgcqkz0p authors: yamamoto, naoki; bauer, georg title: apparent difference in fatalities between central europe and east asia due to sars-cov-2 and covid-19: four hypotheses for possible explanation date: 2020-08-05 journal: med hypotheses doi: 10.1016/j.mehy.2020.110160 sha: doc_id: 315576 cord_uid: bgcqkz0p the comparison of the numbers of cases and deaths due to sars-cov-2 / covid-19 shows that people in central europe are much more affected than people in east asia where the disease originally occurred. trying to explain this difference, this communication presents four hypotheses that propose the following reasons for the observed findings: 1) differences in social behaviors and cultures of people in the two regions; 2) possible outbreak of virulent viruses in central europe due to multiple viral infection, and the involvement of immuno-virological factors associated with it, 3) possibility of corona resistance gene mutation occurring among east asians as a result of long-term co-evolution of virus and host, and 4) possible involvement of hygienic factors. direct or indirect supportive evidences for each one of our hypotheses are presented and experimental approaches for their evaluation are discussed. finally, we suggest that the dynamics of the pandemic also shows that the problems of the new coronavirus can be overcome due to people's awareness of the epidemics, rational viral diagnostics and a high level of medical care. the new coronavirus sars-cov-2, causing an infectious disease named covid-19 has caused a major pandemic with more than 13 million people infected and more than 570,000 already dead [1, 2] . its momentum is disrupting the economy, society, and healthcare systems, filling hospitals with patients, emptying public spaces, and drawing people away from work and friends. due to the test strategy used in nearly all countries, "people infected with sars-cov-2" or simply named "covid-19 cases" are usually people with clinical symptoms or contacts to infected people. the number of infected people without clinical symptoms is therefore unknown. further testing, including antibody tests, will most likely reveal that much more people around the world have been infected than the number of defined cases of covid-19. this may upset modern societies on a scale never seen before. on the other side, it may be assumed that these infected people might contribute to herd immunity and slow down further spread of the virus, provided their antibody response is longer lasting and has neutralizing potential. these aspects need further experimentation and proof. in the 21st century, information (including scientific and technological knowhow) circulates around the world instantly. the world has entered an era where the traffic of people, economic goods, money, but also viruses and other microbes seems to be nearly unlimited. therefore, after the outbreak of the new coronavirus epidemics in china, the transport of the virus to other parts of the world, particularly to europe, 4 was fast and efficient. of particular note is the striking difference in the extent of medical impact caused by sars-cov-2 in eastern asia versus central europe [3, 4] . this difference is prominent, when i) the number of infected persons with clinical symptoms, ii) the ratio between infected people with clinical symptoms and the total population of the countries, iii) the number of deaths, or iv) the death ratios of infected people with symptoms are compared between eastern asia and central europe. in this communication, we compared selected countries from central europe and east asia with respect to the medical impact of sars-cov-2 and covid-19. based on this analysis, we propose four hypotheses that might explain the observed differences. for each one of these hypotheses, we present direct or indirect evidences to support them. none of these hypotheses by itself can explain the observed differences. rather, the mechanisms defined in individual hypotheses seem to interact and thus cause the overall effect observed. we are aware that additional mechanisms, not covered by our analysis, may also contribute to the pandemics. for the analysis of the difference regarding the number of infected people and the death tolls due to covid-19 between central european and east asian 5 countries, we have chosen italy, spain, france, germany and uk from central europe and china, south korea, japan, and taiwan from south east asia. mongolia and north korea were excluded, since not sufficient information was available from both countries. for comparison, the united states, which have the highest number of infected and dead people due to covid-19, were included into our analysis. table 1 first shows the populations and gdps, in order to help estimating the scale, medical level, and affluence scale of the selected countries. it is obvious that east asia is one of the most densely populated areas in the world. it can also be seen that there is not much difference with respect of the gdps, except for china. however, china's gdp has grown rather rapidly in recent years, and it is certain that it will reach the economic level of the other countries sooner or later. european countries ranged from 1993 to 5359 per million people, whereas those of east asian countries were in the range of 18~211. the ratio between the two was about 32. these numbers depend on the number of tests performed in individual countries, as well as on differences in the test strategy, resulting in a certain degree of uncertainty. to get a more precise picture of comparison, covid-19-related 6 deaths per nation's total population (per million people) were calculated based on the total population of each country. as seen in table 1 , the numbers of central european countries were in the range of 391-548 deaths/million people, with the only exception being germany's lower number of 83. in contrast, deaths/million people in east asian countries were in the range of 0.3-5, i. e. they were nearly 150 times lower than the values found for central european countries. importantly, also the death rate of infected people seems to be much lower in east asian countries, compared to the central european countries (except germany). the relatively lower number of infected people as well as covid-19-associated deaths in germany seems to be due to strong differences in the percentage of infected people with clinical symptoms between the south and north of germany (table 2) . it seems that measures taken after the first cases in bavaria (a large state in the south east of germany, which was first hit by the pandemics) were successful to prevent a strong spreading on the long run. germany had the advantage to be affected by covid-19 later than china and italy. getting valuable information from other countries was essential for slowing down and partially restricting the pandemics in germany. furthermore, the relatively high availability of equipment for intensive care reduced the death rate of infected people. importantly, the picture of inhomogenous distribution of the disease and associated deaths as seen for the whole of germany is also seen when the spreading of infections and 7 deaths is analyzed within bavaria, the state being affected the most ( table 2 ). the detailed analysis of cases and deaths in districts points to hotspots of infection and death, from which the neighbouring areas seem to be reached out. this results in an overall picture with a relatively high number of cases and deaths in the hotspot (tirschenreuth) that far exceeds the average number of cases / population and deaths / population of total germany. the immediate neighbouring districts in the north and south show about half the cases / population and less than half the deaths / population than the hotspot, whereas districts distant of the hotspot are characterized much lower numbers. this picture points to strong initial effects from local infection events, but, importantly, it also indicates that further spreading had obviously been prevented through adequate measures. since the data on the number of covid-19-caused deaths in each country gave reliable data that showed strong differences between east asian and central european countries, we tried to explain these differences by four intercalated hypotheses. given the host-virus relationship, it is necessary to consider factors affecting both virulence of the pathogens and the resistance of the hosts to virus 8 infection. several aspects might be involved in the difference. for example, lippi et al. investigated potential reasons for the noticeable difference in covid-19-associated mortality rates between asian and european populations from clinical and demographic aspects in italy versus china [5] . these authors confirmed that a higher burden of comorbidities, male sex, and older age may be considered substantial determinants of enhanced risk of death in italy compared to china. similarly, in new york city where the highest number of deaths is recorded compared to other states in the united states, factors such as high population density, the possible super spreaders of virus, the degree of poverty between races, and the lack of insurance have become important issues [6] . hypothesis #1 is based on the difference in social behavior and customs of people in each area, i.e. in europe and south east asia. this might explain the difference to some extent. when comparing the lifestyles of european countries with that of asia, the first noticeable difference is the closeness of direct human contact. in asia, bowing is the mainstream greeting, and even with the spread of western culture, shaking hands is still not very common. of course, besides handshaking, there can be no hugs or kisses that are popular in western culture (if any, those are performed only after building a very close relationship). it is easy to imagine that these common actions in western societies help to spread respiratory viruses like sars-cov-2 very efficiently. these differences between europeans and asians, considered from a perspective of the social science might be very important in the progress of the pandemic. there is also a marked difference in obesity between westerners and asians, mainly due to differences in food culture. in addition, people wear shoes indoors in western societies, while it is strictly forbidden to do so in east asia. although the weight of this habit in preventing virus infection is not clear at this moment, this difference indicates that asians very clearly distinguish between outdoor and indoor in daily life. the habit of wearing a mask in case of a cold or fear of it also seems quite asian-specific. thus, it is very likely that differences with respect to these actions play an important role in the spread of infection. social distancing has been proven to avoiding new corona infections, and is a drug-free means of controlling de novo infections. shaking hands, kissing, and hugging are not allowed during social distancing. in favour of our hypothesis #1, the switch from european style of close contact to the asian style during social distancing is regarded as an essential part of successful slowing down and preventing further infections with sars-cov-2. potential effects of repeated infection on the severity of the clinical outcome, contributions of antibody-mediated enhancement of infection to the severity of disease, as well as genetic changes of the virus due to mutation of its rna genome might be underlying the observed effects. in italy, the death toll from the new coronavirus was 25,085 by the april 22, the third highest in the world after the united states and spain. of these, more than 10,000 people were confirmed to be infected among medical staff. this finding shows that inadequate protection of medical staff from infection is a major issue. many of the doctors who died were practitioners. they were fighting the new coronavirus without adequate protective equipment (sometimes due to unavailability of material) or underestimation of the contagiousity of the new virus, driven by the strong wish to help their patients. thus, it is highly likely, especially during the medical collapse, that these doctors will have got infections repeatedly from the infected patients one after another. so the question is what would be severe disease [7] . mice developed higher viral loads, more severe lung pathology, and greater inflammatory responses and generated only limited influenza a virus-specific b and t cell responses. although several pathways could contribute to higher viral loads in mice that received influenza a virus repeatedly, the authors suggested the possibility that the inflammatory response elicited by the first dose of influenza a virus damaged the mucosal barrier, thus allowing the virus given as a second or third dose to penetrate more deeply into the lungs. higher viral loads will lead to the induction of stronger cytokine storms. these data are in agreement with clinical findings in humans, where high-risk individuals were exposed to multiple small doses of hbv, as well as in the woodchuck model, in which animals were repeatedly exposed to small quantities of infectious hbv [8] . in both cases, viral infection was molecularly evident and there were detectable virus-specific cd8-t cell responses but undetectable virus-specific antibody responses. as to repeated infections, another possibility is also considered that is involvement of the antibody-dependent enhancement (ade), which is a well-known phenomenon in the field of viral immunology. first, let's assume the situation of the individual who received a coronavirus infection followed by a second one. one week or so after initial infection, antibodies against the virus are elicited, and the second virus reacts with this antibody causing more serious effects. this phenomenon to increase viral infectivity and virulence has been observed with many viruses including several coronaviruses, hiv, zika virus and mosquito-borne flaviviruses (dengue virus and yellow fever virus). indeed, olsen and colleagues have shown antibody enhancement of infection with one of the animal coronaviruses, feline infectious peritonitis virus by a subset of specific monoclonal antibodies, especially those directed against specific sites on the spike protein [9] . similarly, wang et al. generated monoclonal antibodies against sars-cov spike proteins and found that these antibodies promoted sars-cov infection [10] . ade these aspects may be particulary relevant for a limited number of people such as medical staff. therefore, in addition to that, the emergence of more virulent virus due to mutation of the virus during the course of superinfection might also be assumed. rna viruses are, in general, highly susceptible to mutations, and the base substitution rate, which indicates the degree of change, is estimated to be 7 + 2 x10 -4 nucleotide substitutions per site and per year on average in case of transmissible gastroenteritis virus (tgev), an enteropathogenic coronavirus. this rate falls in the range reported for other rna viruses [11] . in addition, it is also known that coronavirus changes considerably easily due to gene recombination or part of gene loss (deletion). for example, the new strain of canine respiratory coronavirus identified in 2017 is reported to be a recombinant of the existing canine and bovine coronaviruses [12] . in addition, it has been known that the deletion of part of the spike gene has caused the emergence of a prcv from the ancestral porcine gastroenteritis virus [13] . it is possible that the doctor who actually examined many infected patients could be exposed to the coronavirus repeatedly, and among the multiple virus strains infected, more virulent virus strains suitable for 14 spread may be selected and prevailed, at least initially. according to the classical models of virulence evolution of the virus, multiple infections select for raised virulence. to explain why so many people are dying of covid-19 in new york city, sequence analysis of the viral genome has been performed. according to zimmer, the virus mainly came from asia through a small number of infected individuals in california, while in new york, more than 100 people initially brought the virus mainly from europe, suggesting as if the european type viruses are more virulent in its pathogenicity and infectivity than the asian type [14] . a number of studies have supported that through collective actions leading to common good production and immune system impairment, viral cooperation can lead to increased levels of virulence. researchers around the world have already infecting vero-e6 cells [15] . based on more molecular virological studies, tan et al. proposed that sars-cov-2 can be divided into two major lineages (l and s). intriguingly, the s and l lineages can be clearly defined by just two tightly linked 15 snps at positions 8,782 (orf1ab: t8517c, synonymous) and 28,144 (orf8: c251t, s84l). orf1ab encoding replicase/transcriptase is essential for viral genome replication and might also be important for viral pathogenesis [16] . however, there was no evidence so far that this mutation produced a more virulent form of the virus. moreover, the data examined up to now are still very limited, and follow-up analyses of a larger set of data are needed to have a better understanding of the evolution and epidemiology of sars-cov-2. thus, further virological studies must focus on the relationship between differences in nucleotide sequences and infectivity/ pathogenicity of viruses since there is no firm evidence, so far, of the existence of european strains of the coronavirus or its pathogenicity being more virulent than the asian strains. human hosts and their virus have co-evolved for millions of years, during which viruses have adapted to defense system of its host by regulating pathogenic mechanisms. therefore, the possible genetic change and resulted selection of people living in east asia should also be considered from an evolutional perspective. thus, the difference in viral susceptibility and mortality of east asian people to sars-cov-2 could also be explained if people living in east asia may have evolved to be more resistant to viral infections, including those of novel corona 16 viruses. in east asia, especially in china, agriculture started about 13,000 years ago, maybe 3,000 years ahead of europe. this led to an explosive increase in population, urbanization, and population density with the supply of abundant food. as a matter of course, acute viral infections such as measles, rubella, mumps, which could not be established until then, are believed to have taken roots in the human population (in the case of measles, it requires a population more than 250,000 to settle). unlike today, asia had long been much richer than europe before the industrial revolution. under the over-crowded and chaotic conditions, east asians must have experienced overwhelmingly with many plagues including several zoonoses due to the encounter with strange animal species. it is natural to consider that such epidemics are related to the change, choice, and evolution of the people who live there. east asians may have evolved to become more resistant against infectious agents in general including coronavirus. it is possible that difference of the past plagues could contribute to a difference in the susceptibility (and thus, pathogenicity) between europeans and asians against present new corona. present covid-19 is apparently derived from bats directly or via vector animals, and its appearance is closely related to chinese food culture. given this, it is not strange to consider the possibility that this area had been hit by coronavirus infections similar to this time before long ago. in fact, the country experienced similar endemics, sars and mers only 18 and 8 years ago, respectively. this suggests that coronavirus infection itself is one of the most likely candidates for east asian selection and evolution among the past plagues. although humans are a fairly homogeneous group of species as viewed from the genome, the diversity of the genome is well maintained. it avoids all human species from suffering the same disease and is a means of survival as a species, even if some disease prevails. although plague and people have been closely linked, one of the causes of human diversity is infectious disease. many genetic diseases are unfavorable to survival, but in some cases they are also advantageous for survival, and in some cases mutations have given the power to survive from the diseases that have hit the ground in the past. in east asia, where agriculture was established early on and urbanization has been achieved, plagues have been rushing to people in a messy environment since ancient times. we believe that it should be worth considering that individuals with advantageous gene mutations have been selected in relation to various epidemics, and have reached the present day. several genes may be involved in the genetic predisposition to covid-19, and 18 the combination of multiple genes may be important for the severity of the infection. among them, human leukocyte antigen (hla) polymorphisms are associated with susceptibility to various diseases such as autoimmune diseases and infectious diseases. the composition ratio of hla types varies greatly depending on the country and ethnic group. since hla is a protein of the immune system that is responsible for antigen presentation, hla has been attracting attention in relation to disease susceptibility. ellinghaus and colleagues performed gwas on patients in italy and spain [17] . but, it was found that certain hla types are unlikely to be associated with exacerbation of the novel coronavirus at least in italy and spain. nevertheless, since hla types, which are present only in japan and other asian countries, may show resistance to the novel coronavirus, further analysis is necessary. the human angiotensin-converting enzyme 1 (ace1) gene on chromosome 17 has an insertion (i) or deletion (d) of a 287 base pair (bp) alu repeat sequence in intron 16 [18] . therefore, in the i/d polymorphism, there are three different genotypes, ii, id and dd. ace1 is a metalloproteinase, which is a type i transmembrane glycoprotein. this protein plays an important regulatory function in the renin-angiotensin-aldosterone system (raas) and can convert angiotensin i (angi) vasoconstrictor, which is inactive, to angiotensin ii (angii). angii is the core product of the raas system, and causes various biological reactions through the angiotensin receptors (at1 and at2) while ace2 (angiotensin invertase 2) is a homologue of ace and is well known as a receptor for sars-cov-2. however, the original role of ace2 is to digest angii into ang1-7 polypeptides, and protect the heart, vasodilate, resist growth, and resist proliferation. also, the activity of bradykinin can be enhanced by ace2. very recently, we showed a strong negative correlation that the numbers of sars-cov-2 infected cases and deaths due to viral infection decreased with increasing ace1 ii genotype frequency [19] . the serum ace1 level was significantly higher in those with the dd genotype compared with those with either the id or the ii genotype [20] , and viral infection may lead to suppression of ace2 function and causes ace1/ace2 imbalance responsible for ras over-activation and pulmonary shut-down [21] . this can further reduce the effects of ace2, which counteracts the pathophysiological effects of ang ii produced by ace1, and may worsen the pathology. in patients with the d allele, especially those with the dd genotype, higher risk of morbidity and mortality from sepsis, acute respiratory distress syndrome (ards) and certain heart, lung and kidney conditions probably due to inflammation, vasculopathy and coagulopathy induced by angii [22] is reported. thus, the ace1/ace2 imbalance predicts that covid-19 patients with the d allele of ace1, especially the dd genotype, have a higher severity and prevalence of covid-19. further evidence for our hypothesis is provided by results obtained through the 20 study of other viral systems. there are a few lucky people who have escaped infection while being exposed to hiv-1. individuals homozygous for ccr5-î�32 show perfect resistance to hiv-1 [23] . infection with yersinia pestis or smallpox virus were suggested as potential selective pressures favoring ccr5-î�32 [24] . only european or central asians have this characteristic and in norway, ccr5-î�32 allele frequencies reaches nearly 20%. since aids, smallpox and plague are, by nature, independent infectious diseases that should be completely unrelated, it is very intriguing if these infectious diseases are linked by this mutant gene. indeed, in 1999, lalani et al. showed that poxviruses, can exploit chemokine receptors, especially ccr5 to infect some cell types, notably migratory leukocytes [25] . this further suggests a need searching for polymorphism and virological studies to see if there is a difference in the function of the ace2 gene as a sars-cov-2 entry receptor between asians and europeans. besides, several other examples are available in the resistance to certain type infections and genetic mutations. relationship between sickle cell anemia and malaria is well known [26] . although less dramatic, it is speculated that the relationship between typhoid fever and cystic fibrosis, which is a recessive genetic disease commonly found in europeans, is similar. there is also information regarding the relationship between human abo blood type and disease, while ab type is strong against cholera and o type is resistant to tuberculosis [27] . however, 21 our hypothesis suffers from the lack of analogous data available in other viral infections. in other words, if this theory is relevant, we should realize earlier that there is a difference in susceptibility and pathogenicity between western and asian people even in the case of other viral infections before this corona pandemic. still, it is not impossible to explain with a claim that there was no report from the past because there was no appropriate viral pandemic involving europe and east asia in the past. if there is, it may be the spanish flu occurred at the beginning of the last century or some influenzas after that. however, in the case of spanish flu, it was before the identification of the influenza virus, and it was a special event taking place towards the end of world war i in europe, so it is quite difficult to compare the difference in the pathogenicity of the influenza virus in both areas. or is the new coronavirus indeed the first case to show such ethnic differences in terms of pathogenicity? it is hoped that this point will be answered when data in the comparative studies on new coronavirus infections in the united states, where many european and asian immigrants live, will be accumulated in the very near future. in relation to this natural selection of human traits about viral resistance, there 22 are also some records on the relationship between hygienic condition and resistance to infectious diseases. it is generally accepted that asia used to have a denser human population and to have lower hygienic conditions than europe. is corona's low pathogenicity for east asians not related to the situation of asia being less-hygienic than in europe? a similar paradoxical seeming suggestion has been raised for childhood leukemia: the more often a child is infected during the first year of life, the less likely it seems to develop leukemia. epidemiological studies performed by kinlen [28] , and greaves and wiemels [29] separately showed that high socioeconomic status and lack of contact with multiple infections early in life could be a risk factor. based on these observations, zur hausen and de villiers made the following proposal by assuming the existence of a fairly universal lesser-known tumor virus such as ttv. many viral infections during pregnancy and perinatal have a negative effect on the persistence and increase of this oncovirus. intermittent viral infections, by inducing interferon, significantly reduce tumor virus load and reduce the risk of viral chromosomal alterations, prerequisites for malignant transformation [30] . very recently, katoh et al. reported a possible association between lower rate of fatality induced by coronavirus and immunization rate against encephalitis [31] . 23 artificial vaccines against japanese encephalitis (je) may result in relatively lower mortality rate in some countries. je immunization is widespread or included in national programs in many asian countries including china, south korea, japan, and taiwan. in all of these countries, the fatality rate due to covid-19 is very low when compared with countries that don't immunize against je. also, a similar hypothesis has been proposed that the inoculation of bcg vaccine may be effective against infectious diseases caused by the new coronavirus [32] . it is thus very intriguing to find out the reason why recipients are cross-protected against covid-19 conferring lower fatality rate in the countries where immunization is performed against some infectious diseases such as encephalitis or tuberculosis. it will be important to explore the underlying mechanism, such as whether this can be explained by mere nonspecific activation of immunity. as the aspect of nonspecific activation of immunity is considered as one possible mechanism that counteracts sars-cov-2 infection as well as the death rate of infected patients, it might seem worthwhile to ask the question whether the lower rate of infection and mortality due to sars-cov-2 in germany, compared to other european countries, might be connected to differences in vaccination coverages. unfortunately, such an analysis is difficult and has severe inherent limitations, as there is a very high degree of variability of vaccination coverage in germany with respect to age, sex and geography [33] . this does not allow to consider germany as one entity, but rather would require to focus on many different regions and groups, for which it seems difficult to obtain the required complete set of data. however, when the influence vaccination coverage for risk groups is compared between 11 european countries [34] germany is only on place 10 among 11 -certainly not in favour for a more advanced immunization profile of the country. furthermore, the analysis of the national vaccination calendars of france, united kingdom, italy, spain, sweden, portugal and germany [35] shows a large overlap of essential immunizations in these countries -a finding that is not in favour of assuming a specific aspect of immunization in germany that might have a particular negative impact on sars-cov-2 infections and disease. there is no doubt that central europe is much more affected by sars-cov-2 and covid-19 than east asia. the strong difference between east asia and central europe cannot be explained by eventual differences in the frequency of testing, as this would only affect the number of detected cases per inhabitants, but not the number of deaths. we are convinced that the behavioral difference in human contact in both areas of the world can be considered to have a very important influence on the spread of the sars-cov-2, as seen by the impressive positive effect of social distancing on the control of covid-19 in europe. this shows that hypothesis # 1 seems to be relevant to a significant degree for the differences between east asia and central europe. however, hypothesis # 1 cannot explain the complete picture observed, as it would only have an impact on the number of cases in relation to the population, but not on the death rate of cases. as the death rates per cases are also lower in east asia compared to central europe, mechanisms suggested in hypothesis # 2-4 might also contribute to the overall effect. in addition, mechanisms not included into our hypothesis might play essential roles and await to be defined in the future. essential parts of our hypotheses for which we have no direct supportive information so far can be experimentally verified or falsified in the future. these so far unresolved aspects are i) the possible existence of more virulent strains of 26 sars-cov-2 in europe, ii) the effects of repeated infections, possibly in combination with iii) ade, iv) polymorphism of ace2 or some other genes such as tmprss2 [36] and ace1 [19, 37] , and their relation to the function of viral receptor. covid-19 positive cases are already over 5.3 million even at this point in total while number of people infected with sars coronavirus-1 was only about 10,000. considering its near-future expansion in developing areas such as africa and south america, the new coronavirus may reach an even stronger impact than sars-cov-1. moreover, this coronavirus is very easy to mutate due to its original properties. taking these facts into account, this sars-cov-2 has the potential to persist in every corner of the world, has a great possibility of finding and adapting to the best environment in various climates and people's lives, and becoming established in human society. however, the pandemics have taught us some essentials for counteracting in the future. at the beginning of the outbreak of covid-19 in europe, the initial response, especially the delay in response to outbreaks (clusters), demographics, social behavior and lower testing capacity, etc. were sometimes very problematic in response to covid-19. these experiences allowed states that were hit later by the pandemics, like germany, to adjust countermeasures. in germany, the federal and local governments have been involved in the fight against covid-19 from an early stage, and especially with an emphasis on looking for signs of early onset, pcr 27 testing of very large numbers of samples for free, and isolation of defined cases. the medical system had time to be prepared and intensive care beds equipped with artificial respirators were reserved for covid-19 and increased in number. the needed specialized staff was trained. social distancing guidelines were introduced and widely followed. this resulted in slow-down of the pandemic. therefore, we can be confident, that even if european corona strains were more virulent than asian strains, or if europeans were more susceptible to coronaviruses, the authors declare no conflict of interest. world health organization. naming the coronavirus disease (covid-19) and the virus that causes it covid-19: what is next for public health? who scientific and technical 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relatively recent zoonotic coronavirus transmission event most new york coronavirus cases came from europe, genomes show. the new york times patient-derived mutations impact pathogenicity of sars-cov-2 on the origin and continuing evolution of sars-cov-2. national science review genomewide association study of severe covid-19 with respiratory failure online ahead of print sequence variation in the human angiotensin converting enzyme sars-cov-2 infections and covid-19 mortalities strongly correlate with ace1 i/d genotype an insertion/deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels covid-19 and individual genetic susceptibility/receptivity: role of ace1/ace2 might the double x-chromosome in females be protective against sars-cov-2 compared to the single x-chromosome in male? implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review homozygous defect in hiv-1 coreceptor accounts for resistance of some multiply-exposed individuals to hiv-1 infection evaluating plague and smallpox as historical selective pressures for the ccr5-delta32 hiv resistance allele use of chemokine receptors by poxviruses sickle cell disease and malaria morbidity: a tale with two tails blood type biochemistry and human disease epidemiological evidence of an infectious basis for childhood leukaemia origins of chromosome translocations in childhood leukaemias virus target cell conditioning model to explain some epidemiologic characteristics of childhood leukemias and lymphomas cross-protection induced by encephalitis vaccines against covid-19 might be a reason for relatively lower mortality rate in some countries is bcg vaccination causally related to reduced covid-19 mortality? online ahead of print vaccination coverage in german adults influenza vaccination coverage among high risk groups of 11 european countries how much money is spent on vaccination across western european countries sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven potease inhibitor covid-19 infections are also affected by human ace1 d/i polymorphism the data show that the two most southern states, bavaria and baden-wã¼rttemberg have much more cases of covid-19 and covid-19-related deaths (both in absolute numbers and per 100 000 people) than the two northern states within bavaria, there are very strong differences between tirschenreuth (one of the hotspots of covid-19 in germany, located in the north east of bavaria on the border to the czech republic) and its directly neighbouring districts wunsiedel compared to districts that are more distant to the hotspot (oberallgã¤u in the north west corner, main-spessart in the south west corner and regensburg in the center of bavaria). taken together, these data show the high efficiency of sars-cov-2 for spreading from a site of initial infection, but also the efficiency of adequate countermeasures taken the authors state no conflict of interests. key: cord-336912-44hifagu authors: wernly, bernhard; wernly, sarah; magnano, anthony; paul, elizabeth title: cardiovascular health care and health literacy among immigrants in europe: a review of challenges and opportunities during the covid-19 pandemic date: 2020-10-27 journal: z gesundh wiss doi: 10.1007/s10389-020-01405-w sha: doc_id: 336912 cord_uid: 44hifagu objectives: europe is a destination for many migrants, a group whose proportion of the overall population will increase over the next decades. the cardiovascular (cv) risk distribution and outcomes, as well as health literacy, are likely to differ from the host population. challenges related to migrant health status, cardiovascular risk distribution and health literacy are compounded by the ongoing coronavirus disease 2019 (covid-2019) crisis. methods: we performed a narrative review of available evidence on migrant cv and health literacy in europe. results: health literacy is lower in migrants but can be improved through targeted interventions. in some subgroups of migrants, rates of cardiovascular disease (cvd) risk factors, most importantly hypertension and diabetes, are higher. on the other hand, there is strong evidence for a so-called healthy migrant effect, describing lower rates of cv risk distribution and mortality in a different subset of migrants. during the covid-19 pandemic, cv risk factors, as well as health literacy, are key elements in optimally managing public health responses in the ongoing pandemic. conclusions: migrants are both an opportunity and a challenge for public health in europe. research aimed at better understanding the healthy migrant effect is necessary. implementing the beneficial behaviors of migrants could improve outcomes in the whole population. specific interventions to screen for risk factors, manage chronic disease and increase health literacy could improve health care for migrants. this pandemic is a challenge for the whole population, but active inclusion of immigrants in established health care systems could help improve the long-term health outcomes of migrants in europe. non-communicable diseases (ncds) are the primary cause (around 70%) of death worldwide. among ncds, cardiovascular disease (cvd) is the top cause of death, being responsible for about 50% of mortality (cosentino et al. 2020; knuuti et al. 2020) . the management and outcomes of ncds have improved over the past few decades. the scientific community contributed to a better understanding and new pharmacologic and interventional treatment options (cosentino et al. 2020; knuuti et al. 2020 ). however, from both an individual level and public health perspective, disease prevention is preferable to managing established chronic disease. health literacy is fundamental to successful prevention (magnani et al. 2018) . large-scale immigration of non-european refugees peaked in 2015 in europe but is likely to continue in upcoming years. immigrants differ from the host population with regard to genetics, baseline risk distribution, lifestyle and health literacy (cainzos-achirica et al. 2019 ). these differences affect the prevalence and incidence of ncds. also, access to health care is challenging for immigrants in some countries. the united nations defines a long-term migrant as a "person who moves to a country other than that of his or her usual residence for a period of at least a year." europe was a source of migration in the nineteenth century, but is now a destination for migrants. between 2005 and 2010, the number of migrants living in europe increased from 65 million to 70 million and is expected to continue to rise (rechel et al. 2013 ). these 70 million migrants suffer from high rates of unemployment and low socioeconomic status and are, therefore, not only a humanitarian but also an economic and public health challenge (rechel et al. 2013) . health care data on migrants in europe is scarce for several reasons, including nonstandardized definitions of migrants in health care systems and limited resources for public health research (rafnsson and bhopal 2008) . however, the description of challenges and opportunities migrants pose for public health might be crucial for improving health care for all. in december 2019, the new coronavirus severe acute respiratory syndrome coronavirus 2 (sars-cov-2) emerged, causing coronavirus disease 2019 (covid-2019). clinically, covid-19 manifests similarly to influenza (symptoms such as fever, cough dyspnea, myalgia), but appears to have a higher risk of mortality than influenza, particularly in the elderly (huang et al. 2020) . the world health organization (who) declared the ongoing crisis a pandemic. as a consequence, policymakers reacted to covid-19 with extensive public health measures, most notably non-pharmacologic intervention and physical distancing, which have been shown effective in prior pandemics (markel et al. 2007 ). there is increasing evidence supporting the concept that patients with pre-existing cv conditions are at higher risk of death due to covid-19 (huang et al. 2020) . although covid-19 primarily manifests as a respiratory disease, patients with covid-19 die from inflammatory, cv and respiratory causes (huang et al. 2020) . both the disease itself and the social, public and economic consequences of the covid-19 pandemic are likely to affect the lives of migrants throughout europe. the integration of migrants in the european public and health care systems is likely to be affected by covid-19. furthermore, the successful management of the sars-cov-2 pandemic using nonpharmaceutical interventions depends on the compliance and participation of migrants. we, therefore, aimed to summarize the evidence on cvd and health literacy of immigrants in europe. further, we evaluated the relation between the ongoing covid-19 pandemic and migrant cv risk distribution and health literacy. we performed a narrative review of cv risk distribution and health literacy in migrants in the european union, including switzerland, norway and the united kingdom. migrants, immigrants and refugees included people from all developing countries as well as eastern european countries and the balkan region, which are not part of the european union. this group was analyzed in light of the challenges related to the ongoing covid-19 pandemic. we performed a search on medline and google scholar using the keywords "migrant," "refugee," "cardiovascular," "diabetes," "hypertension," "non-communicable disease," "sars-cov-2," "covid-19" and "covid" in different combinations. in total, the search yielded 2183 manuscripts. after deletion of duplicates and reports not concerning countries of the european union, as well as manuscripts considered to be outdated based on our subjective clinical/public health expertise, 185 references were screened in depth. also, reviews and statements on the topics of health literacy and migrant health were screened for relevant literature. further, we screened co-citations using the cocites algorithm for other relevant manuscripts. based on available evidence and our judgment, the final 59 manuscripts were included in this narrative review. cvd is highly prevalent and leads to high mortality, morbidity and costs in both developing and developed societies (benjamin et al. 2019) . however, the rates of cvd also differ within western and non-western countries, as the distribution of risk factors and preventive measures of local health care systems vary rechel et al. 2013 ). moreover, the economic capabilities of health care systems to provide cvd management according to the latest guidelines differ and likely contribute to differential outcomes worldwide (cosentino et al. 2020; knuuti et al. 2020) . the european host societies are more often urban and evidence higher levels of environmental pollution (sohail et al. 2015) . the host societies also promote behavioral changes among refugees, such as a sedentary lifestyle, which consequently changes the cv risk profile of migrants (sohail et al. 2015) . depending upon the host country and the degree of integration, access to health care and the living conditions of migrants can influence outcomes in either first-generation or later-generation migrants or in none of the migrants (raymundo et al. 2020) . migrant populations are difficult to characterize, since their situations vary greatly. in one review, the rates of ischemic heart disease and stroke were heterogeneous among migrants in europe (sohail et al. 2015) . migrants from the middle east and south asia exhibited similar or higher rates of cvd and stroke compared to the host population (sohail et al. 2015) , in contrast to migrants from northern africa, who may have a lower rate of stroke. in another study from the netherlands, south american migrants had higher stroke rates, while north african migrants demonstrated lower risk for cvd (bos et al. 2004 ). this finding of lower risk for cvd in north african migrants was confirmed by a spanish study, which reported lower rates in north african populations as compared to higher rates in asian and sub-saharan african groups (regidor et al. 2009 ). of note, the living conditions in the host countries are an additional contributing factor for differential rates of cvd, as south asian migrants were at an even higher cvd risk than their relatives in the country of origin (bhatnagar et al. 1995) . in the rodam [research on obesity & diabetes among african migrants] study, sub-saharan african migrants in europe showed higher rates of cvd than their counterparts living in a rural environment . while some of the effects might also be attributable to rural versus urban environments, the differences between migrants and their peers in an urban home country setting were small ). finally, the cvd outcomes and mortality of migrants differ between european host countries (bhopal et al. 2012; sohail et al. 2015) . interactions between the country of origin, host country and rural versus urban environment all play a role in determining cvd risk . in sub-saharan african migrants, hypertension is consistently more prevalent than in host populations commodore-mensah et al. 2014; modesti et al. 2014 ). in the netherlands, the rates of hypertension in male migrants of sub-saharan african origin was above 60%, compared to 34% in dutch males (agyemang et al. 2015) . studies across europe have confirmed the finding of a higher prevalence of hypertension in immigrants . also, the disease was less successfully managed in migrants compared to the host population, which could indicate worse access to health care but also compliance problems (agyemang et al. 2005; agyemang et al. 2015) . in addition to hypertension, rates of type 2 diabetes are higher in migrants . diabetes is a key risk factor for cvd, and its management is difficult and usually long-term in nature (pernow et al. 2019) . strikingly, diabetes is more prevalent among virtually all ethnic migrant groups sohail et al. 2015) . a meta-analysis by meeks et al. recently confirmed this finding and found higher rates of diabetes among asian, middle eastern and african migrants compared to european host populations . mainly migrants from south asia suffer from very high rates (3-6 times) of diabetes compared to european host populations . moreover, the onset of diabetes is not only more common but occurs more than 10 years earlier in immigrants (snijder et al. 2017) . migrants are more likely to suffer from both microand macrovascular complications related to diabetes (vandenheede et al. 2012) . in one study, diabetes mortality was almost twice as high in migrants as in european host patients (vandenheede et al. 2012) . both the living conditions in the host countries and genetic factors may explain this finding (galbete et al. 2018) . the rates of obesity are higher in migrants as well ). also, differential patterns in diets, physical exercise and socioeconomic "dysstress" likely contribute to the higher burden of diabetes in immigrants (cosentino et al. 2020 ). however, these factors might not be enough to explain the differences in prevalence and outcome, and a deeper understanding of both access to health care but also genetic and epigenetic factors is crucial for fully evaluating the observed differences. given the complex and interdisciplinary management of diabetes, this finding underscores the potential impact on european health care systems (cosentino et al. 2020) . this conundrum reflects the multifactorial pathogenesis of cvd, which is the common final pathway of arterial hypertension, obesity, diabetes, socioeconomic factors and behavioral factors-such as physical exercise and nutrition-as well as genetic factors (cosentino et al. 2020; knuuti et al. 2020) . these are all likely to either differ between migrants and the host population or be influenced by the migration and the subsequent changes in living conditions, income, access to health care and environmental factors. migrant health is not a unidimensional subject. there is also evidence for the so-called healthy migrant effect, describing lower rates of cv risk distribution and mortality in migrants as compared to the host population (delgado-angulo et al. 2020; gkiouleka and huijts 2020). in a danish study including more than 50,000 migrants and 200,000 age-and sex-matched danes, the mortality rates were consistently lower in immigrants (norredam et al. 2012) . a swedish register study supports this finding of lower cv events in migrants (helgesson et al. 2019 ). byberg et al. observed a similar pattern in a large register evaluating cvd incidence and mortality in 114,331 migrants matched 1:6 to persons born in denmark: migrants had lower rates of death, and the subgroup of family-reunified migrants had lower rates of cvd (byberg et al. 2016) . some studies have reported that the observed differences in cvd risk between migrants and the host population decline in a time-dependent manner (harding et al. 2008 ). in the netherlands, north african migrants lost the advantage of lower cvd over time as the gap closed (van oeffelen et al. 2014 ). these findings of increasing cvd rates in migrants over time is supported by intergenerational studies (sundquist and li 2006; van oeffelen et al. 2013) . in sweden, second-generation migrants tended to exhibit higher rates of cvd than first-generation migrants, and the risk almost converged to the rates of the host population (sundquist and li 2006) . health literacy is an essential cornerstone of health promotion (kickbusch 1997 ). nutbeam proposed three levels of health literacy (nutbeam 2000) . first, functional health literacy relates to basic knowledge, including literacy, arithmetic, an understanding of disease and health services. second, interactive health literacy corresponds to the social skills necessary for communication with health care providers. third, critical health literacy refers to a broader knowledge of health-relevant information and the ability for informed decision-making (nutbeam 2000) . the health literacy of migrants could be impaired-but also improved through tailored interventions-on all of these levels (fernandez-gutierrez et al. 2018) . of note, a systematic review found interventions to be effective in increasing health literacy in immigrants (fernandez-gutierrez et al. 2018 ). however, specific programs targeting health literacy in migrants are scarce and not well studied, and there is likely both opportunity and demand for improvement (jones et al. 2011) . health literacy is key to successfully preventing and managing ncds (magnani et al. 2018) . interestingly, some studies indicate high awareness of ncd risk factors among migrants . the rates of treatment were higher in some groups of migrants compared to the respective host population . still, there are substantial data indicating suboptimal management and control of cvd risk factors in migrants . therefore, language barriers, differential perception of risk factors and concepts of health and disease are likely to contribute to a lack of adequate health care in migrants (nutbeam 2000) . health care providers need to recognize these differences on an individual basis. from a broader perspective, policymakers need to consider addressing and reaching out to migrants in innovative ways (jervelund 2018) . for example, in the united states, blood pressure measurement in barbershops, a popular social gathering place among american black men, was shown to improve control of arterial hypertension in this population (rader et al. 2013) . patients screened for diabetes in barbershops evidenced higher rates of impaired glucose tolerance compared to the general population (osorio et al. 2020 ). the ongoing covid-19 crisis will affect humans across the globe as the epidemiology of this virus continues to unfold. however, it becomes increasingly clear that cvd constitutes a significant risk factor for severe illness (zheng et al. 2020) . the specific pathways of this association are the subject of ongoing research. still, protecting the vulnerable will be a key strategy in controlling covid-19 (verity et al. 2020 ). therefore, identification of patients at high risk for severe lifethreatening covid-19 is necessary. migrants evidence higher rates of cvd, particularly hypertension and diabetes, which have been linked to adverse outcomes in covid-19. therefore, the protection of these individuals is important. however, extending such protection relies on educating these patients about the new disease. patients need to understand the risks of infection, how to limit exposure and who is at risk. as a result of the described limitations in health literacy but also language barriers, protecting migrants at risk will be challenging (spiegel et al. 2020) . specifically, approaches in different languages need to be tailored to enable the public health systems to reach out to these patients (greenaway et al. 2020) . migrants are more likely to live in areas with greater population density, both in migrant camps and in european urban areas (costa and de valk 2018) . the basic public health measures, including physical distancing, hand hygiene, and quarantine of symptomatic individuals and contact persons, are difficult to implement under these conditions (maroko et al. 2020) . therefore, the distribution of migrants from camps to other, less densely populated areas with access to adequate housing and hygiene is now not only a philanthropic, but also a public health demand . these measures, mitigating the spread of the sars-cov-2, will improve the health not only of migrants but of all inhabitants (brandenberger et al. 2020) . as long as migrant camps persist, disease-specific management should be available: testing, tracking and tracing of both migrants inside and workers from outside have to be in place to avoid the introduction and transmission of sars-cov-2 (brandenberger et al. 2020 ). information about the virus and non-pharmacologic intervention measures should be available in the migrants' native language, partly as an important countermeasure against fake news spreading via social media (islam et al. 2020) . increasing the health literacy in newly arrived migrants could increase the acceptance of non-pharmacologic intervention, help to detect and isolate infected individuals and protect the vulnerable (christie and ratzan 2020). migrants are over-represented in the european homeless population (anh ly et al. 2020) . for homeless persons, hygiene measures, self-isolation if symptomatic and social distancing may be nearly impossible (bhopal 2020; tsai and wilson 2020) . oftentimes, homeless migrants sleep in crowded institutions during the winter. in this setting, transmission is likely and mitigation complicated (bhopal 2020; tsai and wilson 2020) . limitations of this review include its narrative design. further, the terminology for immigrants is not precise and the population is highly diverse-in demographics, home country and host country. thus, analysis as a single group based on their commonality as immigrants is an inherent oversimplification. moreover, the distribution of source and host countries evolves over time within the growing european union. therefore, the literature selection was based on both structured review of available evidence and our subjective judgment of the suitability of the manuscripts reviewed here. migrants and the european host population differ regarding cvd risk distribution and outcomes. both biological (genetic, epigenetic) and non-biological (socioeconomic, behavioral) factors contribute to the observed differences. cv migrant health and risk factors are a multidimensional matter. some immigrants do have higher rates of some cvd, most importantly hypertension and diabetes. lower rates of health literacy and signals towards worse control of chronic diseases in migrants could lead to significantly worse outcomes in this population. however, in other migrant subgroups, cv outcomes are even better than the host population. this "healthy migrant effect" is likely multifactorial but could include genetic reasons, the age-distribution, a selection bias ("migration of the fittest") and lifestyle factors. this effect was predominantly described in the first generation of migrants, and there is evidence suggesting that the healthy migrant effect diminishes over time. the european population should try understanding and integrating the reasons behind better health in some migrants. implementing these measures in the whole community could benefit public health. migrants are both an opportunity and a challenge for european public health. young and healthy migrants will likely contribute workforce, gross domestic product and wealth necessary to provide resources for the public health. tailored programs to increase health literacy, screen for risk factors and manage chronically ill migrants such as the american barbershop interventions could improve outcomes. while the european host population does have a strong tradition of gathering in barbershops, other similar environments popular with immigrants could be a stage for basic health care and health literacy interventions. during the pandemic, the european union may benefit from granting migrants universal access to the local health care systems. excluding migrants from health care likely decreases testing and tracing in this population group, which could counteract local containment, mitigation and suppression strategies. another concern during the covid-19 pandemic is that patients with chronic illnesses may not seek care due to social distancing measures and restrictions in access to care. a delicate balance exists between ensuring social distancing to minimize sars-cov-2 infections and promoting necessary contact between patients and health care providers. the application of e-health and telemedicine might be limited in migrants because of socioeconomic factors, language barriers and health literacy (hollander and carr 2020) . thus, emerging methods of physically distanced care for the host population may be much more difficult in migrants. once a vaccination is available for sars-cov-2, health literacy might be key to promoting vaccination among immigrants, although the role of health literacy and vaccination hesitancy and acceptance is a subject of concern (lorini et al. 2018 ). the higher rates of risk factors and the lower rates of health literacy are a significant concern for migrants. the younger age of migrants, especially those who arrived recently, could constitute an advantage for the aging european populations. younger patients have lower rates of severe illness due to covid-19 and may contribute to herd immunity, which may ultimately be necessary to protect the vulnerable. during the pandemic, the universal inclusion of migrants in health care systems could help to ensure testing, tracking and tracing in the whole population. european societies need to provide both care and information to immigrants. this pandemic is a challenge for the whole population, but the necessary active inclusion of immigrants in the health care systems could also help with the long-term integration of migrants in europe. funding open access funding provided by paracelsus medical university. ethics statement not applicable for a narrative review. the authors whose names are listed above certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. cardiovascular disease, diabetes and established risk factors 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congestive heart failure by country of birth incidence of acute myocardial infarction in first and second generation minority groups: does the second generation converge towards the majority population? migrant mortality from diabetes mellitus across europe: the importance of socio-economic change estimates of the severity of coronavirus disease 2019: a model-based analysis covid-19 and the cardiovascular system publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-270940-acwkh6ed authors: kallio-kokko, hannimari; uzcategui, nathalie; vapalahti, olli; vaheri, antti title: viral zoonoses in europe date: 2005-06-29 journal: fems microbiol rev doi: 10.1016/j.femsre.2005.04.012 sha: doc_id: 270940 cord_uid: acwkh6ed a number of new virus infections have emerged or re-emerged during the past 15 years. some viruses are spreading to new areas along with climate and environmental changes. the majority of these infections are transmitted from animals to humans, and thus called zoonoses. zoonotic viruses are, as compared to human-only viruses, much more difficult to eradicate. infections by several of these viruses may lead to high mortality and also attract attention because they are potential bioweapons. this review will focus on zoonotic virus infections occurring in europe. during the past 15 years a number of new virus infections have emerged or re-emerged. most of them, such as sin nombre and andes hantaviruses, sars coronavirus, avian influenza, nipah and hendra viruses, have appeared in subtropical or tropical regions. dengue is spreading to new areas and west nile virus has reached the new world. infections by several of these viruses may lead to high mortality and also attract attention because they are potential bioweapons. some viruses such as tick-borne encephalitis virus are spreading to new areas along with climate and environmental changes. most of these infections are zoonoses and clearly viruses shared by animals and humans are, unlike human-only viruses, much more difficult to eradicate. here, we review zoonotic virus infections occurring in europe. the infections like lassa fever and dengue that are imported to europe but are not indigenous to european nature will not be discussed in detail in the review. we have divided the virus infections into two categories, those that are transmitted to humans directly from vertebrate animals (like rodents, foxes, bats and birds) and those that are primarily transmitted by arthropods (mosquitoes, ticks, sandflies). the latter class is formed by arboviruses but notably they have vertebrate hosts in nature. hantaviruses are enveloped viruses with a tri-segmented negative-stranded genome and belong to the family bunyaviridae [1, 2] . the 6.4 kb l (large) segment rna encodes the 250 kda rna polymerase, the 3.6 kb m (medium) segment the two glycoproteins 68-76 kda gn and 52-58 kda gc, -formerly known as g1 and g2; and the 1.7 kb s (small) segment the 50-54 kda nucleocapsid protein (n) ( table 1 , fig. 1 ). in addition, the s segment of some hantaviruses has another open reading frame named ns but its product or function remains to be discovered. viral messenger rnas of the members of the bunyaviridae are not polyadenylated and are truncated relative to the genome rnas at the 3 0 termini. messenger rnas have 5 0 -methylated caps and 10-18 nontemplated nucleotides which are derived from host cell mrnas. the termini of all three segments are conserved and complementary to each other, a feature that has assisted in cloning and discovery of new hantaviruses. unlike most other bunyaviridae, hantaviruses are not arthropod-borne (arboviruses), but are rodent-borne, roboviruses. each hantavirus is primarily carried by a distinct rodent/insectivore species although a few host switches seem to have occurred during the tens of millions of years of their co-evolution with their carrier animals [3] . we now know that the genetic diversity of hantaviruses is generated partly by (i) genetic drift (accumulation of point mutations and insertions/deletions) leading to quasispecies [4, 5] , (ii) genetic shifts (reassortments of genome fragments within the same virus genotype/species), and (iii) according to recent findings [6, 7] , by homologous recombination, a mechanism not previously observed for negative-strand rna viruses. hantaviruses, which cause hemorrhagic fevers with renal syndrome (hfrs) in eurasia and hantavirus cardiopulmonary syndrome (hcps) in the americas, are prime examples of emerging and re-emerging infectious agents. like most of these infections hantaviral diseases are zoonoses. with the exception of the south-american andes virus, which can be transmitted directly from human to human, hantavirus infections are thought to be transmitted to humans primarily from aerosols of rodent excreta. only some [9, 10] . topografov hantavirus isolated from siberian lemmings (lemmus sibiricus) has not been detected in north european lemmings (lemmus lemmus) although it can grow in them [11] . infections in rodents are mainly asymptomatic and persistent. hantavirus infections are quite common in europe [8] (table 3) , puumala virus is common in northern europe, european russia and parts of central-western europe (fig. 2) . dobrava virus is found mainly in the balkans (fig. 2) . saaremaa virus has been detected in eastern and central europe but its epidemiology is not well defined (fig. 2) . apart from laboratory infections [12, 13] seoul virus has been detected in wild rats, only in france [14] . it is also apparent that many parts of europe, such as britain, poland and byelorussia, remain ''white'' on the european hantavirus map [8] . this means either that hfrs is rare or nonexistent in these regions or is not widely recognized and diagnosed by the biomedical community. in northern europe hfrs as well as the carrier rodents exhibit peaks in 3-4 year cycles [15] while in central europe the hfrs incidence follows the fluctuations of ''mast years'', i.e. the availability of beech and oak seeds for the hantavirus-carrying rodents. in central europe hfrs peaks in the summer while in northern europe most cases occur in late autumn and early winter, from november to january. risk factors to catch hantavirus infections and hfrs include professions such as forestry, farming, and military, or activities such as camping, and the use of summer cottages. males are more likely to be exposed than females [15, 16] . puumala and dobrava viruses both cause hfrs but the infections differ considerably in severity [17] : both are characterized by acute-onset fever, headache, abdominal pains, backache, temporary renal insufficiency -first oliguria, proteinuria and increase in serum creatinine and then polyuria -and thrombocytopenia but the extent of hemorrhages (hematuria, petecchiae, internal hemorrhages), requirement for dialysis treatment, hypotension and mortality are much higher in [19] . this is important since the infection is so common in many areas of europe [8] (table 3 , fig. 2 ). in addition, in some patients puumala virus infection may invade the pituitary gland and lead to mortality or at least hypophyseal insufficiency requiring hormone-replacement therapy [20] . the pathogenesis of hfrs is poorly understood [17, 21] . however, it is known that b3 integrins can mediate the entry of pathogenic hantaviruses [22] and that hantaviruses can regulate apoptosis [23] [24] [25] [26] 28] . also there is evidence [17, 21] that increased capillary permeability is an essential component in the pathogenesis of both hfrs and hcps, although different target tissues, kidneys and lungs are affected in the two diseases. hfrs patients show locally increased levels of tnf-a in the plasma and kidneys [27, 28] and high levels of urinary secretion of the proinflammatory cytokine il-6 [29] . studies with a monkey model mimicking human puumala virus infection [30] may assist in elucidating the mechanism of pathogenesis. of the four structural proteins, both in humoral and cellular immunity, the n protein appears to be the principal immunogen [31] . cytotoxic t-lymphocyte (ctl) responses are seen [32] and may be important both for protective immunity and pathogenesis of hantavirus infections [21] . the diagnosis of acute hfrs is primarily based on serology, since viral rna cannot be regularly detected in the blood or urine of patients [33, 34] . both immunofluorescence tests and enzyme immunoassays are widely used for detection of specific igm or low-avidity igg antibodies, characteristic of acute infection [35] [36] [37] . in addition, immunochromatographic 5-min igm-antibody tests [38, 39] have been developed. vaccines against hantavirus infections have been used for years in china and korea, but not in europe or the americas [40] . no specific therapy is used in europe, although both ribavirin and interferon-a have been successfully used in trials in china [41, 42] . a major problem is that at the time hfrs patients are hospitalized, virus replication is already disappearing. members of the genus lyssavirus within the family rhabdoviridae are bullet-shaped, enveloped viruses approximately 60 nm in diameter and 200 nm in length. the 12 kb non-segmented negative-strand genome encodes five proteins (starting from the 3 0 end): the 58-62 kda nucleoprotein (n), the 35-40 kda phosphoprotein (p), the 22-25 kda matrix protein (m), the trimeric 65-80 kda glycoprotein (g) and the 190 kda polymerase protein (l) ( table 1 , fig. 1 ). proteins are separately transcribed in cascade by a special mechanism from a single 3 0 -end promoter which results in a decreasing transcription and expression gradient for proteins encoded from the 3 0 to 5 0 end. the major antigen with neutralizing epitopes and pathogenetic determinants is the glycoprotein, which is responsible for receptor recognition and membrane fusion. after endocytosis the viral envelope fuses with endosomal membranes provoking the release of the internal viral nucleocapsid in the cytoplasm where transcription and replication takes place. the helically wound nucleocapsid results from the intimate association of the nucleocapsid protein and the rna genome. it serves as template for the polymerase (l protein and p cofactor) for transcription and replication. it buds to intracytoplamic membranes in infected neurons, but on plasma membranes in salivary gland epithelial cells. the lyssaviruses currently consist of 7 established genotypes, or lineages, of rabies(-like) viruses [56] of which the classical rabies virus, found throughout the world and associated with terrestrial mammalian hosts and american bats, forms genotype 1 ( table 2 , fig. 3 ). other lineages, or genotypes, are found in bats, of which mokola and lagos bat viruses seem to be less pathogenic, and towards which the vaccines based on the classical genotype 1 rabies virus are not protective [43a,43b] . in addition to the 7 genotypes, new bat lyssavirus genotypes have been recently found, e.g. from russia [43c]. during the past 100 years or more in europe, classical rabies virus has made two major host shifts, firstly from the dog to red foxes, and then to racoon dogs brought from east asia to be raised for fur; this species then became widely established in the wild (fig. 3) . phylogenetic data also suggest that westand southward spread of rabies virus occurred during the last century [44a] . although in europe the most important carriers of classical rabies virus are foxes and racoon dogs, the virus can be transmitted to secondary hosts such as domestic animals (dog, cat, cattle, horse, sheep) or e.g. deer -practically any mammal species could be a potential carrier. bats are a special case; lyssaviruses are maintained in bats, even in the absence of classical rabies in carnivores; thus in countries where classical rabies has been eliminated, bat rabies has become the dominating or only source of rabies virus and retains the potential for host-switching into the carnivore reservoir which constitutes a more direct threat for public health [44b]. as many bats are protected species, the detection or ''absence'' of bat rabies is dependent also on the intensity of screening efforts [45, 46] . as of the beginning of 2004, the following countries in europe were declared ''rabies-free'' by who (meaning no indigenous cases occurred during the last two years): belgium, cyprus, finland, greece, iceland, ireland, italy, luxembourg, norway, portugal and sweden (fig. 3) . in 2003, rabies virus was detected in europe in 7095 wild animals (excluding bats), 3951 domestic animals; 33 bat and 6 human rabies cases were diagnosed (see table 4 ). the countries where rabies was circulating include (in diminishing order of cases) russia, ukraine, lithuania, belarus, latvia, estonia, croatia, poland, slovakia, serbia-montenegro and turkey with hundred(s) to thousands of (animal) cases, romania, bosnia-herzegovina, germany, moldova and bulgaria with dozens of cases, and individual cases were registered (some imported and not affecting the rabies-free status) in slovenia, the netherlands, denmark, france, albania, finland, austria and switzerland ( members of 6 out of the 7 lyssavirus genotypes (except lagos bat virus, i.e. genotype 2) have caused rabies disease in man. the infection is inevitably fatal in humans or other mammals unless immune intervention (vaccination and administration of antibodies) is used. transmission may occur though the bite of an animal delivering the virus deep in to striated muscle or connective tissue, but infection may also occur after abrasion of the skin or licking of mucous membranes. the bite of a bat with small teeth may go unnoticed; on the other hand the bat lyssaviruses may infect human skin more easily than has been recognised. the incubation period is 20-60 days, but has been shown in some cases to be months, even years. the classical picture of rabies includes prodromal illness with fever and non-specific symptoms, as well as itching and local paresthesia. this is followed by neurological signs, consisting of either encephalitic ''furious rabies'' or paralytic ''dumb rabies''. in the former, episodic hyperactivity and excitation of the cns manifest as, e.g. hydrophobia, hypersalivation and convulsions. the patient finally develops paralysis, coma and cardiorespiratory failure. in the paralytic form, no excitation is seen, but paralytic disease develops to coma and death [45,52a,52b] . after entry of the virus to the body, the virus must gain access to peripheral nerves and to be transported towards the cns. rabies virus components are attached either directly or by encapsulated vesicles to the dynein motor carrying the ''cargo'' along the axonal microtubular system towards the cell stroma, approximately at a speed of 25 mm/day [45, 53, 54] . it is transmitted after replication on neuronal membranes transsynaptically to adjacent neurons and finally invades the cns where it first disturbs the limbic system associated with the excitation, and later neocortex, with little histopathological changes in neurons. centrifugal spread of the virus from the cns to many tissues through somatic and autonomic nerves also occurs, where the salivary glands are especially important for the spread of the virus to the next victim. immunological responses do not occur before cns involvement. all the viruses in phylogroup i are also pathogenic to mice by i.m. injection, and can cross-neutralize each other. this has practical implications, as fortunately the vaccine strains (of genotype 1) also appear to protect against the ebvl viruses [55] . a pathogenic determinant common to phylogroup i viruses seems to be amino acid r333 in the glycoprotein [56] ; substitution of this amino acid also abolishes the retrograde transport [57] . when symptoms develop, no cure is available. however, after exposure to a bite or scratch of a potentially rabid animal, rabies must and can effectively be prevented by post-exposure prophylaxis, originally developed by louis pasteur. the treatment includes in a non-vaccinated person (a) washing (with water and detergent) and disinfecting the wound to minimize the amount of cell-free virus (this alone can increase survival 50%), (b) starting a post-exposure vaccine regimen which includes (in europe) five doses of cell-culture derived vaccine intramuscularly into the deltoid muscle on days 0, 3, 7, 14, 28 and (c) in case of severe or deep injury additional passive anti-rabies immunoglobulin, which should be administered principally to the wound area. if the person was pre-vaccinated or the animal can be caught and studied for the presence of rabies, the protocol can be adjusted accordingly [45,52a] . clinical suspicion of rabies in a case of encephalitis of unknown origin is the starting point. ante mortem diagnostics can be achieved most easily with rt-pcr from saliva. in addition, rabies antigen can be detected in brain or nuchal skin biopsies, and in some cases antibodies in serum or csf may be found. post-mortem diagnostics is most rapid with antigen detection or rt-pcr from the brain, virus isolation is also possible. in addition to post-exposure prophylaxis, vaccines in humans can be used for pre-exposure prophylaxis (3 doses) in risk groups (veterinarians, wildlife workers, travellers to endemic areas; especially small children who may be unable to explain a potential exposure to a rabid animal) [45,52a,58] . the primary method for control of rabies is vaccination of dogs (and cats). this practice was established at the beginning of the last century in most of europe, but has not yet been achieved in many developing countries, where annually 60 000 people still die of rabies. in most of europe (excluding eastern europe) rabies has been eradicated from terrestrial wildlife species (carnivores) by aerial distribution of vaccine baits across the countryside. the vaccines used to protect wildlife species include attenuated vaccines as well as a recombinant vaccinia virus carrying the rabies virus glycoprotein (the latter has in one case caused a skin infection in man). although rabies in terrestrial animals can be controlled efficiently, eradication from the bat reservoir is not currently feasible. arenaviruses are the only members of the rna virus family arenaviridae. these viruses are enveloped, lipid solvent-sensitive, pleomorphic particles with a mean diameter of 120 nm (ranging between 50 and 300 nm). host cell-derived ribosomes are present in the virions, and give the virus particles a ''sandy'' appearance under the electron microscope, hence the name arenavirus (arena: sand in latin). the virion structure of arenaviruses is quite simple, virus particles contain two rna segments (s and l) linked to nucleocapsid proteins and viral polymerase molecules, and these nucleocapsidpolymerase complexes are surrounded by a lipid envelope into which two glycoproteins (g1 and g2) are linked protruding on the outside of the virion. arenaviral rna segments have an ambisense coding arrangement, the s segment (3.5 kb) encoding a 63-kda nucleocapsid protein (n) in the viral complementary sequence, and in the viral-sense 5 0 -end sequence a 75-kda glycoprotein precursor (gpc) which is posttranslationally cleaved to two glycosylated proteins 34-44 kda g1 and g2; and the l segment (7.2 kb) encoding a 180-kda viral polymerase (l) in the viral complementary sequence, and in the viral-sense 5 0 -end of the sequence a 10-14 kda ring finger z protein, which has been shown to have a role in arenavirus budding [59a] (table 1 , fig. 1 ). initiation of transcription may involve cap-snatching, although the transcription mechanism is not yet fully elucidated. arenaviruses include 23 viruses all carried by different rodent hosts (except tacaribe virus which has been isolated only from fruit bats) [59b]. arenaviruses are capable of causing chronic infections in their rodent hosts, and infectious virus is present in the blood and is also secreted into body fluids (saliva, urine, semen), which is presumably the route of transmission to humans. the appearance and incidence of arenaviral infections are closely associated with the distribution of the rodent host species and the rodent population dynamics. arenaviruses have co-evolved with their specific host species during millions of years, and have been divided into old world and new world groups first on a serological bass, and later into evolutionary lineages (new world group) using genetic analysis [60a,60b,60c]. both groups contain viruses that are included in the category a pathogen list (defined by cdc, usa), which means that the propagation of these agents is allowed only in biosafety level 4 laboratories. these highly pathogenic arenaviruses include the south american junin, machupo, guanarito, and sabia viruses from the new world group, and the african lassa virus from the old world group. all these viruses can cause hemorrhagic fevers in humans, and are considered potential bioterrorism agents being thus included in biohazard preparedness programs. in europe, these viruses occur only rarely as imported cases. the only arenavirus endemic in europe is lymphocytic choriomeningitis virus (lcmv), shown to circulate in mus musculus populations (table 2) , and associated with pet hamster derived epidemics [59b,61a]. relatively few epidemiological data are available concerning the actual distribution of lcmv in europe, but in addition to serological evidence from mus sp. material from spain [61b], antibodies against lcmv have been detected in rodent species other than mus musculus (our unpublished data), which indicates that other yet unknown arenaviruses may circulate in europe. at least ten arenaviruses have been reported to be able to cause disease in humans. as mentioned above, five arenaviruses (lassa, junin, machupo, guanarito, and sabia viruses) are even capable of causing a lifethreatening viral hemorrhagic fever [62a,62b] . none of these five viruses are endemic in europe, but a few imported lassa virus infections have been diagnosed in germany and great britain during the last few years with no secondary infections detected [63] [64] [65] . increased travelling increases also the risk for transmission of exotic arenaviruses to non-endemic areas such as europe. lcmv is thus far the only known endemic arenavirus in europe [62b]. in humans lcmv infections are mostly either asymptomatic or influenza-like diseases. in some cases aseptic meningitis or meningoencephalomyelitis is seen. lcmv is also capable of causing congenital infections manifested by hydrocephalus, microcephalus, chorioretinitis, and mental or psychomotor retardation [66,67a,67b] . lcmv infections are rarely fatal for humans. the diagnosis of arenaviral infections is based on serology and/or direct detection of the virus [68] . for serodiagnosis methods using immunofluorescence assay (ifa) as well as enzyme immunoassay (eia) have been described. either a four-fold rise in igg antibody titers or presence of igm antibodies is considered indicative of acute infection. the antibodies that appear first in the acute phase of infection are directed against the nucleocapsid protein; neutralizing antibodies against the glycoproteins appear later in the convalescent phase (if at all). this means that typing of the causative agent is difficult on a serological basis at the early stage of infection, and is actually possible only in the convalescent phase due to the slow rise of virus typespecific neutralizing antibodies. for direct detection of the virus, antigen detection assays are useful in the early diagnosis of lassa fever especially. also reverse transcriptase (rt)-pcr tests have been developed to detect arenaviral rna in patient samples [69a,69b,70a,70b,70c]. virus isolation attempts can also be successful. the supportive treatment of arenaviral infections includes ensuring the fluid, electrolyte and osmotic balance. in severe hemorrhagic fever-cases early diagnosis is important because the use of ribavirin has been found effective if the treatment commences within the first six days after onset of symptoms [71] . immune plasma containing neutralizing antibodies has also been useful in some cases. for prevention of arenaviral diseases, several attempts to develop vaccines have been made [72a] . one vaccine, candid 1, has been successfully used in the prevention of argentine hemorrhagic fever caused by junin virus with a clear reduction in the number of infections observed in humans [72b,73]. the genus orthopoxvirus in the family poxviridae consists of large 220-450 nm brick-shaped viruses, with a double-stranded dna genome (160-220 kb) ( table 1) , that are serologically cross-reactive and -protective. the middle part of the genome is very conserved among orthopoxviruses encoding structural proteins and replication machinery whereas the ends are more variable comprising genes involved with host-specificity and counteracting the immune response [74] . replication of orthopoxviruses occurs in the cytoplasm and includes translation of early mrnas (such as dna polymerases and immune defense molecules), dna replication, translation of intermediate mrnas (for late transcription factors), and late mrnas encoding structural proteins and late enzymes, respectively. altogether, e.g. the cowpox virus genome encodes nearly 200 open reading frames. intracellular non-enveloped virions are first formed, comprising the majority of the infectious viral progeny; some particles develop in er/golgi into enveloped, either cell-attached or extracellular viral particles, often motile due to attached actin tails [75] . homologous recombination occurs readily between orthopoxvirus sequences which has raised some concerns about the use of vaccinia virus-based vaccines in wild animals [76] . some orthopoxviruses are host-specific, whereas some are more promiscuous but have a distinct reservoir. their nomenclature may be misleading; e.g. monkeypox is not carried by monkeys, neither is cowpox carried by cows. smallpox or variola virus, now eradicated and historically the cause of one of the most feared human diseases, was specific to man. many other orthopoxviruses circulate in wildlife species and are often zoonotic. examples include the vaccinia virus, the modern smallpox vaccine, the origins of which are unclear but was originally described as cowpox by edward jenner [77] in late 18th century england, and which later has also re-escaped to nature in other parts of the world [78] ; monkeypox virus, pathogenic to primates, including humans, causing a smallpox-like disease with secondary transmission and with a likely reservoir in small rodents in central africa; cowpox virus, which is the main orthopoxvirus in europe and may be transmitted to man either directly from rodents or from a secondary carrier, typically cat. cowpox virus has been detected in western eurasia and in europe, voles of clethrionomys and microtus species and apodemus mice are the main reservoir hosts [79] ( table 2) . shedding of the virus from rodents is apparently transient. infection of cattle is rare; domestic cats relatively frequently present with clinical disease, but infection of zoo animals, e.g. elephants, has also been reported [80] . following the cessation of smallpox vaccination, more than 25 years ago, the number of humans susceptible to cowpox has increased. more than 60 human cowpox cases have been reported in the literature since 1969 [81, 82] . all age groups may acquire cowpox, but most cases have been in girls under 12 years of age, who have had a cat or e.g. a field mouse as a pet. infection probably occurs through abrasions in the skin; persons with atopic eczema are more prone to the infection. [81] [82] [83] [84] . the incubation period is 5-7 days, after which papules develop into lesions 1-3 cm in diameter which proceed through pustular, ulceral and eschar stages over a period of a about two weeks. they may be painful and vary in number, size and severity. local lymphadenopathy, pyrexia and nausea may occur; secondary bacterial infections are common. typically, solitary lesions are found, located mainly in fingers, hands or face (e.g. eyelid) [81, 85] . in 6-8 weeks the lesions heal gradually, some residual scars may remain. in some cases severe generalized skin infection occurs [83] , especially in atopic and in immunocompromised individuals and may in extreme cases lead to death [86] . cidofovir (a phosphorylated nucleoside analog of cytosine) may have potential as an antiviral against cowpox virus [87] . man-to-man transmission of cowpox virus (unlike for monkeypox) has not been reported. it is usually possible to detect orthopoxvirus particles directly from the skin lesions by electron microscopy. the virus can also be readily isolated in e.g. vero cells or chorioallantoic membrane of chicken embryos from the lesions and subsequently characterised [80] . several sensitive pcr approaches have been described, some related to the bioterrorism (smallpox) preparedness [88] [89] [90] ; in each case further typing at the species level is needed. in addition, during acute cowpox infection, igm antibodies and low-avidity igg antibodies have been detected [83] . following the cessation of smallpox vaccination approximately 30 years ago, the younger age groups are the most susceptible population, both to smallpox and to cowpox, which is more closely related to vaccinia virus. recent estimates indicate as low as 40% protection levels among europeans. for instance in finland, in the age group over 50, everybody had orthopoxvirus antibodies as measured by immunofluorescence assay. the seroprevalence decreased gradually towards younger age groups reflecting the gradual cessation of smallpox vaccination, with the last vaccinations in finland occurring in 1977 [83] . smallpox was finally declared to be eradicated from the world in 1980 [91] after which few people in europe have received the vaccine. in addition to wild rodents carrying cowpox, import of exotic pets may also pose a risk for orthropoxvirus transmission, as was seen in a recent outbreak of monkeypox virus in the usa [92] . orthomyxoviruses are enveloped, negative-strand rna viruses with 6-8 genome segments, of which avian influenza, (i.e. influenza a) viruses may cause severe disease in domestic poultry and cause zoonotic infections. the influenza viruses in wild aquatic birds are the source of these epidemics in chickens as well as providing a gene pool for reassortants with human influenza a viruses which then may become established in humanto-human transmission resulting in influenza pandemics. in addition, influenza a viruses are known pathogens of pigs, horses, mink, seals and whales [93, 94] . influenza a virus is 80-120 nm in diameter and has 8 genome segments varying in size from 0.89 to 2.3 kb. the three largest segments 1-3 encode the polymerase subunits pa (83 kda), pb1 (87 kda) and pb2 (84 kda), respectively; whereas the segments 4-6 each encode one viral protein, namely the 63 kda hemagglutinin (ha), the 56 kda nucleoprotein (np), and the 50 kda neuraminidase (na), respectively (table 1 , fig. 1 ). the two smallest segments, 7 and 8, encode each two proteins, the 28 kda matrix protein (m1) and the 11 kda membrane protein (m2), and the 27 kda ns1 and the 14 kda ns2 proteins, respectively (table 1 , fig. 1 ). in common with the bunyaviridae, the genomic rna is packed in the nucleoprotein which carries polymerase subunits, and the 5 0 and 3 0 -ends are conserved and complementary to each other and thus able to form panhandle structures in which the promoter regions reside. ''cap-snatching'' from cellular mrnas and an oligo-u motif are used to create viral mrnas starting with a cap structure and ending in a poly-a region. the virus enters the cells after binding to the sialic acid receptors by endocytosis, which is followed by acidification of the endocytic vesicle and, mediated by the ion channel forming m2 protein, of the interior of the virus, which leads then to fusion of the viral and endosomal membrane and release of the viral nucleocapsids to the cytoplasm, respectively. however, untypically for an rna virus, the replication, transcription and nucleprotein assembly occur in the nucleus. the envelope proteins are processed to the plasma membrane, where budding of the virions finally occurs. the envelope proteins are also the most important antigenic determinants. the homotrimeric hemagglutinin (ha), defines the ''h type'' which is responsible for the binding to the sialic-acid containing host cell receptors and membrane fusion properties. the neuraminidase (na) defines the ''n type'', and cleaves terminal sialic acid residues from glycoconjugates enabling the virus to reach target cells in the mucin-rich epithelium and facilitating release of the virus from the cells [93, 94] . the catalytic site of the neuraminidase is a target for antivirals oseltamivir and zanamivir, and the m2 protein is a target for amantadine and rimantadine. to become active, the hemagglutinin protein needs to be cleaved by trypsin-like proteases found in respiratory and gastrointestinal epithelia. human-adapted influenza viruses replicate in the respiratory tract, whereas in avians the virus replicates primarily in the gut. when transmitted to and within poultry, the normal hemagglutinin of influenza a virus h5 or h7 of wild aquatic birds of the ''low pathogenic type (lpai) may be mutated. accumulation of basic residues at the cleavage site makes the ha cleavable by most proteases of cells, such as furin, and results in ''highly-pathogenic avian influenza'' (hpai) virus able to replicate in most tissues killing rapidly up to 100% of chickens [93] [94] [95] . hpai, also known as ''fowl plague'' was first described in 1878 and the virus was first isolated in 1901 suggesting that humans have been directly exposed to avian influenza a viruses for centuries [96] . influenza a virus gene pools reside in wild aquatic birds where at least 15 ha types and 9 na types are found, as compared to 3 ha (h1-h3) and 2 na (n1, n2) types circulating in man. also, the genes in aquatic birds are in evolutionary stasis without undergoing changes due to selective pressures. influenza a viruses in man are under constant selective pressure imposed by population immunity causing the hemagglutinin of influenza a virus to change its antigenic properties by accumulation of mutations (genetic drift). however, through double infection and reassortment (genetic shift), novel (e.g. hemagglutinin) genes from aquatic birds may become established in human influenza viruses giving rise to pandemics due to lack of adaptation to and immunity in, humans. previously, it was thought that the different receptor specificity -favoring different side chains of sialic acid -of human and avian influenza viruses would make direct transmission of avian viruses to humans unlikely, but both could be expected to infect swine, which carry receptors for both. thus pigs are considered to be potential reservoirs for generating new influenza virus variants. it has only recently been discovered that viruses considered unique to avian species may also infect man, although this may involve change in receptor specificities [97] . in 1996 conjunctivitis in uk caused by avian influenza viruses (and previously, by seal influenza a viruses) was reported [98, 99] (table 2) . direct zoonotic transmission of avian influenza viruses to man resulting in human respiratory illness, was not known to occur or had not been diagnosed before the outbreak of h5n1 avian influenza virus in hong kong in 1997 where 6/18 patients died of lower respiratory tract infection [100] . after this, in europe, an outbreak of h7n1 hpai avian influenza was encountered in italy (1999) (2000) without reported transmission to humans [101] . in 2003, a major h7n7 hpai avian influenza outbreak occurred in the netherlands [102, 103] . during this epidemic, veterinarians and people who culled infected poultry were at greatest risk of infection. it was noted by active surveillance that human h7 infections (and simultaneous h3 infections) were occurring, and consequently prophylactic treatment with oseltamivir was started. the h7 virus was confirmed to be transmitted to 85 humans of which the majority had conjunctivitis, seven had an influenza-like illness; one veterinarian (who did not receive prophylactic oseltamivir) died. his symptoms started with high fever and headache two days after visiting a farm with infected chickens. one week later, he was admitted to hospital with pneumonia, where his status deteriorated to multi-organ failure, with death due to respiratory insufficiency 2 weeks after onset of symptoms. in addition, in three cases household primary contacts were shown to have the disease by human-to-human transmission [102] . both na inhibitors, zanamivir and oseltamivir inhibited virus obtained from humans during this outbreak and a significant difference was found in avian influenza virus detection between oseltamivir users (1/38) and those who had not taken prophylactic medication (5/52) [102] . outbreaks of avian influenza have continued to occur in other parts of the world, especially the devastating ongoing h5n1 epidemic in south-east asia since late 2003 with as of june 2005 a total of 54 deaths/107 cases in viet nam, thailand and cambodia. the epidemic has had a dramatic impact on poultry farming and industry with million birds dying or being destroyed to reduce virus dispersal. this ongoing epidemic clearly has ''pandemic potential''. avian influenza viruses may be detected by virus isolation (in cell culture or embryonated eggs) or rt-pcr which may be targeted at the specific ha subtype or may be generic to influenza a viruses (e.g. targeting the matrix protein gene) [104] . also, serological tests such as. hemagglutination inhibition may be used. typing may be based on serological methods (such as hemagglutination inhibition), specific primers/probes or sequencing. many commercial influenza a antigen tests detect the nucleoprotein or na activity and should be applicable to the avian viruses, although this is poorly studied and documented. furthermore, it should be noted that rt-pcr from throat swabs of the lethal case in the netherlands were negative [102] . avian influenza, or ''fowl plague'' outbreaks usually arise following contact with wild aquatic birds, such as mallards and ducks, in which the virus replicates as a rule without causing symptoms. the virus that is excreted in the gut can typically be isolated (or detected by rt-pcr) from cloacal swabs. hinshaw et al. [105] studied over nine thousand birds and detected 30% prevalence in young and 11% prevalence in adult birds. influenza virus is readily transmitted in cold environments and is stable for 126-207 days at +17â°c, or in wet faeces (as shown for h5n1 virus) for at least 4 days at 25â°c and more than 40 days at +4â°c [106, 107] . the main preventive and control measures include proofing the chicken breeding facilities against wild birds. raising chickens and turkeys in the open is a risk, minimizing secondary spread of outbreaks by stamping out the infected poultry, followed by cleaning, disinfection and controlling movements of humans and animals, trade embargoes and reporting the outbreaks (''fowl plague'' is in the top priority ''list a'' of the international animal health code of the office international des epizooties). selling poultry live, a common practice in south-east asia, is a definite risk factor. vaccination of poultry has been used as an additional control measure but may lead to undetected shedding and transmission of mutant virus selected under the pressure imposed by the vaccine [94] . to prevent further transmission to humans, rapid measures are needed due to the short incubation period. the dutch experience suggests that results can be achieved by personal protection (e.g. protective eye glasses, masks) for all workers who screen and cull poultry, vaccination with regular inactivated influenza virus vaccine and prophylactic oseltamivir for those handling potentially infected poultry, to be continued for 2 days after last exposure [102] . for humans, specific vaccines containing h5 and h7 antigens would be welcome. the only known zoonotic agent of the togaviridae family to cause human disease in europe is the mosquito-borne sindbis virus (sinv), in the genus alphavirus. sinv is distributed throughout the old world and australia and causes rashes and polyarthritis outbreaks in northern europe, similar to chikungunya, oã�nyong-nyong virus and ross river virus in far east asia, africa and australia, respectively, whereas other alphaviruses causing encephalitic infections in man (venezuelan, western and eastern equine encephalitis virus) are found in the new world. alphaviruses are enveloped, positive-strand rna viruses with an 11 kb genome. the non-structural proteins (nsp1-4) are encoded from the 5 0 -terminus of the genome, and a separate subgenomic 26s rna from the 3 0 -end is used as a messenger for the structural proteins: the 30-33 kda capsid protein (c), and the 45-58 kda envelope glycoproteins (e1 and e2) [94] (table 1 , fig. 1 ). sinv was first isolated in the nile delta in the 1950s from a pool of mosquitoes without knowledge of any disease association. it is now known to be the causative agent of mosquito-borne epidemic polyarthritis with accompanying rashes and when described in northern europe it was given the names ockelbo disease, pogosta disease, or karelian fever when found in sweden, finland and russia, respectively. most infections occur during august-september, and larger outbreaks tend to appear with a seven-year interval (e.g. in finland, 1282 serologically verified cases occurred in 1995, 600 cases in 2002; and in sweden 50-65 cases are reported during peak years) [108, 109] , with a peak incidence (56%) in 50-year old females. the association of sinv with pogosta disease was first discovered in the early 1960s and it is believed that the virus may have been distributed throughout northern europe around this time. this conclusion is based on the evidence that thousands of human and bird sera collected during the early 1960s in finland, were negative for sinv antibodies, whereas in the 1990s 2-5% of the population were sinvantibody positive [108] . antibodies to sinv without polyarthritis outbreaks have been recorded in italy, romania, greece and the former yugoslavia [109] . however, human disease due to sinv has been recorded in south africa, from where it may have originated. sinv was isolated from mosquitoes in sweden, norway and russia in the early 1980s [109] [110] [111] and sinv antibodies are found in wild tetraonic and migratory birds, most commonly (in sweden) from passeriformes such as redwing (turdus iliacus), fieldfare (turdus pilaris), blue tit (parus caeluleus), chaffinch (frinigilla coelebs), songthrush (turdus philomelos); thrushes have been suggested to be a major candidate as an amplifying host [109, 112] . in addition, antibodies are commonly found in galliformes [109, 108] . phylogenetically, sinv strains are similar in northern europe and south africa (in the north to south dimension), but differ considerably from strains circulating in asia and australia, where sinv-associated rash-arthritis is not recorded. this is consistent with the notion of a north-south dispersal of sinv strains by migratory birds [113] . several bird species can be infected experimentally [114] . it is evident that sinv cycles between birds and ornithophilic (culex and culiseta) mosquitoes (table 2) . however, it may spill over to other hosts (evidence from many vertebrates from a frog to a bear) and vectors (including ticks and aedes mosquitoes) [109] . recently, during an outbreak in finland in 2002, the causative agent of pogosta disease was isolated for the first time in europe from skin biopsies and a blood sample of patients [115] ; the virus strains were most closely related to sinv strains isolated from mosquitoes in sweden and russia 20 years previously. the incubation period for the disease is about one week and the onset is accompanied by arthritis/arthralgia and itchy rash as the dominant symptoms, and also fatigue, mild fever, headache and muscle pain. hematological laboratory parameters are within the normal range and levels of c-reactive protein (crp) are not elevated. the rash is usually located on the trunk and thighs and lasts for a couple of days. one third to a half of patients, suffer from joint pains for more than 12 months [116, 117] . usually several joints are affected, the most common being the ankle, wrists, knee, and finger joints (50% or more of patients), as well as hip, shoulder and elbow joints [118,119a,119b ]. diagnosis is based on serology using enzyme immunoassay, immunofluorescence assay or hemagglutinationinhibition, and detection of seroconversion or a 4-fold rise in titre between two samples, or positive igm in a single sample. the first sample is usually taken during the first week after onset of illness, another sample is required to diagnose or exclude sinv infection; igm antibodies are detectable until approximately 6 days post-onset, and igg antibodies can be detected approximately 10 days after onset of illness [119b,120] . in some cases persisting igm antibody can be detected years after infection [117] . for research purposes, the virus can be detected by 121] or isolated from skin biopsies [115] . no specific preventive measures are available, apart from avoiding mosquito bites. flaviviruses comprise a diverse group of pathogens that have been traditionally classified as arthropodborne viruses. they are linear positive single-stranded rna viruses with a monopartite genome (10-11 kb) that encodes 3 structural proteins: the 13 kda capsid protein (c), the 51-59 kda major envelope protein (e) and the 8.5 kda glycoprotein m (in mature virions); and 7 non-structural proteins (ns1, ns2a, ns2b, ns3, ns4a, ns4b and ns5) (table 1, fig. 1 ). noncoding or untranslated regions flank the infectious rna genome. when seen in the electron microscope flaviviruses appear as uniform spherical particles, 40-60 nm in diameter. the virus particles consist of a lipid envelope that has a surface covered by protrusions that contain envelope (e) and membrane (m) structural proteins, organized as dimers. this envelope surrounds an isometric capsid protein of approximately 30 nm in diameter [122] [123] [124] . there are currently about 70 members in the family flaviviridae [125] which have been found infecting a wide variety of organisms including mammals, arthropods, avian and amphibians. many of these viruses are major pathogens of humans, domestic and farmed animals as well as wildlife species. with the possible exception of the dengue viruses, the flaviviruses are zoonotic, depending almost entirely for their existence on wildlife vertebrate and in many cases, invertebrate species. the type species of the genus is yellow fever virus (yfv), hence the term ''flavi'' from the latin word flavus, which in turn describes the yellowish color of the skin in yellow fever infections [126] . the classification, and serological and phylogenetic studies of flaviviruses reflect the importance of the vector on the biology and evolution of this genus. there are essentially three groups of flaviviruses: tick-borne, mosquito-borne and non-vectored flaviviruses, although this grouping is, to some extent, arbitrary since some mosquito-borne viruses are also transmitted by ticks and vice versa [127] (table 2 ). phylogenetic analysis also shows very strong correlations between genetic relationships, epidemiology and ecology of these viruses [128, 129] . some flaviviruses are responsible for a significant proportion of the morbidity and mortality that is registered annually worldwide. they cause epidemic outbreaks that involve encephalitis and/or haemorrhagic fever, often fatal and involving millions of humans or in some case birds or mammals. important flaviviruses affecting humans are the dengue viruses, yellow fever virus, west nile virus (wnv), tick-borne encephalitis virus (tbev), japanese encephalitis virus, saint louis encephalitis virus, and murray valley encephalitis virus among others. dengue virus alone causes more than 50-100 million cases worldwide each year and some 2500 million people are now at risk from dengue infections [130] . the most important flavivirus in europe is tbev, which is endemic in many european countries, and also in russia, ( table 5 , fig. 4 ) northern china and northern japan [126,131a] . it affects thousands of people annually and has a significant impact on public health. the virus is transmitted to humans mainly through a tick bite, however, the infection has also been reported to occur by drinking unpasteurised goat milk from viraemic animals [131b,131c]. the virus is maintained in nature in a cycle involving ticks and wild vertebrate hosts and also by transovarial and transstadial transmission in its vector [126, 132] . serological evidence and viral isolations, as well as sequence similarities have suggested that migratory birds could also play a role in the transmission of tbev from central europe to scandinavian countries; moreover, endemic areas of tbev are regions of high migratory bird activity [133] . tbev is classified taxonomically into three subtypes: european subtype, far eastern subtype, and siberian subtype. the first subtype is transmitted mainly by ixodes ricinus, and the last two by ixodes persulcatus [134, 135] . the distribution of tbev is well coordinated with the distribution of its vector, furthermore, different genotypes are located in distinct geographical areas and associated with specific vector hosts. recent data have shown the co-circulation of all three subtypes of tbev in the same geographical region, specifically in latvia, where the two vector ixodes species habitats meet [136] . however, the endemic region in europe is patchy and covers only part of the geographical range of e.g. ixodes ricinus. there has been an increase of the incidence of tbev in many of its endemic areas but not in austria where a countrywide successful vaccination campaign was established reducing the disease incidence to lower levels [131c,131d,137a]. tbev affects principally the nervous system and can cause several clinical features of different severity table 5 tick-borne enchephalitis viral infections in europe per country through time year 1990 year 1995 year 2000 year 2002 austria 89 109 60 60 belarus -a 66 23 18 croatia 23 59 18 30 czech r. 193 744 719 647 denmark --3 1 estonia 37 175 272 90 finland 9 23 41 38 france 2 6 0 2 germany -226 133 including meningitis, meningoencephalitis, meningoencephalomyelitis and meningoradiculoneuritis. hospitalization varies from days to months and in some cases years of treatment and rehabilitation are necessary as sequelae occur in approximately 1/3 of the patients. the incubation period of tbe is between 7 and 14 days. the disease is characteristically biphasic. the first phase (day 2-4 of onset of symptoms) is viraemic and can be either asymptomatic or fever, malaise, headache, anorexia, nausea, and muscle pains may be present. the second phase occurs in up to 30% of the patients after about 8 days lag period (approximately 21 days after the tick-bite) as a neurological disease of which about 0.5% has a fatal outcome [137b,137c,137d]. the neurological symptoms and severity vary: the clinical picture includes meningitis (in about half of the patients), meningoencephalitis, meningoencephalomyelitis and meningoradiculoneuritis. hospitalization varies between days and months and in some cases years of treatment and rehabilitation are necessary in case of e.g. paresis. altogether, neuropsychiatric sequelae occur in approximately 1/3 of the patients. louping ill virus (liv) is endemic in ireland, in the northern region of great britain and in norway (fig. 4) affecting principally sheep with a disease that is known as ovine encephalomyelitis, infectious encephalomyelitis of sheep, or trembling-ill. liv is transmitted to sheep by the tick vector ixodes ricinus. the natural life cycle of liv resembles that of tbev, it can be sustained in the natural environment through non-systemic transmission of virus between ticks cofeeding on rodents and other wild animals, which in turn infect grazing animals such as sheep and goat as a zoonotic disease. louping ill virus has also been observed in a bird-tick-bird cycle involving the red grouse (lagopus lagopus scoticus), ptarmigan bird species and the ixodes tick [138] . infection with liv in sheep is characterised by a biphasic fever, depression, ataxia, muscular in-coordination, tremors, posterior paralysis, coma, and death. there is evidence for infection by liv in other domestic species and wildlife, i.e. cattle, horses, pigs, dogs, deer, shrews, wood-mice, voles, and hares [139,140a] . it is generally believed that the majority of avian infections occur through a tick bite, however laboratory experiments and field observations have demonstrated that the red grouse can also become infected by feeding on infected ticks indicating that the vector bite is not the only route of infection [140b] . humans are also susceptible to infection with liv. however, the majority of the cases reported are accidentally acquired infections in laboratory workers. the second most frequent infection results from handling infected animal carcasses. infection with liv in humans can cause a neurological disease resembling the clinical picture observed for tbev infections, i.e. biphasic encephalitis, influenza-type illness, fever, articular pain, meningitis, myagia and poliomyelitis-like illness [141] . other possible transmission routes for liv infection to humans include drinking contaminated milk from goat or sheep in an acute phase of infection [142] , tick-bite, exposure to infective material, or through skin abrasions or wounds. antigenic and phylogenetic studies have shown that liv is most closely related to strains of the western european subtype of tbev and it is estimated to have emerged from this lineage approximately 800 years ago [143] . west nile virus (wnv) was first discovered in 1937 in uganda [144] . it occurs throughout africa, the middle east, europe, russia, india and indonesia and was recently introduced into north america (new york) [126, 145] . in the old world wnv is primarily considered to be an african virus which annually disperses northwards out of africa when birds migrate to europe, the middle east and asia [145] . in humans, the majority of wnv infections cause a nonsymptomatic or mild febrile illness; however some infections can cause encephalitis and in most severe cases can lead to death, particularly in elderly patients. the incubation period is between 3 and 15 days after a mosquito bite (http://www.cdc.gov/ncidod/ dvbid/westnile/wnv_factsheet.htm). west nile virus is an illustrative example of the human impact on the dispersal and evolution of flaviviruses. the virus appeared for the first time in the usa, in new york in 1999 causing sixty-two confirmed human infections and seven deaths [146] . the virus successfully over-wintered and during the next years dispersed widely throughout north america and now more recently also to central america and the caribbean. in north america the virus infects a very wide range of mosquito and animal species. the exact mechanism of introduction into north america is not known [146-148a] . to date, more than 14 000 human cases and 586 deaths from wnv have been reported in the united sates of america (http:// www.cdc.gov/ncidod/dvbid/westnile). in europe, outbreaks caused by wnv have been recorded since the early 1950s, especially in mediterranean countries, romania and southern russia (fig. 4) . larger outbreaks (over 800 cases) have been reported since the mid 1990s in urban settings, especially a large outbreak in bucharest, romania in 1996 [145a,145b,145c] . in southern russia, specifically in volgograd, astrakhan and krasnodar regions, wnv has caused large epidemics of approximately 1000 human cases, with 4% mortality rate of reported cases. molecular epidemiological studies have shown that the latest large outbreaks in volgograd were caused by strains genetically similar to that of romania-1996 , kenya-1998 and newyork-1999 reflecting the widespread distribution capacity of these epidemic viral strains [149b,151b]. the incidence of wnv in europe is largely unknown. phylogenetic studies have showed that wnv has diverged into two main lineages, which form internal clusters or clades [149c,150a,150b,150c]. more recently, a novel virus (rabensburg virus), antigenically and genetically closely related to wnv was isolated from a culex pipens mosquito pool in czech republic. this new virus could represent a third lineage of wnv, however more studies are needed to confirm this hypothesis or to determine whether or not this could represent a new member of the flaviviridae family [151a] . usutu virus (usuv) was first isolated from a mosquito in africa in 1959 [148c]. it was characterised serologically and classified within the japanese encephalitis virus serocomplex. usutu virus had rarely been isolated since then, with only one reported human case and being present only in two regions of africa. however, in the late summer of 2001, usuv was found in vienna in austria during a study of an avian epidemic characterized by fatal encephalitis that was thought to be caused by wnv. the virus caused die-off among the bird population, especially blackbirds, in vienna (fig. 4) and when isolated from birds and mosquitoes it showed 97% genetic identity to the african usuv [148b]. this is the first time usuv has been observed outside africa and also the first time it has been associated with fatal disease in animals. the virus re-appeared in the late summer of 2002 in the same region of vienna [149a] . most recently, in 2003 the virus has been isolated from humans (associated with rash in one patient) and from birds in austria and evidence exists as to the virus being able to overwinter establishing itself in this geographical area (nowotny, n. second european congress of virology, eurovirology 2004). as mentioned above the distribution of flaviviruses is worldwide, and we have described the zoonotic flaviviruses endemic to europe. however, it is important to note the increasing incidence of imported flaviviruses totaling over 500 cases mainly due to changes in human behavior, such as increased travel to non-european destinations (http://www.eurosurveillance.org). the dengue viruses (denv) are a world-wide public health problem. they are transmitted to man by mosquitoes, particularly aedes aegypti and cause a wide range of different clinical outcomes [151c,152a] . it is estimated that 100 million cases of dengue fever (df) and 250 000 of dengue hemorrhagic fever (dhf) cases occur annually [126] . in a study based on the epidemiology and clinical course of 294 travellers with symptoms of dengue infection it was found that the incidence of df among european travellers is underestimated, since diagnostic procedures, in general, for febrile patients often do not include tests for tropical arthropod-borne diseases, such as dengue virus [152b] . there have also been some imported cases of yfv to europe mainly by tourists travelling from endemic areas. however, the incidence of yfv as an imported disease is much lower than that of dengue infections (http://www.eurosurveillance.org) presumably because of the different nature of these diseases, denv having spread worldwide throughout the tropics and yfv occurring only in its endemic regions in africa and south america [152c]. traditionally, diagnosis of flaviviruses in europe has been restricted to detecting tbev infections through serological assays; igm-capture enzyme immunoassay, hemagglutination inhibition-, and immunofluorescence assay. igm antibodies in serum, and in some cases in cerebrospinal fluid during the neurological disease usually provide the diagnosis. rt-pcr is rarely positive at the second phase of the disease [153a]. because of the close antigenic relatedness of flaviviruses, laboratory findings can easily lead to misdiagnosis [153b]. in a study conducted in hungary, tbev-positive serum panels were tested retrospectively against wnv and some sera were found to show higher titres to wnv than to tbev when compared in serological assays (e. ferenczi, personal communication). as mentioned above, a study including travellers returning to europe from tropical destinations proved that many cases remain undetected. there is a need to improve the diagnosis for flaviviruses in order to determine the true incidence and prevalence of these infectious diseases in europe, and to study the ecology of imported viruses to determine which viruses have been able to establish themselves in the continent and which are still continuously being imported from africa or asia. meanwhile anti-vector campaigns and vaccination for travellers to endemic areas are the only measures to prevent and control these infectious diseases [146] . there are effective vaccines for tbev and yfv but a protective immunogen does not exist for denv or wnv. tbev vaccines from two commercial manufacturers (baxter and chiron) are available and widely used, especially in austria and germany, both are based on formalin-inactivated virions, three injections are needed for full protection. booster immunizations are recommended every 3-5 years for people living or spending holidays in endemic areas. 3.3. nairoviruses: crimean-congo hemorrhagic fever virus the genus nairovirus (family bunyaviridae) is composed of 34 predominantly tick-borne viruses that have been divided into seven serogroups [154] including several associated with severe human and livestock diseases (especially crimean-congo hemorrhagic fever virus (cchfv) and nairobi sheep disease virus). of the pathogenic viruses only cchfv causes significant human morbidity and mortality and is found in europe. like other members of the bunyaviridae family nairoviruses possess a tripartite single-stranded rna genome of negative polarity consisting of large (l), medium (m) and small (s) segments. the 12 kb l segment encodes an rna-dependent rna polymerase (deduced size 448 kda in cchfv), the 4.9 kb m segment encodes the precursor for the two envelope glycoproteins gn (75 kda in cchfv) and gc (37 kda in cchfv), and the 1.7 kb s segment the viral nucleocapsid n (50 kda) ( table 1 , fig. 1 ). like with other members of the bunyaviridae viral messenger rnas (mrna) are not polyadenylated and are truncated relative to the genome rnas at the 3 0 termini. messenger rnas have 5 0 -methylated caps and 10-18 nontemplated nucleotides which are derived from host cell mrnas. the nairovirus l segment encoding the rna polymerase is conspicuously large, almost twice the size of many other members within the family bunyaviridae, and may thus provide other functions such as viral helicase and a papain-like cysteine protease activity predicted from the nucleotide sequence [155, 156] . viral protein analysis has suggested that gn and gc may be derived from 85 and 140 kda precursors, of which the latter contains an n-terminal region with a highly o-glycosylated mucin-like domain [157] . the cchfv nucleocapsid protein colocalizes and interacts with human mxa protein; this interaction may explain the antiviral effect of interferons on cchfv [158] . similar to the hantavirus-rodent association, the high genetic variation of viruses of the genus nairovirus reflects the diversity of their predominant tick hosts [159] . within cchfv isolates, comparison between m and s segment phylogenetic groupings suggests that reassortment events have occurred in some virus lineages [160] . reverse genetics, recently established for cchfv [161] , provides a unique opportunity to study the biology of nairoviruses and tailor optimal therapeutic and prophylactic measures against cchfv infections. cchfv is transmitted most efficiently by hyalomma ticks, followed by rhipicephalus, dermatocentor spp and many other species of ixodid (hard) and some argasid (soft) ticks (table 2) . among ticks cchfv is capable of transmitting infection both transovarially and transstadially. the life cycle of cchfv also includes a tick-vertebrate host cycle involving both wild and domestic animals. the virus or antibodies against it have been detected in rodents, hares, hedgehogs and some birds but human infections seem to be principally from contacts with livestock (mainly cattle, sheep, goats) including in africa farmed ostriches and less often ticks [162, 163] . thus cchfv is more commonly seen in persons exposed to blood and tissues of infected animals during occupational activities, such as farming, herding, veterinary examination and abattoir work. nosocomial infection is common and often results in small outbreaks. yet, outdoor and recreational activities also represent a risk factor. in addition, horizontal transmission of cchfv from mother to child may occur [164] . the global distribution of cchf follows closely that of hyalomma spp. in the middle east, asia, africa and southeast europe [162, 163] . sequence analysis of cchfv s rna segments gives patterns following links between different geographic locations, in some cases suggesting links originating from trade in livestock and long-distance carriage of virus or infected ticks during bird migration [165] . in europe, cchf occurs in the balkan peninsula (albania, bulgaria, greece, turkey, yugoslavia) but also in southern russia, hungary, france and portugal [162, 166, 167] . the symptoms and signs of crimean-congo hemorrhagic fever are similar to those of other viral hemorrhagic fevers [162, 163] . the incubation period is generally short ranging usually from 2 to 9 days. there is typically a very sudden onset of illness with fever, rigors, chills, intense headache and backache or leg pains, myalgia, nausea, and vomiting. patients may also present with photophobia, somnolence and menigism with confusion or aggression. hemorrhages in the form of petecchiae, ecchymoses, epistaxis, melena and bleeding from various organs usually begin a few days later. tachycardia is common and lymphadenopathy is seen occasionally. the case-fatality rate is 20-35%. the pathology consists of hemorrhagic and necrotic lesions in various organs as well as fibrin deposits. the methods used for detection of cchfv infection in humans or livestock include indirect immunofluorescence on virus-infected or n-expressing transfected cells. both igm and igg antibodies reactive for cchf appear within a week in patients [162, 168] . alternatively a recombinant nucleocapsid protein-based enzyme immunoassay [169] [170] [171] may be used. rapid detection and quantification of cchfv rna is possible by real-time reverse transcription pcr [172] . ribavirin is clearly effective in treatment of crimean-congo hemorrhagic fever [173, 174] but supportive treatment (blood, thrombocytes, coagulation factors) is equally important. immune plasma from recovered patients has also been used to treat patients but not in controlled studies with a follow-up of virus-neutralizing activities [162] . the most effective method of preventing infections is to take measure to avoid exposure to ticks (protective clothing, tick repellent, frequent body searches to remove ticks). inactivated virus prepared in mouse brains has been used on a limited scale as a vaccine in southeastern europe and the former ussr but the sporadic and unpredictable occurrence of the disease renders it difficult to identify target populations and has slowed development of a safe and modern vaccine [162] . orthobunyaviruses belong to the family bunyaviridae. these enveloped viruses have a three-segmented negative-strand rna genome. the 0.97 kb s segment encodes the 19-25 kda nucleocapsid protein (n) and a 10-13 kda nonstructural protein (ns); the 4.5 kb m segment encodes the polyprotein precursor of two glycoproteins, g1 and g2 (108-210 kda and 29-41 kda, respectively), and a nonstructural protein nsm (15) (16) (17) (18) ; and the 6.9 kb l segment encodes the rna polymerase (260 kda) ( table 1 , fig. 1 ). viral messenger rnas are not polyadenylated and are truncated relative to the genome rnas at the 3 0 termini. messenger rnas have 5 0 -methylated caps and some nontemplated nucleotides which are derived from host cell mrnas. orthobunyaviruses are transmitted to humans by a variety of mosquito species, and in europe two known human pathogenic representatives of the genus circulate, tahyna virus and inkoo virus (mostly transmitted by aedes spp.) [109, 175, 176] (table 2 ). these viruses belong to the california serogroup, and their incidence is associated with the distribution of the carrier mosquitoes. the natural cycle of these viruses involve also mammal hosts. tahyna virus circulates throughout most of europe, whereas inkoo virus is mainly reported from northern europe [109,177a] . tahyna virus causes an influenza-like disease which may also present as a meningitis. the infection caused by inkoo virus is mostly sub-clinical or a mild disease, although encephalitis has been reported. the most typical symptoms associated with encephalitis or meningitis caused by californian serogroup viruses include fever, headache, nausea, vomiting, convulsions and confusion. in europe the seroprevalence for californian serogroup viruses varies from 1% to 69%, depending on the geographic area [109] . in finland the seroprevalence against inkoo virus varies from 2% to 6% (ã� land islands) to 61-69% (finnish lapland) [109, putkuri et al, unpublished results] . in disease-endemic areas the seropositivity of the population increases with age [177b]. the diagnosis of orthobunyaviruses is based on serology, either as a rise in igg-antibody titers, or the presence of igm antibodies. also rt-pcr methods are under development to detect viral rna in cerebrospinal fluid samples of patients with encephalitis. phleboviruses are one of the five groups within the family bunyaviridae. they have a negative singlestranded rna tripartite genome, namely: l (6.4 kb), m (3.2-4.2 kb) and s (1.7-1.9 kb). the l segment encodes a single protein of 240 kda (rna polymerase) in the complementary sense. the m segment encodes a protein precursor of 130 kda in the complementary sense which is cleaved into two glycoproteins g1 (56 kda) and g2 (59 kda). the s segment has an ambisense coding arrangement, and it encodes the nucleocapsid protein (n) of 27 kda in the complementary sense and a non-structural protein (nss) of 30 kda in the virion sense [178, 179] (table 1, fig. 1 ). viral messenger rnas (mrna) are not polyadenylated and are truncated relative to the genome rnas at the 3 0 termini. mrnas have 5 0 -methylated caps and some nontemplated nucleotides which are derived from host cell mrnas. when seen under the electron microscope the virions are spherical and enveloped and approximately 80-110 nm in diameter. glycoprotein projections of 5-10 nm are also seen embedded in the membrane. there are between 200 and 1500 spikes per virion [178, 179] . phleboviruses are arthropod-borne viruses and are transmitted mainly by phlebotomine sandflies, hence the derivation of its name ''phlebo'' (table 2) . however, mosquitoes and ticks can also transmit phleboviruses. phleboviruses are distributed throughout most of the world but have not been reported in australia [180] . the first documented record of a disease resembling those caused by phleboviruses dates back to the 1900s in the mediterranean countries of europe [178] . however, the first virus isolation occurred for rift valley fever virus in 1930 in kenya [181] . retrospective serological studies have indicated that outbreaks caused by phleboviruses have occurred since 1912 in the sub-saharan africa region [182] . phleboviruses are major causal agents of encephalitis in humans, especially among children, in mediterranean countries. they also have an important impact in livestock especially in african endemic areas. infection of livestock is characterised by a high rate of abortions and pathologies associated with hemorrhagic illness (leukopenia, thrombocytopenia, fibrin thrombi, intravascular coagulopathy, etc.) [183] [184] [185] . the distribution of the disease follows that of its vector. however the natural history of phleboviruses is largely unknown and for many species the amplifying host has not been identified [185] [186] [187] . in general, phlebovirus infections cause a 2-4 days illness characterised by an incubation period of 2-6 days followed by fever, general malaise, headache, photophobia, and back and joint pain [188] . the illness occurs during the summer months when the activity of phlebotomine flies is high [178] . there are three recognised members of the genus phlebovirus, associated with disease in humans. rift valley fever virus (rvfv), which is the type species of the genus and is transmitted by mosquitoes, causing an influenza-like disease that affects domestic animals and humans. the majority of human infections are asymptomatic; however, in 0.5% of cases it can cause severe haemorrhagic fever, encephalitis and death. the geographical distribution of rvfv includes africa, egypt, saudi arabia and yemen and occurs as epizootics involving aedes spp. mosquitoes and domestic animals [180] . toscana virus (tsv) causes a mild influenza-like disease that can occasionally develop into an acute neurological disease, such as meningitis or meningoencephalitis in italy and possibly other mediterranean countries. a similar virus (granada virus) was recently isolated in spain [193] . tsv is the number one cause of encephalitis among children in italy. the distribution of the virus follows that of its vector, phlebotomus perniciosus, found in italy, spain, portugal, and cyprus. human cases have also been reported from southern france and greece. the virus replicates in the sandfly vector population; however, experimental evidence suggests that an amplifying vertebrate host is needed to sustain the virus in the arthropod population [189] [190] [191] [192] [193] [194] . sandfly fever virus (sfv) sicilian and naples viruses can cause a mild-influenza like disease. the distribution of sfv also follows that of its vector, phlebotomus papatasii, found in the mediterranean basin extending to the middle east and arabian peninsula, the caucasus mountains, pakistan and india [185] [186] [187] . diagnostics of phlebovirus is performed mainly by igm-capture eia and ifa. the virus can be isolated using intracranial inoculation in suckling mice or using a susceptible tissue culture cell line (vero, llc-mk2, bhk-21) [178,195a] . toscana virus and naples sandfly fever virus group together and are distinct antigenically and phylogenetically from sicilian sandfly fever virus [195b] . prevention of infections by phleboviruses varies depending on the type species. immunising livestock with the formalin-inactivated or live-attenuated vaccines can prevent rvfv by avoiding epizootics and hence human infections [178, 196] . in the case of tsv and sfv, prevention is limited to controlling the vector population through insecticides and repellents [197, 198] . what are the reasons for the appearance of all these emerging and re-emerging viruses? have changes taken place in the viruses themselves? apparently not. the principal reasons are changes in the environment and human activity that have created new attacks with nature. factors such as climate change, increasing intensity of agriculture, the building of dams and introduction of other irrigation measures which generate new breeding sites for mosquitoes, crises and wars which bring rodents and arthropods closer to humans, population growth and especially in suburban slums, and global air traffic are important factors generating such new contacts, or may affect the ecological cycles of these viruses. many epidemics may be unexpected outcomes of such changes. moreover, the new molecular biology techniques facilitate detection of new viral agents. many prevention and control measures, such as the anti-aedes campaigns, have been abandoned in tropical countries. the yellow-fever vaccination campaigns have 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research on roma health often reveals higher burdens of disease in the communities studied. this paper aims to review the literature on communicable diseases among roma across eastern and central europe. a pubmed search was carried out for communicable diseases among roma in these parts of europe, specifically in romania, bulgaria, hungary, serbia, slovakia, the czech republic and north macedonia. the papers were then screened for relevance and utility. nineteen papers were selected for review; most of them from slovakia. roma continue to have a higher prevalence of communicable diseases and are at higher risk of infection than the majority populations of the countries they live in. roma children in particular have a particularly high prevalence of parasitic disease. however, these differences in disease prevalence are not present across all diseases and all populations. for example, when roma are compared to non-roma living in close proximity to them, these differences are often no longer significant. the romani, or roma are the largest transnational minority in europe. through linguistic, anthropological and more recently genetic mapping, their roots can be traced to original nomadic communities in north-west india [1] . they began their migration westwards between the 6th to 10th century, with groups settling along the way, finally entering europe in the 12th century. roma communities across europe and central asia gradually formed diverse endogamous sub-groupings, still retaining large parts of their language and culture [1, 2] . in europe alone they now number around 11 million, the vast majority living in eastern and central europe (table s1 ). the history of roma people in europe is marked by discrimination and persecution. in romania, they were enslaved [3] ; in britain they were declared criminals and had to choose between exile or death [4] . during nazi rule, they became the victims of genocide, which the roma call "porajmos" [5] . in eastern europe, roma children were taken from their parents in an attempt at assimilation. more recently, in the czech republic, roma women were unwittingly sterilised even after the turn of the millennium [6] . even now, in 2020, in the midst of the coronavirus pandemic, a few roma settlements in slovakia and bulgaria are being subjected to disproportionately high levels of surveillance and policing [7] . these are just a few examples of discrimination and persecution which the roma have endured and continue to face. though commonly thought of as itinerant, most roma are actually settled, partly on account of forced assimilation policies. by all accounts, the roma are extremely disadvantaged. most people identifying as roma live in informal settlements, often with facilities which are far below the national standards of the countries they are settled in [8] . roma are also routinely found to have worse social, economic and health indicators than their non-roma counterparts. ninety percent of roma live below national poverty lines. less than one third are in paid employment. only 15 per cent of roma have completed high school, and 45 per cent of roma households lack proper sanitation [8, 9] . roma children are only 34 to 45 per cent as likely to be vaccinated as non-roma, and they routinely face barriers in accessing healthcare [10] [11] [12] . in 2005, nine central and southern eu countries-bulgaria, croatia, the czech republic, hungary, north macedonia, romania, serbia, montenegro and slovakia-along with several international organisations, launched the decade of roma inclusion 2005-2015, committing to allocate resources with the aim of integration and ending discrimination and poverty of roma communities. this was followed by the roma integration 2020 project, with similar goals [13] . there are numerous papers examining the prevalence of specific diseases in certain roma communities. this paper aims to examine the occurrence of communicable diseases among roma across eastern and central europe. publications were selected based on a pubmed search, starting in 2005 and ending july 2020. the literature selected describes the occurrence of communicable disease among the roma in eastern european countries. these were limited to eu member states or states in the accession process with sizeable roma populations. eu member states and those in the accession process were chosen for ease of comparability based on the similarity of their legal systems, policies and institutions. the roma population had to be sizeable, i.e., being defined as at least 5 per cent of the total population and/or amounting to at least 200,000 persons. the size of the roma population was also taken into account for compatibility purposes. for example, russia and ukraine are currently not in the process of eu accession and were therefore excluded, despite having sizeable roma populations. the countries of study selected were romania, bulgaria, hungary, serbia, slovakia, the czech republic and north macedonia (table s1 ). including countries outside of these parameters was beyond the scope of this short study, but they nevertheless warrant further research. turkey, which has an estimated roma population of 2.75 million, was excluded since eu accession negotiations have reached a virtual standstill. spain, france and the uk, which are eu member states with sizeable roma populations outside central and eastern europe, were also intentionally excluded. the following search strategy was employed. the search string detailed the target population, i.e., the roma; the geographical focus, i.e., the seven specified countries; and lastly communicable diseases (supplementary material s1). text word terms were used for "roma" and its more commonly-used exonyms and endonyms, such as romani, gypsy, romany, sinti. certain terms carrying a geographical marker not relevant to the intended geographical area of study, such as gitano, which is one of the terms used for roma people in spain, were intentionally excluded. gypsy, sinti and their various iterations were included, despite being geographically inappropriate, owing to their generic usage for the roma in english publications. text word terms were employed for the countries selected to make the search as broad as possible. using the same search string without specifying countries yielded almost 1177 results, many of which focused on orthopaedic papers dealing with range of motion (rom), rod outer-segment membrane protein, or non-included countries such as greece and spain. for communicable diseases, a combination of mesh and text word terms were used for the various communicable diseases specifically, including but not limited to listing all the diseases mentioned on the who regional office for europe's pages on communicable diseases [14] , as well as umbrella terms such as sexually transmitted diseases. this was done to make the search as broad as possible. the decade of roma inclusion was launched in 2005, when several european governments committed to improve the conditions of their roma minorities. this search yielded 96 results. other filters such as language and "human" or "other animal" were not used, since the paper classification was often incomplete. out of the 96 papers, all of which pertained to humans, only 85 were marked as "human". the titles and abstracts were then preliminarily screened for relevance, as shown in figure 1 . papers were included if they pertained to prevalence of any communicable diseases among the roma community within any of the specified seven countries. papers exclusively describing outbreaks were therefore excluded. the papers had to have been published in english and had to have full text availability. opinion pieces, editorials and commentaries were excluded. if titles and abstracts were ambiguous in terms of the above criteria, the full text was scanned as well. this resulted in 35 papers which were selected for closer examination. papers were further excluded, if on scanning the full texts they were found not to fulfil the inclusion criteria stated in the initial screening, such as describing prevalence data. this resulted in papers being excluded for not reporting data on the basis of ethnicity and not reporting specific disease occurrence. further exclusions were made for multiple papers based on the same databases, for which the population and prevalence data were identical. this was the case of five papers from the hepameta team in slovakia. in this case, only the first published paper was included. as umbrella terms such as sexually transmitted diseases. this was done to make the search as broad as possible. the decade of roma inclusion was launched in 2005, when several european governments committed to improve the conditions of their roma minorities. this search yielded 96 results. other filters such as language and "human" or "other animal" were not used, since the paper classification was often incomplete. out of the 96 papers, all of which pertained to humans, only 85 were marked as "human". the titles and abstracts were then preliminarily screened for relevance, as shown in figure 1 . papers were included if they pertained to prevalence of any communicable diseases among the roma community within any of the specified seven countries. papers exclusively describing outbreaks were therefore excluded. the papers had to have been published in english and had to have full text availability. opinion pieces, editorials and commentaries were excluded. if titles and abstracts were ambiguous in terms of the above criteria, the full text was scanned as well. this resulted in 35 papers which were selected for closer examination. papers were further excluded, if on scanning the full texts they were found not to fulfil the inclusion criteria stated in the initial screening, such as describing prevalence data. this resulted in papers being excluded for not reporting data on the basis of ethnicity and not reporting specific disease occurrence. further exclusions were made for multiple papers based on the same databases, for which the population and prevalence data were identical. this was the case of five papers from the hepameta team in slovakia. in this case, only the first published paper was included. a quality assessment was then carried out. this relied on the joanna briggs critical appraisal checklist for prevalence studies [15] . this was further quantified by assigning a numerical value of 1 to every yes. ultimately, 19 papers were selected for review, as illustrated in figure 1 and table 1 . the included papers studied mostly high-risk sub-populations of roma. all the papers involved roma in settlements with substandard living conditions. twelve of the 19 papers are from slovakia. the czech republic and north macedonia are not represented in the final selection of papers to be studied. many papers are authored by the same research teams, for example, six papers from slovakia a quality assessment was then carried out. this relied on the joanna briggs critical appraisal checklist for prevalence studies [15] . this was further quantified by assigning a numerical value of 1 to every yes. ultimately, 19 papers were selected for review, as illustrated in figure 1 and table 1 . the included papers studied mostly high-risk sub-populations of roma. all the papers involved roma in settlements with substandard living conditions. twelve of the 19 papers are from slovakia. the czech republic and north macedonia are not represented in the final selection of papers to be studied. many papers are authored by the same research teams, for example, six papers from slovakia are by the hepameta team and rely on the same database, which examines a cross-section of roma and non-roma in košice in eastern slovakia. table s2 . + roma and non-roma from settlement regions in addition to non-roma from other regions. ro-romania; bg-bulgaria; hu-hungary; sk-slovakia; srb-serbia. the prevalence of human immunodeficiency virus (hiv) among pregnant roma women (n = 862) was 0.6 per cent vs. 0.1 per cent among "white" women (n = 10,192) in a pilot prevention of mother-to-child hiv transmission programme in south-east romania. the study was carried out in constanta county, which was known for an hiv outbreak [16] . young roma men in bulgaria (n = 405) had an hiv prevalence of 0.5 per cent [20] . in budapest, hungary, however, neither of the two populations of roma surveyed had hiv, despite one group being made up of injecting drug users (idus) [18, 19] . hepatitis infection prevalence in table 2 [22] . a subpopulation of the same sample was tested for hepatitis e virus (hev), and 21.5 per cent of roma tested positive vs. 7.2 per cent of non-roma [31] . a romanian cervical cancer screening study found human papillomavirus (hpv) prevalence among roma (n = 124) to be 6.5 per cent vs. 15.5 per cent of women identifying as romanian (n = 1615). in fact, the only minority with a lower prevalence at 4.2 per cent consisted of women identifying as ukrainian (n = 24) [32] . parasitic disease in children was the focus of six of the ten studies covering parasitic diseases. except for one paper describing an 8.7 per cent prevalence of trichomonas among young roma men in sofia, bulgaria [17] , all the other papers cover roma in slovakia ( table 3) . the prevalence of microsporidia in the stool samples of clinically-healthy roma children (n = 72) from settlements in eastern slovakia was 30.6 per cent. of these, the prevalence of enterocytozoon bieneusi was 4.2 per cent and encephalitozoon cuniculi 26.4 per cent. the highest prevalence was found in boys aged 6-9 years (n = 11) at 45.5 per cent, and the risk of infection was 1.8 times higher in the group of boys [21] . among children aged 1-2 years hospitalised at the institute for child and youth health care of vojvodina in novi sad, serbia, 10.0 per cent of roma children (n = 59) had parasitic skin disease (pediculus humanus capitis and scabies) vs. 0.0 per cent of the non-roma children (n = 59) [24] . the prevalence of cryptosporidium in the stool samples of clinically-healthy roma children (n = 53) in eastern slovakia was 11.3 per cent, whereas 0.0 per cent of the non-roma children sampled (n = 50) tested positive. roma babies less than one year old had the highest prevalence, at 22.7 per cent [25] . in the košice region of eastern slovakia, seropositivity to toxocara was 22.1 per cent among roma (n = 429) compared to 1.0 per cent among non-roma (n = 394). increasing age (odds ratio (or) 2.512, 95% confidence interval (ci) 1.477-4.271) and the lack of household hygiene facilities (or 2.512, 95% ci 1.477-4.271) were both strong risk factors for seropositivity [26] . in another slovakian study, prevalence among roma children (n = 67) was 40.3 per cent vs. 2.3 per cent among non-roma children (n = 44) [34] . the prevalence of helminthic infections in hospitalised and non-hospitalised children in the prešov and košice regions of eastern slovakia was 25.8 per cent among roma children (n = 275) vs. 0.7 per cent among non-roma children (n = 150). a single species, ascaris lumbricoides, accounted for 87.5 per cent of all helminthic infections. the age groups 3-5 years (n = 64) and 6-10 years (n = 57) among roma had the highest prevalence of these infections at 31.3 per cent and 30.2 per cent, respectively [27] . in medzev, 36 km west of košice, 85 per cent of roma children (n = 60) had helminthic infections vs. 23.8 per cent of non-roma children (n = 21). seroprevalence for strongyloides stercoralis specifically was 33.3 per cent in roma children vs. 23.8 per cent in non-roma [28] . in the hepameta population, seropositivity for trichinella or echinococcus was 0.5 per cent and 0.2 per cent among roma tested (n = 429). however, no significant difference was found with regard to non-roma (n = 394) [29] . prevalence of toxoplasma gondii in the hepameta population in eastern slovakia, determined by seroprevalence of t. gondii antibodies, was 45.0 per cent among roma (n = 420) compared to 24.1 per cent among non-roma (n = 386). prevalence among non-roma living in the vicinity of the roma settlements (n = 158) was 30.4 per cent compared to 19.7 per cent among non-roma outside this area (n = 228) [30] . in a group of roma children from across slovakia (n = 67), seroprevalence was 20.9 per cent vs. 7.1 per cent among non-roma children (n = 42) [33] . papers on bacterial disease among the roma all examine sexually transmitted diseases (table 4) . a study of young roma men in sofia, bulgaria (n = 296) found that 21.7 per cent had at least one std (trichomonas, chlamydia, gonorrhoea or syphilis) and that the rates of gonorrhoea and syphilis were 1807 and 312 times the national levels, respectively [17] . a later study by the same group of researchers examining a larger group of young roma men found much lower rates of infection [20] . the prevalence of syphilis in a sample of volunteers tested at a health camp in a predominantly roma neighbourhood of budapest, hungary was 1.8 per cent among roma (n = 50) vs. 0.0 per cent among non-roma (n = 14) [18] . a study by the same authors on idus in budapest showed that 16.7 per cent of roma idus (n = 42) were positive for either chlamydia or syphilis vs. 8.3 per cent of non-roma idus (n = 144), while none of the idu's sampled tested positive for gonorrhoea [19] . the prevalence of chlamydia trachomatis in the hepameta population in eastern slovakia was 7.2 per cent among the roma (n = 208) compared to 5.3 per cent among non-roma (n = 132). however, this difference was not significant. roma women (n = 142) had a prevalence of 8.5 per cent compared to 4.5 per cent among roma men (n = 66). there was no difference in prevalence among non-roma men (n = 75) and women (n = 57) [23] . the aim of this paper was to review the literature on communicable diseases among roma across eastern and central europe. we found that roma communities have disproportionately high prevalence of communicable diseases, and are identified as being at high risk of infection throughout these parts of europe. studies on communicable diseases among roma appear to originate primarily from slovakia. romania, which has the highest population of roma in the eu, has surprisingly little research published on them. in this review only two papers on romanian roma met the selection criteria. the reasons for this disparity need to be examined. this review was only concerned with papers written in english, so it is possible that more information is available in the national languages. the papers reviewed all involved segregated roma, i.e., those living in settlements. though this might seem to be a limitation, it is known that most roma in europe identifying as roma live predominantly in informal settlements [8] . furthermore, data collection along ethnic lines remains a contentious issue [35] . additionally, most integrated roma no longer identify as roma, or might not even know of their roma heritage [36] . as a result, there is a lack of usable data on roma living outside the settlements. this review indicates that roma sometimes do not have a higher prevalence of communicable diseases. no significant difference between roma and non-roma was found in chlamydia cases in the hepameta population in eastern slovakia. in fact, roma men had fewer cases of chlamydia than either non-roma men or women. nevertheless, the authors of this review tentatively state that roma are at a higher risk of contracting chlamydia, and are more likely to suffer from adverse effects of infection because of the barriers to healthcare which they face [23] . drawing from the same hepameta population, seropositivity for trichinella or echinococcus showed no statistical differences between roma and non-roma [29] . among a group of idus in budapest, neither the roma nor the non-roma idus had hiv [19] . non-roma living in close proximity to roma do not have very different prevalence of communicable diseases than the roma. in fact, roma may even have lower rates of disease. this is evidenced by some surprising findings. non-roma residents of a predominantly roma neighbourhood of budapest had higher hbv rates than their roma neighbours, while neither of the groups had any cases of hiv [18] . a hepameta subpopulation in slovakia showed higher rates of t. gondii among non-roma living in close proximity to roma settlements [30] . roma have a relatively high prevalence of communicable diseases overall. notwithstanding the instances mentioned above, roma have a higher occurrence of communicable diseases than non-roma. the most common reasons hypothesised by authors for the higher rates of disease are lack of water, poor sanitation and hygiene, crowded living spaces, high-risk sexual behaviours, and exposure to animals and waste [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] . several studies found that roma, especially roma children, have a particularly high prevalence of parasites. this is especially troubling, given that roma children have been found to suffer from significantly higher levels of morbidity than their non-roma peers [24] , and because parasites such as microsporidia and toxocara can be life-threatening. many of these are diseases of poverty, so they can potentially be treated and prevented, but they may result in significant morbidity if not managed. some studies found that roma have high rates of sexually transmitted diseases. in sofia, for example, the prevalence of gonorrhoea and syphilis was many hundred times the national levels [17] . on the other hand, despite repeated studies describing high-risk sexual behaviour, the prevalence of stds is sometimes not very high [20, 23] . amirkhanian et al. hypothesize that this is probably due to the social insularity of the groups [20] . this might also explain the lower rates of hpv among roma in romania [32] . this review is the first to attempt an examination of the prevalence of communicable diseases among roma across eastern and central europe. however, some limitations should be mentioned. papers were not screened very stringently for quality, given the dearth of research in this area. while this enabled the review to include a much broader range of papers, it also meant however that not all the papers included lent themselves to rigorous statistical analysis. papers written in languages other than english were not searched for or included, as a result of which useful data might be missing. transnational, national and regional databases of health were not examined either. finally, analyses of impacts, such as socio-cultural aspects of the community, could only be included in as far as they were analysed in the reviewed papers. firstly, the higher prevalence of disease within roma settlements, along with many of the risk factors for infections, should be a cause for concern and action. the roma minority represents an untapped repository of knowledge and skill, and a lot more resources should be devoted to removing barriers to their full participation in all areas of society. secondly, and perhaps more concerning to many, there is the fact that as long as segregated roma continue to exhibit a higher prevalence of disease, they remain a reservoir for neglected and immunisable diseases which could easily spill over into the general population. this has happened several times already in the case of measles [37, 38] . lastly, roma communities that do not have a high disease burden also need attention. once diseases enter these insular communities, they are likely to spread rapidly given the high infection potential associated with lack of infrastructure, poor hygiene and frequent high-risk behaviours [23] . roma in eastern and central europe continue to have a higher prevalence of communicable diseases than the majority populations of the countries they live in. roma children in particular have a particularly high prevalence of parasitic disease. however, these differences in disease prevalence are not always present across diseases and roma populations. in the case of hpv in romania for example, roma women have less than half the rate of the disease than non-roma romanian women. additionally, when roma are compared to non-roma living in close proximity to them, these differences are often no longer significant. this does not change the reality that roma communities continue to score lower on socio-economic indicators, have a disproportionately high incidence of communicable diseases, and have been found to be at high risk of infection. the following are available online at http://www.mdpi.com/1660-4601/17/20/7632/s1, table s1 : roma over europe, s1: search terms, table s2 : quality assessment. the authors declare no conflict of interest. reconstructing the population history of european romani from genome-wide data european roma groups show complex west eurasian admixture footprints and a common south asian genetic origin the cost of roma slavery trouble with gypsies in early modern england roma holocaust remembrance has lessons for europe today roma women reveal that forced sterilisation remains policing of european covid-19 lockdowns shows racial bias-report. the guardian the situation of roma in 11 eu member states; publications office of the european union undp in europe and central asia. 2020. available online the roma vaccination gap: evidence from twelve countries in central and south-east europe are barriers in accessing health services in the roma population associated with worse health status among roma? access to health care for roma children in central and eastern europe: findings from a qualitative study in bulgaria roma integration 2020|roma decade. rcc.int. 2020. available online communicable diseases. euro.who.int. 2020. available online mother-to-child transmission of hiv infection in romania: results from an education and prevention programme hiv risk behavior patterns, predictors, and sexually transmitted disease prevalence in the social networks of young roma (gypsy) men in sofia hiv and selected blood-borne and sexually transmitted infections in a predominantly roma (gypsy) neighbourhood in budapest, hungary: a rapid assessment vulnerability to drug-related infections and co-infections among injecting drug users in high-risk sexual behavior, hiv/std prevalence, and risk predictors in the social networks of young roma (gypsy) men in bulgaria occurrence of microsporidia as emerging pathogens in slovak roma children and their impact on public health high hepatitis b and low hepatitis c prevalence in roma population in eastern slovakia the prevalence of chlamydia trachomatis in the population living in roma settlements: a comparison with the majority population the health status of roma children-a medical or social issue significantly higher occurrence of cryptosporidium infection in roma children compared with non-roma children in slovakia seroprevalence of human toxocara infections in the roma and non-roma populations of eastern slovakia: a cross-sectional study schusterová, i. occurrence of the most common helminth infections among children in the eastern slovak republic the roundworm strongyloides stercoralis in children, dogs, and soil inside and outside a segregated settlement in eastern slovakia: frequent but hardly detectable parasite a community-based study to estimate the seroprevalence of trichinellosis and echinococcosis in the roma and non-roma population of slovakia exposure to toxoplasma gondii in the roma and non-roma inhabitants of slovakia: a cross-sectional seroprevalence study seroprevalence of hepatitis e virus in roma settlements: a comparison with the general population in slovakia hpv testing for cervical cancer in romania: high-risk hpv prevalence among ethnic subpopulations and regions the cross-sectional study of toxoplasma gondii seroprevalence in selected groups of population in slovakia seroepidemiology of human toxocariasis in selected population groups in slovakia: a cross-sectional study collecting ethnic statistics in europe: a review the socio-economic determinants of the health status of roma in comparison with non-roma in bulgaria, hungary and romania measles outbreak in a french roma ongoing measles outbreak in greece related to the recent european-wide epidemic key: cord-319365-v75pvlka authors: navajas-romero, virginia; díaz-carrión, rosalía; casas-rosal, josé carlos title: comparing working conditions and job satisfaction in hospitality workers across europe date: 2020-07-23 journal: int j hosp manag doi: 10.1016/j.ijhm.2020.102631 sha: doc_id: 319365 cord_uid: v75pvlka job satisfaction is important in the tourism sector since workers’ satisfaction is key to providing high-quality service, which is very important in determining organizational success. the working conditions that influence job satisfaction depend to a large extent on the institutional context, which shows similarities in some european countries. this research aims to compare working conditions and job satisfaction among european country blocks that have similar institutional characteristics. unlike previous studies, this research adopts a comprehensive approach by considering institutional and organizational factors in the analysis of employees’ perceptions of job satisfaction. the sample is made up of 1633 workers in 16 european countries. the results demonstrate the existence of three different models of working conditions in europe leading to differing levels of job satisfaction in tourism. these models do not correspond to the clusters identified by the previous literature, which adopts an institutional perspective. and internationally (lee and chelladurai, 2018) in different sectors such as in banking and the public or hospitality sector (ariza-montes et al., 2018; kong et al., 2018) . most of these studies were conducted without taking into account the institutional context. economic conditions, unemployment rate, and national level of inequality of a national territory, among other institutional factors, generate similar working conditions among countries in terms of salaries, working hours, job security, and flexibility (posada-kubissa, 2018; tangian, 2008) . working conditions are particularly context-sensitive due to their strong linkage to the industrial relations system of a country, unemployment rate, etc. (van dierendonck et al., 2016) . despite the existence of a supranational government in the eu, the institutional context differs across countries, and therefore working conditions and employee satisfaction are also different across europe. previous studies have classified countries according to their institutional context and identify different models of human resource management in europe (e.g., brewster and tregaskis, 2003; ignjatović and svetlik, 2003; nikandrou et al., 2005) . it is interesting to complement these studies that present an institutional focus with a perspective centered on organizational practices and employees´perceptions. for employment practices to create value for companies and society, they must generate job satisfaction. due to the importance of job satisfaction at individual, organizational, and societal levels, including employeesṕ erception of their job satisfaction, the analysis becomes crucial. a deep understanding of the differences in job satisfaction across europe could set the basis for a deeper discussion and formulation of novel hypotheses regarding the influence of institutional factors on working conditions. this understanding could lead companies and policy-makers to propose policies for improving working conditions in order to enhance job satisfaction and social welfare. although some studies that compare job satisfaction across european countries can be found in the literature (e.g., eskildsen et al., 2004; millán et al., 2013; pichler and wallace, 2008) , comparisons are made across national territories without considering the homogeneity that may exist among european countries. according to the literature, these countries can be grouped by blocks according to the similarities in their approach to the welfare state-which impacts, among its main facets, working conditions. the welfare state model of each country is determined, among other aspects, by public policies, labor regulation, and organizational practices-fundamentally, human resources management practices. hence, the literature establishes blocks of countries based on their similarities in their institutional setting and their prevailing organizational human resources management models (e.g., albareda et al., 2007; brookes and barfoot, 2005; filella, 1991; ronen and shenkar, 1985; tangian, 2008) . the underlying premise is that there is some convergence toward homogeneity of these characteristics of countries within the same cluster and differences with respect to the rest of the blocks. studies that analyze whether this convergence leads to homogeneity in workers´perception of labor conditions and job satisfaction across europe are rare. this study tries to contribute to this end by exploring working condition models in europe from an organizational perspective and considering workers´perceptions. this might allow identification of possible deviations between the institutionally established regulations at the national or supranational level and the patterns of interaction of the workers and organizations in the labor market. this can help us understand which models lead to higher levels of job satisfaction and whether there is convergence in this aspect in the european context. the research seeks: (i) to analyze the different models of working conditions-what likely leads to differences in perceived job satisfaction-that exist in europe; and (ii) to explore whether these models differ among the clusters of countries based on institutional characteristics identified in the previous literature. from these objectives, the following research question is derived: does the clustering of european countries according to institutional characteristics correctly reflect the differences in labor conditions and subsequently job satisfaction across europe? this article is divided into six sections. first, a review of the relevant literature is presented in the second section. next, the methodology of the research and the results are explained in the third and fourth sections. finally, a discussion of the results and the conclusions, which includes the limitations and suggestions for future research, are detailed in the fifth and sixth sections. job satisfaction is an essential aspect for firms to gain a competitive advantage in all sectors, given the central role that employees play in business success (kramar, 2014) . however, despite the importance of job satisfaction, there is no general agreement regarding its definition. different authors have contributed to its clarification. among the mostcited definitions is the one given by spector (1997) , who emphasizes that job satisfaction refers to the way employees feel about their job and depends on different factors. mahdieh and sotoudehnama (2018) affirm that job satisfaction depends on factors such as personal, organizational, managerial, academic, professional, and economic variables. goetz et al. (2016) underline four factors as determinants of job satisfaction: professional development, interpersonal relations, economic expectations, and working conditions. there are principally two methodologies for assessing job satisfaction: the integral measurement of a single factor and the comprehensive multidimensional measurement. the difference between the two methods lies in the fact that while the former relies on a single item to measure job satisfaction, the latter employs several factors. most research on job satisfaction at the national level adopts a multidimensional measurement approach. for instance, the descriptive work index (jdi) developed by locke et al. (1964) includes different dimensions of the job such as promotion, payment, and relationships with managers and colleagues. spector (1997) created a job satisfaction survey (jss) that contains nine dimensions: salary, promotions, additional benefits, incentives, superiors, colleagues, operating environment, intrinsic work characteristics, and communication. parent-thirion et al. (2016) developed their job quality index (jqi) from seven variables (earnings, prospect, social environment, physical environment, work intensity, skills and discretion, and work time quality) that are related to the multidimensional nature of work. the jqi has been considered for the present investigation because it is comprehensive in coverage, transparent in method, and widely employed in the research on job satisfaction and the quality of work in the european context (e.g., erro-garcés and ferreira, 2019; punzo et al., 2018; soriano et al., 2018) . it is the basis for the development of the sixth european working conditions survey (ewcs) which, according to grimshaw et al. (2017) , yields solid and reliable information. in 2000, the eu launched the european employment strategy with the aim of creating more (quantity) and better (quality) jobs (ariza-montes et al., 2019) . ewcs asks workers about the intrinsic characteristics of their jobs: salary, hours, participation, organization, and security, among others. the ewcs has been used in previous studies in which the impact of working conditions on satisfaction is analyzed, but using different perspectives such as new technologies (castellacci and viñas-bardolet, 2019) , gender issues (brinck et al., 2019; gómez-baya et al., 2018) , and workers' age (berde and rigó, 2020; okay-somerville et al., 2019) . the tourism sector is characterized by high levels of seasonality, which leads to labor practices that do not favor workers' commitment and permanence in the company in the long term (hofmann and stokburger-sauer, 2017) . the characteristics of the job positions in the tourism sector are related to higher levels of job dissatisfaction compared to other industries, which explains why more than half of the workers in the tourism sector are dissatisfied and consider moving to other sectors (stamolampros et al., 2019) . factors explaining the low levels of job satisfaction observed in the tourism sector are related to characteristics of job positions and to the lack of professionalization of the human resources management in this industry (jovanović et al., 2019; lillo-bañuls et al., 2018; zopiatis et al., 2014) . on the one hand, the characteristics that make this sector present low levels of job satisfaction compared to other sectors are related to low salaries (earnings), long working hours (work intensity), low job security, and the scarcity of promotional possibilities (prospects) (zopiatis et al., 2014) . the low work time quality of the jobs in the tourism sector is associated with the continuous relationship with customers, shift work, unsocial hours, and night work (lillo-bañuls et al., 2018) . this, together with the scarcity of occupational health and safety practices that favor an adequate physical environment, make employees working in this sector experience difficulties maintaining a work-life balance and a healthy lifestyle that would prevent stress and not lead to low levels of job satisfaction (hofmann and stokburger-sauer, 2017) . this stress is increased by the lack of perceived organizational support and autonomy that characterize jobs in the tourism industry (loi et al., 2014; tongchaiprasit and ariyabuddhiphongs, 2016) . the low levels of employee recognition, centralization in decision-making, and presentism that characterize this industry are associated with a lack of professionalization of human resources in the tourism industry (nickson, 2013) . the degree to which employees perceive social support from their superiors (the quality of the social environment at work) and are provided with autonomy to perform their job (skills and discretion) highly determine employees' level of satisfaction and work engagement since the social support of managers and supervisors influence workers´perception of justice at the workplace (jovanović et al., 2019) . to obtain a comprehensive view of job satisfaction and its antecedents in the tourism sector, different dimensions must be considered. this study combines different factors that determine the quality of work (earnings, prospect, social environment, physical environment, work intensity, skills and discretion, and work time quality) to provide a holistic view of working condition that allows the comparison of the quality of work and the level of job satisfaction across europe by relying on the employee's own perspective. the eu´s regulations favor workers' mobility within europe. labor mobility is the result of different levels of national unemployment rates, salary level, flexibility, etc. (fahri and werning, 2014) . taking into account that the quality of employment varies across european countries, factors that strongly explain workerśmobility and differences in job satisfaction depending on the country can be observed, as indicated in the literature (e.g., leineweber et al., 2016; salpigktidis et al., 2016; thite et al., 2012) . these differences can be explained by the distinct institutional settings of each territory (salvatori, 2010) . as derived from the premises of institutional theory, coercive pressures-especially national regulations-highly determine human resource management practices, so they might lead to differences in working conditions across countries (western, 1998) . the different labor legislations across european territories, despite european countries sharing a supranational government, influence working conditions and job satisfaction (brewster and hegewisch, 2017) . according to institutional theory, in addition to the coercive pressures exerted by legislation in a country, there are normative pressures, which are related to the appropriate and desirable norms of behavior for both organizations and individuals that predominate in a country (acemoglu and johnson, 2005; dimaggio and powell, 1983; scott, 1987) . these pressures also vary across territories and can be determinant in working conditions. countries that present similar institutional contexts-that show similar coercive and normative pressures-might present differences in terms of employee job satisfaction. this could be the case in countries such as denmark and norway, which present both institutional and cultural similarities but significantly differ in their working conditions (bech et al., 2017) . reviewing the literature, it can be observed that previous research has made efforts to identify blocks of european countries according to their institutional context (e.g., albareda et al., 2007; brookes and barfoot, 2005; filella, 1991; ronen and shenkar, 1985; tangian, 2008) . one of the most commonly used classifications identifies four clusters of countries in europe: anglo-saxon (ireland and the united kingdom), central european (austria, belgium, germany, the netherlands, and switzerland), latin (france, greece, italy, portugal and spain) and nordic (denmark, finland, norway and sweden) (filella, 1991; ronen and shenkar, 1985) . numerous aspects of institutional context determine working conditions. pichler and wallace (2008) emphasize the key role played by four institutional factors in working conditions: economic conditions, unemployment rate, the national level of inequality, and the degree of unionization. economic conditions of a territory highly impact the labor market in terms of job rewards in both extrinsic (average wage level, working hours, etc.) and intrinsic terms (meaningful, high-skilled jobs, etc.). the national unemployment rate and the national level of inequality also influence working conditions and job satisfaction. high levels of unemployment hinder job mobility regardless of a workers' level of satisfaction. employees, even those who are dissatisfied, will remain in their jobs because of the lack of opportunities in the labor market. the scarcity of job opportunities and the excess of job demand might lead employers to offer poorer conditions in terms of salary, working hours, etc. socio-economic inequality is also a determinant of job dissatisfaction if employees perceive that similar jobs lead to great differences in economic outcomes. the degree of unionization in a country seems to be highly determinant of the average wage level and other conditions of work that influence the welfare of employees. in highly unionized countries, employees are more likely to find better jobs in terms of salary, working hours, etc. accordingly, working conditions are generally better in countries that present a solid economic situation, a low unemployment rate, and a high level of unionization. this is the case for companies in the nordic cluster, which have good working conditions in comparison with the rest of european companies (eskildsen et al., 2004) . this can be explained by the high level of trade union intervention in those countries, where labor reforms encourage workers' representatives to negotiate working conditions with trade unions. as indicated in the literature, another institutional characteristic that determines working conditions is the country level of regulation (gialis et al., 2017; keune and jepsen, 2007) . the level of regulation is closely related to the level of flexibility in the labor market and to the degree of job security (posada-kubissa, 2018). labor flexibility is negatively associated with job satisfaction and employees´physical and psychological health since flexibility is associated with low levels of job security (carr and chung, 2014; probst et al., 2017) . flexibilization comes from deregulation; job security pursues the maintenance of social advantages through a compensatory system. both depend on the country and are not only affected by economic conditions, but by collective agreements, and by the agents involved: governments, employers, and trade unions (tangian, 2007) . in this line, sapir et al. (2004) identified four different social systems within europe according to the level of flexibility of each country. gil-alana et al. (2019) affirm that a robust social security system is associated with low levels of inequality. from the aforementioned two premises are derived: (i) that the institutional context strongly influences working conditions and that these become a determinant factor in job satisfaction (williams and hall, 2000) ; and (ii) that since institutional pressures are similar in each country block-anglo-saxon, central european, latin, and nordic-similar working conditions within each cluster (intra-group similarities) and differences across clusters are expected (inter-groups differences). this is because, among other aspects, government regulations determine an organization's freedom of action regarding employees' minimum wages, training and development investments, working hours, etc. (vaiman and brewster, 2015) . although the influence of the institutional context on working conditions is expected, companies' freedom of action within the framework of labor regulations is also expected to determine working conditions. in this way, workers in the tourism sector of countries with similar institutional settings could present discrepancies in their working conditions and, subsequently, in their job satisfaction. providing evidence about this would justify the need to group countries according to their working conditions model, a categorization that would more accurately show the reality of the labor market from an employee's perspective. in order to address the research objectives, the methodology used to develop the empirical analysis is presented below. to investigate differences in job satisfaction and in the quality of work among countries that show significant institutional differences, we have focused on the tourism sector due to the relevant role it plays in the european economy. the data used for the research were extracted from the sixth ewcs (the most recent available). this survey contains data on 43,850 working individuals 15 years old or older residing in private homes in one of the 33 european countries studied (28 countries of the eu; albania; the former yugoslav republic countries of macedonia, montenegro, and serbia; and turkey). this survey was developed by the european foundation for the improvement of living and working conditions (2020) (dependent on the european commission) to obtain information on the quality of work and employment in europe. to perform the analysis, countries that present significant institutional and organizational differences were selected (filella, 1991; ronen and shenkar, 1985) . the sample includes the following countries and country clusters: the united kingdom and ireland (anglo-saxon); austria, belgium, germany, the netherlands and switzerland (central european); france, greece, italy, portugal, and spain (latin); and denmark, finland, norway and sweden (nordic). the sample used in this study is formed of 1633 employees of 16 european countries that work in the tourism sector. table 1 shows the number of observations for each country cluster. to select workers from the tourism sector, the statistical classification of economic activities in the european community, nace 1 codes were used. according to eurostat, the following codes were included as part of the tourism sector: 491 (passenger rail transport and interurban); 493 (other passenger land transport); 501 (sea and coastal passenger water transport); 503 (inland passenger water transport); 511 (passenger air transport); 551 (hotels and similar accommodation); 552 (holiday and other short-stay accommodation); 553 (campgrounds recreational vehicle parks and trailer parks); 561 (restaurants and mobile food service activities); 563 (beverage serving activities); 772 (rental and leasing of personal and household goods); 791 (travel agency and tour operator activities); and 799 (other reservation service and related activities). filtering by these criteria, 1633 employees (7.2 % of 43,850) made up the sample. we based our research on the sixth edition of the ewcs, which includes the dimensions of the european jqi developed by parent-thirion et al. (2016) . this index is formed of seven dimensions that determine working conditions: earnings, prospects, social environment, physical environment, work intensity, skills and discretion, and work time quality. 2 all the constructs used in the analysis except salary (expressed in euros) and job satisfaction (expressed on a four-point likert scale) are numerical variables expressed on a scale of values between 0 and 100. according to parent-thirion et al. (2016) , the constructs were defined as follows: earnings: the importance of earnings as a motivational factor has been widely studied in the literature (suzuki et al., 2018) . this construct is defined as the net hourly earnings of workers. prospects: this refers to the job characteristics that contribute to a person's material and psychological needs, encompassing the need for income and for employment continuity. de witte et al. (2016) point to these factors as determinants of job satisfaction. skill and discretion: this dimension refer to the skills required for the job and the level of job autonomy. both are pointed to in the literature as relevant factors influencing job satisfaction since they enhance job identification and commitment (fregin et al., 2018; mateos-romero and del mar salinas-jiménez, 2018) . social environment: this dimension measures the social support perceived by employees (good social relations with line managers and fellow workers) and the absence of abuse in the company, which becomes especially important for workers' welfare as it moderates the negative impact of stressors (wisse et al., 2018) . this construct includes two constructs: adverse social behavior and social support. physical environment: this dimension refers to environmental hazards and to factors related to posture-related risks, which become relevant factors in the health of employees, a fundamental aspect of job hygiene and satisfaction (devonish, 2018; koh et al., 2017) . work intensity: this dimension refers to the intensity of work demands. high work intensity is associated with a risk of suffering high levels of occupational stress, which in turn is associated with low levels of job satisfaction (iranmanesh et al., 2017; rushton et al., 2015) . work time quality: this dimension refers to the organization and length of working time. the number of working hours, shift work, night work, etc., are determinant for the achievement of a good work/life balance, subsequently playing a significant role in job satisfaction (eagan et al., 2015; roy, 2017) . job satisfaction: the level of satisfaction is a variable included in the sixth ewcs survey and is measured as a four-point likert scale. the question is: "in general, are you very satisfied, satisfied, not very satisfied or not at all satisfied with your working conditions?". all the items used for the construction of the variables are included in the sixth ewcs and are shown in the appendix, together with the results of the reliability tests obtained with the cronbach alpha coefficient for the tourism industry. the main objective of the empirical analysis is to determine whether the classification of countries based on the institutional context adequately reflects the different models of working conditions-and subsequently differing levels of job satisfaction-existing in europe in the tourism sector, and if not, to propose a more appropriate classification of countries. to do this, based on the classifications of filella (1991) and ronen and shenkar (1985) , a comparison of working conditions among countries of the same clusters (intra-group comparison) is made. the existence of a high heterogeneity among countries of the same block would indicate an inappropriate grouping of countries located within the same institutional block. this analysis will be completed with an inter-group comparison, in which a high homogeneity in the working conditions of countries of different blocks would indicate a reduced discriminatory capacity among the blocks. therefore, a high intra-group heterogeneity and a reduced inter-group heterogeneity would allow us to conclude that the classification made by previous studies does not correctly classify countries according to the labor conditions perceived by workers. next, through a two-step cluster analysis, a new classification is proposed that improves intra-group homogeneity and inter-group heterogeneity. the suitability of this new group of countries will be evaluated using the methods previously described. the normality of these variables was previously checked for the selection of the method of analysis. to address the research objectives, both inter-group and intra-group differences have been analyzed for both job satisfaction and working conditions. first, the analysis of intergroup differences-among country blocks-has been performed using the mann-whitney test. this technique allowed a comparison of the level of job satisfaction among country clusters (anglo-saxon, central european, latin and nordic). second, the existence of significant intragroup differences among countries within the same cluster in the level of job satisfaction have been studied using the mann-whitney and kruskal-wallis tests due to the ordinal nature of this variable. as the mann-whitney test can only be used to make comparisons between two groups, it has been employed to test the intra-group differences in the level of satisfaction within the anglo-saxon cluster (between ireland and the united kingdom). since the kruskal-wallis test allows comparing more than two groups, it was used to analyze the existence of intra-group differences for the central european, latin, and nordic clusters. working conditions have also been compared among country blocks (inter-groups) and among countries within the same block (intragroups). first, the analysis of inter-group differences in working conditions has been performed using the t-student test. this technique allowed the comparison of the working conditions among all the country blocks. second, as working conditions (earnings, prospects, social environment, physical environment, work intensity, skills and discretion, and work time quality) are numeric variables and normally distributed, t-student and analysis of variance (anova) have been used to analyze the intra-group differences. as the t-student test can only be used to compare two groups, it was employed to analyze the intragroup differences of working conditions within the anglo-saxon cluster. as anova allows comparisons among more than two groups, it was used to assess the existence of intra-group differences among the central european, latin, and nordic blocks. the effect sizes have been estimated with the statistic proposed by rosenthal (1994) for the mann-whitney contrasts (0.1, 0.3, and 0.5 are used to indicate small, medium, and large effect sizes); cohen's d statistic for t-student contrast (0.2, 0.5, and 0.8 are used to indicate small, medium, and large effect sizes), and η 2 statistic for the anova test (0.01, 0.06, and 0.14 are used to indicate small, medium, and large effect sizes) proposed by cohen (1977) . a 2 statistic is used for the kruskal-wallis test (0.01, 0.08, and 0.26 are used to indicate small, medium, and large effect sizes) (tomczak and tomczak, 2014) . the existence of significant intra-group differences and limited differences among blocks of countries that present different institutional settings justifies the need for a new classification of european countries. to create this new grouping, a two-step cluster analysis has been developed. to confirm the validity of the proposed clusters, the intra-group and inter-group differences in the level of job satisfaction and in working conditions have been analyzed using the same statistical techniques previously explained. the descriptive analysis of the data shows that the average age of employees of the sample is heterogeneous, standing at just over 40 years, with a standard deviation of 12.92 years. the male gender is slightly predominant; they represent 56.2 %, compared to 43.8 % of women, which contrasts with the existing proportion in this sector at the european level, where these proportions are inverse. secondary education is the predominant level of education among workers in the sample (74.1 %), followed by university studies (19.1 %), and primary education (6.8 %). the most represented sub-sectors in the sample are "beverage serving activities," which represent the majority group (54.8 %), "passenger rail transport and interurban" and "other passenger land transport" (21.2 %), and accommodation ("hotels and similar accommodation," "holiday and other short-stay accommodation," and "campgrounds recreational vehicle parks and trailer parks") (15.1 %). following the international standard classification of occupations (isco-08) based on oecd (2012), 71.8 % of the workers in the sample are "white collar" employees, of which less than a quarter are highly qualified. within the "blue collar" employees-who represent 28.2 % of the total sample-only 7.5 % are considered highly qualified. presuming that the institutional environment is a factor that could significantly affect the degree of satisfaction of workers, in particular those who work in the tourism sector, we have explored the levels of job satisfaction across country blocks that present institutional differences. using the mann-whitney test, we analyzed the differences among working conditions in country blocks with different institutional contexts. the results show that there are mainly significant differences in the level of satisfaction in the latin countries with respect to the rest of the blocks, while the differences among the rest of the blocks are not significant. in addition, the effect size is very small, even in the case where the differences are significant (table 2) . hence, there is a high homogeneity in job satisfaction across country blocks that present different institutional settings. when analyzing the intra-block differences, within the nordic cluster, denmark and finland do not present any unsatisfied employees. about 90 % of employees present high and medium-high levels of satisfaction in austria and switzerland (within the central european cluster), the latter not presenting any unsatisfied employees (see table 3 ). the analysis of intra-group differences shows that these differences are significant; therefore, a lack of homogeneity in job satisfaction among countries in the same block is observed, mainly in the central european and nordic blocks, in which the effect size is medium. inter-groups differences in job satisfaction. mann-whitney test. p-value (effect size). accordingly, differences in the degree of job satisfaction among countries within the same block are found, indicating high intra-group heterogeneity. the differences in working conditions among the blocks of countries identified in the literature-based on their institutional characteristics-were also studied. the results show that the latin cluster presents significant differences with respect to the rest of the blocks in all the analyzed variables (except the social environment variable), with some effects of medium size. the results show the absence of significant differences between the anglo-saxon cluster and the central european block in all the variables studied. the same is observed when comparing the former with the nordic group, except in the labor expectations and the physical environment variables, although with a small effect. the differences between the nordic and the central european blocks are reduced since, in addition to finding differences in the previous variables, significant differences are also observed in the skills needed to develop the work, although with a small effect (see table 4 ). hence, there is a high homogeneity in the working conditions across country blocks that present different institutional settings. comparing the working conditions of the countries within each cluster, ireland and the united kingdom (anglo-saxon block) show a great homogeneity in all variables except salaries-workers in the tourism sector in the united kingdom receive higher salaries than in ireland. however, differences among countries of the same block are significant if we analyze the rest of the blocks, as can be extracted from the results of the intra-group anova test (see table 5 ). among the nordic countries, significant differences are observed in the prospects, physical environment, work intensity, and skills and discretion variables. the differences found among the countries of central europe are also significant. a high disparity in wages across countries within this block can be observed, motivated by the high average salary in switzerland, followed by the significant differences in job prospects, in the social environment, and in the skills required for the jobs. hence, the results indicate the existence of a high degree of heterogeneity in the working conditions of countries within the same block. based on the previous results which show differences in working conditions among the countries of the same block and scarce differences among blocks established according to their institutional characteristics (with the exception of the latin cluster), we propose the creation of a classification of countries according to the similarity in their working conditions in the tourism sector, specifically from the seven jqi dimensions (earnings, prospects, social environment, physical environment, work intensity, skill and discretion, and work time quality). to create this new clustering, a two-step cluster analysis was performed (see table 6 ). the results of the cluster analysis show that, on the one hand, there are countries such as greece and spain (group 3) that show worse working conditions and, consequently, lower levels of job satisfaction in comparison with the rest of the countries. at the other extreme are denmark, finland, france, and sweden (group 2), which present the most advantageous working conditions and the highest degree of job to confirm the validity of these results (average silhouette value is greater than 0.5), the working conditions of the groups created and the job satisfaction among blocks and within blocks are analyzed. regarding the latter, significant differences between clusters in terms of working conditions and job satisfaction are observed (see table 7 ). comparing job satisfaction among blocks, significant differences are observed. likewise, analyzing the working conditions among blocks, differences among all of them exist, with the exception of clusters 1 and 2, which show similarity in their work time quality; and between clusters 2 and 3, which show similarity in physical environment and work intensity. there is a high heterogeneity in the variables related to working conditions in the three groups identified, endorsed by mediumhigh effect sizes in many of the comparisons that are also higher than the effects found in the original blocks identified in the literature. regarding the differences across countries within each cluster, it can be observed that there are no significant differences in job satisfaction among the countries that are part of the same block (see table 8 ). regarding working conditions, a high degree of homogeneity is observed. countries in groups 2 and 3 show the greatest homogeneity in working conditions. although there are significant differences, especially in group 1, the effect sizes are small. this is observed in the anova test (except in earnings and, to a lesser extent, in prospects in group 1), and in the rest of the tests performed, as shown in table 8 . the workers in the three defined blocks are homogeneous in terms of characteristics such as age, gender, seniority in the company, and the percentage of self-employed people, as shown in table 9 . studying the working conditions of each block, a great disparity between the salaries of groups 2 and 3 is observed. the group composed of greece and spain presents lower values in all variables except social environment and work intensity. groups 1 and 2 show similar results, but working conditions are slightly more favorable in group 2. this group presents better results with respect to the rest in skills and discretion, intensity, and prospects, while group 1 shows more favorable conditions in the social environment and physical environment dimensions with respect to the rest. this research identifies a novel grouping of european countries according to the working conditions prevailing in the tourism sector. the differences among country clusters are manifested in different levels of employee satisfaction since the institutional context greatly influences working conditions, which in turn determines job satisfaction (salvatori, 2010; western, 1998) . despite the relevant role of the table 6 proposed country blocks according to their working conditions in the tourism sector. group 1 austria -belgium -germany -italy -ireland-netherlands -norway -portugal -switzerland -united kingdom group 2 denmark -finland -france -sweden group 3 greece -spain variables group 1 group 2 group 3 work intensity physical environment work time quality prospects skills and discretion social environment earnings institutional context-where planning and policymaking occur-in shaping working conditions, this issue has received little attention in the literature on tourism. studies focused on institutional context and working conditions and job satisfaction in the tourism industry are rare. according to western (1998) , working conditions are highly influenced by national regulations-and especially by labor regulations-and therefore by the institutional context. the strength of unionization becomes an important factor influencing job satisfaction because employees' wellbeing is highly determined by salary and work intensity, among other working conditions, which are especially influenced by the levels of unionization (pichler and wallace, 2008) . since strong unionization in a country can lead to better working conditions, the relevance of the institutional context as an antecedent of working conditions and job satisfaction must be highlighted. classifying european countries according to their working conditions can set the basis for a deeper understanding of the factors that determine job satisfaction in the tourism industry in different territories. as has been concluded from the analysis, a classification of countries based on their institutional characteristics as proposed by the previous literature (e.g., albareda et al., 2007; brookes and barfoot, 2005; filella, 1991; ronen and shenkar, 1985; tangian, 2008) does not group countries correctly according to working conditions and job satisfaction perceived by workers. few differences in worker satisfaction among countries that have different institutional settings and large differences among countries of the same institutional context have been found. similarly, countries of different institutional environments have similar working conditions, while countries of the same context present large differences in working conditions. these results point to the need to propose a new classification or clustering of european countries according to their prevailing working conditions and job satisfaction levels. although the comparison of job satisfaction across european countries has been studied by academics, previous studies have analyzed individual countries without considering the existence of homogeneity among countries and the existence of differentiated blocks in terms of their institutional setting. this research proposes a novel classification of countries according to prevailing labor conditions in each territory-what marks differences in job satisfaction across country clusters. one of the key aspects that determines working conditions is labor flexibility, and this depends to a large extent on institutional context (posada-kubissa, 2018) . tangian (2008) affirms that policies that enhance flexible employment are incompatible with achieving employment security. carr and chung (2014) propose that in countries where the levels of labor flexibility are high, employment security policies should be implemented to increase employees' security. therefore, different levels of employment protection and labor flexibility determine different social systems. despite the eús supranational government, there are differences in social systems across countries (brewster and hegewisch, 2017) . sapir et al. (2004) identified four social models in europe, each emphasizing security versus flexibility to a different extent: flex-insecure, inflex-secure, inflex-insecure, and flexsecure. according to our analysis, group 1 corresponds to two groups of inflexible countries according to sapir's classification: the continental cluster (inflexible and secure: austria, belgium, germany, italy, norway, the netherlands, and switzerland) and the countries included in the anglo-saxon block (inflexible and insecure: ireland, portugal, and the united kingdom). the former are countries characterized by high income inequality, low-wage jobs, high levels of employment protection, low job security, and by early retirement pensions (sapir et al., 2004) . according to the previous characteristics and inspired by sapir et al. (2004) , we propose to call group 1 as inflexible group. according to probst et al. (2017) , this model was considered to be effective in reducing poverty but ineffective in job creation in the long term. on the contrary, the anglo-saxon model is characterized by low-wage jobs, low job security, and high levels of income inequality. this model was effective in creating employment opportunities but ineffective in reducing poverty. group 2 resulting from our analysis corresponds to the scandinavian model (denmark, finland, france, and sweden) . this country cluster is characterized by a robust social security system. although job protection is low, employment security is high in comparison to the rest of the blocks. this model enhances job creation and a high standard of living. the countries grouped in this cluster present similar levels of employment protection and low levels of inequality (gil-alana et al., 2019) . therefore, following sapir et al. (2004) , we propose to call this country block as flex-secure. group 3 resulting from our analysis, the so-called mediterranean working conditions and demographic characteristics in the proposed blocks. model (greece and spain), emphasizes employment protection and early retirement pensions (probst et al., 2017) . inspired by sapir et al. (2004) , this cluster could be called flex-insecure because both countries in this group show high levels of flexibility and insecurity. according to our results, greece and spain show homogeneity in their working conditions. these countries experienced a deep recession after 2008, leading to an economically inferior position within europe. they are characterized by their weak institutions and the fiscal balance programs that have been implemented by their governments following the recession. both countries have been highly affected by prolonged austerity policies and present the highest levels of unemployment in comparison to other european countries (36.8 % in greece and 34.9 % in spain), according to eurostat (2018) . this can be an important factor that determines the differences found in this research in comparison with the blocks identified by the literature, which groups these two countries according to the institutional and organizational characteristics. while filella grouped italy, france, and spain within the mediterranean cluster in 1991, the socioeconomic development of each country has been different in the past decades. while france and italy have improved their working conditions, spain has remained among the countries with low job security and high flexibility in its labor market, which is reflected in the lowest levels of job satisfaction, showing more similarities to greece in terms of working conditions and job satisfaction than to italy and france. two main motivations led us to focus our analysis on the tourism sector: its high weight in the economy of european countries (world tourism organization, 2018) and its characteristics that entail high levels of precariousness (jovanović et al., 2019) . the results of the empirical analysis show that classifying countries according to their institutional setting does not properly reflect the differences in working conditions and job satisfaction across europe. this study proposes a novel classification of european countries according to working conditions in order to understand the differences in job satisfaction in different european countries from an employee perspective. the results point to differences among countries that present similarities in their institutional context. this is observed in the higher levels of satisfaction that countries such as france, italy, and portugal present in comparison with spain and greece (all of them belonging to the same block according to previous studies). the great differences among countries that belong to the same block and the small differences in working conditions among the countries of different blocks (with the exception of the latin cluster) lead us to posit the need to propose a novel classification of countries according to their working conditions. our research results show the existence of different models of working conditions in europe that go beyond the national borders of each country. the existence of three differing working conditions models-and subsequent differences in the levels of job satisfaction-are determined not only by institutional factors, which are similar among some european countries, but by other factors that need to be further analyzed such as companies' freedom of action in labor policies and workers' perceptions. this follows from the results of our study, which show that the grouping of countries according to their institutional context does not correspond to the grouping of countries according to their working conditions. therefore, it can be inferred that working conditions are not only a reflection of the institutional characteristics of the territories, but that other factors must be explored to understand the differences in working conditions and job satisfaction across europe. although previous classifications of european countries according to their institutional context and the model of managing employees exist (e.g., brewster and tregaskis, 2003; filella, 1991; ignjatović and svetlik, 2003; nikandrou et al., 2005) that take into account different aspects such as regulatory framework, economic and legal characteristics, and the type of educational system prevailing in each country, our research highlights the need to complement these studies with the employee's perspective. human resources policies are instruments that seek to ensure the proper functioning of organizations, but this will not be achieved if these policies do not generate job satisfaction. hence, the relevance of complementing studies that adopt an organizational perspective with the employee's perception of their working conditions and level of job satisfaction. the research makes several contributions to the literature. first, studies on the relationship between the institutional framework and working conditions in the tourism sector are rare. previous research does not explore the differences between the framework in which the working conditions are developed (which is highly influenced by the institutional context where the company operates) and the labor conditions developed at the organizational level, both determining job satisfaction. previous works that classify countries according to their institutional characteristics have only considered the framework in which working conditions are developed, ignoring that organizational management highly determines working conditions. in this vein, this study complements existing literature by proposing a novel classification of european countries based on the working conditions developed at the company level and by considering workers´perceptions about these conditions and their job satisfaction. on a practical level, the research shows how european countries are grouped according to workers' perceptions of their working conditions in the tourism sector. the results show that, although the institutional context is decisive in working conditions, these conditions are not determined entirely by these factors since there are territories with similar institutional settings but with substantially different working conditions. grouping european countries according to their homogeneity in working conditions is particularly interesting for understanding international differences in job satisfaction since work satisfaction is a direct reflection of organizational policies and practices and the extent and character of institutionalized labor norms and regulations. these results have implications for organizations and policy-makers. for organizations, assuming the freedom of movement of workers in europe, companies can attract talented employees from different european countries if they improve their working conditions by assimilating them to the territories with higher levels of job satisfaction. for european policy-makers, interesting conclusions might be drawn from this research. to advance the eu convergence, it is necessary to homogenize the working conditions of the european countries, aiming to reach those conditions that achieve the highest degrees of job satisfaction. this will have benefits not only at the individual level, but also at the organizational and social levels. this need is especially emphasized in the uncertain context in which the tourism sector finds itself due to the covid-19 pandemic. it is difficult to predict the structural changes that the economic crisis expected after the pandemic will generate in the tourism sector, but it is expected that demand could contract in the near future due to the economic crisis predicted by international organizations such as the international monetary fund (2020). the expected contraction in demand could be seen as an opportunity to create a more sustainable tourism model that prioritizes quality over quantity, a more balanced tourism model that distributes its value more equitably and fairly among the different stakeholders. considering the fundamental role played by employees in the quality offered in the tourist service and their important contribution to business success in this sector, a model based on quality must be accompanied by better working conditions that result in greater employee wellbeing. despite the usefulness of this study, the results should be taken with caution due to the following methodological limitations. in the first place, job satisfaction is measured through self-perception, which can generate some bias in terms of the use of variables with an objective nature. second, the problem of comparing countries involves the bias that is introduced regarding different variables such as salary, which cannot be compared in absolute terms without considering the cost of living, and the expectations of employees in each country. future research could include perception variables about satisfaction with a salary instead of the salary in absolute terms to make the data comparable across countries. the classification of countries proposed by this study sets the basis for a deeper discussion on the factors-beyond the regulatory pressures that shape the institutional context-that influence working conditions. therefore, future research could explore factors such as the culture that might be similar in each of the clusters identified and that can be determinants of job satisfaction. finally, exploring job satisfaction in sectors different from tourism might lead to different groupings due to the specific characteristics of each sector. therefore, future research could replicate this study in other industries. unbundling institutions public policies on corporate social responsibility: the role of governments in europe the price of success: a study on chefs' subjective well-being, job satisfaction, and human values decent work as a necessary condition for sustainable well-being. a tale of pi (i) gs and farmers a 'civic turn' in scandinavian family migration policies? comparing denmark, norway and sweden job satisfaction at older ages: a comparative 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prostitución desde el modelo abolicionista (critical reflections on prostitution from the abolitionist model) psychological capital: buffering the v longitudinal curvilinear effects of job insecurity on performance job satisfaction in the "big four" of europe: reasoning between feeling and uncertainty through cub models clustering countries on attitudinal dimensions: a review and synthesis parametric measures of effect size banana time" job satisfaction and informal interaction burnout and resilience among nurses practicing in high-intensity settings burnout syndrome and job satisfaction in greek residents: exploring differences between trainees inside and outside the country labour contract regulations and workers' wellbeing: international longitudinal evidence an agenda for a growing europe. the sapir report the adolescence of institutional theory mediating role of job satisfaction, affective well-being, and health in the relationship between indoor environment and absenteeism: work patterns matter! job satisfaction: application, assessment, causes, and consequences job satisfaction and employee turnover determinants in high contact services: insights from employees' online reviews earnings, savings, and job satisfaction in a laborintensive export sector: evidence from the cut flower industry in ethiopia is work in europe decent? a study based on the 4th european survey of working conditions is europe ready for flexicurity? empirical evidence, critical remarks and a reform proposal internationalization and hrm strategies across subsidiaries in multinational corporations from emerging economies-a conceptual framework the need to report effect size estimates revisited. an overview of some recommended measures of effect size creativity and turnover intention among hotel chefs: the mediating effects of job satisfaction and job stress how far do cultural differences explain the differences between nations? implications for hrm linking hrm practices and institutional setting to collective turnover: an empirical exploration institutions and the labor market tourism and migration: new relationships between production and consumption catering to the needs of an aging workforce: the role of employee age in the relationship between corporate social responsibility and employee satisfaction european union tourism trends job involvement, commitment, satisfaction and turnover: evidence from hotel employees in cyprus key: cord-309527-hf18tqva authors: harley, grace; timmis, andrew; budd, lucy title: factors affecting environmental practice adoption at small european airports: an investigation date: 2020-10-06 journal: transp res d transp environ doi: 10.1016/j.trd.2020.102572 sha: doc_id: 309527 cord_uid: hf18tqva the majority of the world’s 3759 commercial airports handle under 5 million passengers a year and these small airports rarely employ practices to address their environmental externalities. the aim of this research is to investigate the range of environmental practices (eps) that are employed at small european airports and identify the factors which affect their adoption. the findings of an online survey of 413 small airports in the european common aviation area reveal that the eps most commonly adopted concern waste management and noise reduction. privately owned airports were generally more engaged with eps than publicly owned ones. consumer pressure, regulatory intervention, and airport size positively affected the adoption of environmental practices whereas complexity, perceived relative advantage and human resource constraints acted as barriers to adoption. the paper concludes with recommendations for policy and practice to support ep engagement and reduce the environmental impact of small airport operations worldwide. prior to the covid-19 global pandemic, airports facilitated the worldwide transportation of over 4.4 billion passengers and 62 million tonnes of airfreight each year and generated $2.7 trillion in global economic activity (atag, 2018) . commercial aviation activities generate significant global and local environmental externality effects. by 2040, aviation related no x and co 2 emissions are predicted to increase by 16% and 21% respectively (aviation environment federation, 2016; caa, 2017; easa, 2019) and tens of millions of residents of local airport communities are exposed to levels of aircraft noise that exceed who recommended thresholds. the global air transport industry is coming under increased political and consumer pressure to reconcile global demand for flight with commitments to improve its environmental performance (aci-europe, 2009b) . although aircraft emissions have been the focus of systematic academic research since the 1950s, it is only more recently that the need to address airports' wide-ranging environmental impacts, which include 'noise pollution, energy consumption, water pollution, waste management, and the storage and control of hazardous materials' (boiral et al., 2017, p. 1) , has begun to be recognised. an airport's negative environmental externalities arise as a result of both airside and landside operations. many are the result of third-party operations (e.g. aircraft noise and local air pollution) which are facilitated by the airport operator. despite airport operators having little direct ownership of many of the sources of environmental impacts within the airport system, they have a unique role in their management and a significant role in affecting change (for example by setting operational procedures and targets). many large airports have recognised the incompatibility of future operations with the principles of sustainability and have adopted mitigating actions in the form of sustainability programmes. london heathrow's 'heathrow 2.0' strategy and hartsfield-jackson atlanta international's 'greeningatl' are examples of how large airports are embedding environmental practices (eps) in their operations (your heathrow, 2018; hartsfield-jackson atlanta international airport, 2019) . in this context, eps are defined as 'techniques, policies and procedures a firm uses that are specifically aimed at monitoring and controlling the impact of its operations on the natural environment' (montabon et al, 2007, p. 998) . examples of eps which can be employed at airport sites include, but are not limited to, practices which reduce noise pollution, such as imposing noise preferential routes (nprs) continuous descent operations (cdos) and continuous climb operations (ccos) and preferential runway usage (netjasov, 2012; graham, 2018) ; practices which address waste management, such as bulk buying products and/or materials, going paperless in administrative areas and recycling waste (budd et al., 2015; acrp, 2018) ; and practices which preserve and protect wildlife, such as using non-lethal management techniques and providing conservation areas martin et al., 2013) . although heathrow and atlanta are the busiest passenger airports in the uk and us respectively in terms of traveller numbers, small airports (handling under 5 million passengers per annum) are the most numerous and account for the majority of the world's airports (anna. aero, 2019; faa, 2019) . within the european common aviation area 1 (ecaa), over 80% of airports, equivalent to over 400 separate facilities, fall into this category 2 (anna. aero, 2019) . collectively, these sites handle almost four times as many passengers a year as the 80 million processed at heathrow. indeed, in many european countries, air transport activity at small airports caters to a significant proportion of national demand. small airports account for approximately 40% of annual air transport movements in the uk and remote/regional airports fulfil important economic functions in other european countries including france, norway and greece (caa, 2017b; anna.aero, 2019). these small airports often provide lifeline connectivity services or are a major employer and economic driver in the region. consequently, the social and economic benefits they bring are often considered to outweigh their environmental costs (chassé and boiral, 2016) . despite the prevalence of small airports their adoption of eps is limited. for example, small airport participation in the airport carbon accreditation (aca) scheme, an industry initiative to promote 'greener' aviation, is low. the aca scheme, launched in 2009, 'is the only institutionally-endorsed, carbon management certification standard for airports' (aci-europe, 2009a) . while over 70% of larger airports in the ecaa participate in the scheme (25% of which operate at the highest level of accreditation -'neutrality'), only 13% of smaller airports participate in the programme. such statistics corroborate the findings of industry and academic studies which have reported that 'specific measures for sustainability are almost non-existent in small airports' and that 'small airports rated their [environmental] performance lowest of all [studied airports]' (acrp, p. 41, 2016; boiral et al., p. 7, 2017) . as such, the potential for further environmental mitigation at small airports exists. according to borial et al (2017, p.11 ) due to 'their isolation [and] frequent lack of institutional pressures… [small airports] may address sustainability issues in a different manner than other organizations'. this poses a series of important questions relating to the range of eps that are employed at small airports, the factors which affect ep adoption, and the extent of their adoption. the aim of this research is to identify the range of eps that are currently employed at small airports in the ecaa, observe which environmental impact categories are prioritised, and better understand the motivations and barriers to ep adoption in order to propose recommendations for future policy and practice. the rest of this paper is structured as follows: the next section critically reviews the literature concerning airports' environmental impacts, details how eps can be adopted in small organisations (including airports) and proposes the technological, organisational and environmental (toe) framework as a suitable theoretical underpinning for the research. the methods used for the empirical data collection and subsequent analysis are then described in section 3 before the results are presented and their significance discussed. the paper concludes with recommendations for future policy and practice. the negative environmental impacts of airport operations result from both landside (before security) and airside (after security) activity. environmental externalities encompass a wide range of impacts (see ashford et al. (2013) ; graham (2013b) ; roberts-hughes (2014) ; budd et al. (2015) ; koç and durmaz (2015) ; sameh and scavuzzi (2016) ; boiral et al. (2017) ) which can be classified into eight broad categories: 1. water use and quality degradation 2. air quality and air pollution emissions 3. energy consumption 4. noise pollution 5. biodiversity impacts 1 the ecaa encompasses albania, bosnia and herzegovina, north macedonia, montenegro, serbia, kosovo, the eu, norway and iceland; the area is subject to a unilateral agreement forming a single aviation market and the uniform enforcement of regulations across all participating countries (european commission, 2019). 2 aci europe airport size classifications: group 1 -over 25 million passengers a year; group 2 -between 10 million and 25 million passengers a year; group 3 -between 5 million and 10 million passengers a year; group 4 -less than 5 million passengers a year (aci-europe, 2018). 6. waste production 7. land use 8. construction and building to address and mitigate these impacts, which vary in terms of their severity and scale, airports can employ a range of environmental practices (eps). the scope of eps are broad and may address impacts which the airports are directly responsible for creating or those where they can influence third-party sources (e.g. aircraft engine emissions). however, extant research has shown that small airports struggle to engage with eps (acrp, 2008) . a 2016 study, for example, discovered that almost 40% of small us airports did not employ any eps (acrp, 2016) . of the airports which did, 51% focused on addressing energy use using practices such as installing efficient lighting and utilising photovoltaic solar panels, 26% sought to reduce water consumption/improve water quality by taking actions such as modifying irrigation systems and installing low-flow toilets, 5% employed noise reduction practices, which mainly focused on measuring and monitoring noise, and 2% addressed air quality and emissions by utilising electric utility vehicles and retrofitting terminal heating, ventilation and air conditioning (hvac) systems (acrp, 2016) . possible reasons for the low adoption of eps at small airports relate to cost, a lack of resources and possible unwillingness on behalf of the operator to engage with tenant companies on site. for example, eps which involve modifying a third party's operations (for example, airlines or concessionaires) are often avoided by smaller airports for fear of alienating customers and losing revenue (ratliff et al., 2009; boiral et al., 2017) . furthermore, despite the availability of 'guidebook-type' resources for small airports in the us (acrp, 2008 (acrp, , 2010 (acrp, , 2011 (acrp, , 2012 (acrp, , 2015 best practice guidance for small airports in other world regions is limited. this is potentially problematic as the us is atypical in that the majority of its small airports remain in full public ownership (ryerson, 2016) . in many other global markets, airports are increasingly privately-owned or are operated under a mixed public-private ownership structure. 3 this has the potential to affect their environmental behaviours and priorities. although research which directly relates to small airport engagement with eps is scarce, an extensive body of research into small organisations' engagement, across a wide range of industries, with eps, does exist. as small airports share many of the characteristics of small organisations (they employ low numbers of staff, have limited financial resources relative to larger firms in the same industry and are many in number (berisha and pula, 2015) ), they are considered to be small organisations for the purpose of this research. organisational adoption of eps often takes a structured approach which seeks to incorporate environmental considerations at the design and construction phase of a project. they also typically implement environmental management systems (such as iso 14001), create environmental plans, conduct environmental reporting and integrate formal environmental management or master plans into the business (monsalud et al., 2014) . certainly, development of master plans is now relatively commonplace within the airports sector (acrp, 2016). however, in smaller organisations (particularly where the publication of a master plan is not mandated), it tends to be conducted in a more ad-hoc and less formalised way than at larger companies (chan, 2011; acrp, 2015; d'souza and taghian, 2018) . according to acrp (2016), the implementation of sustainable initiatives at airports requires the development of dedicated strategies, the identification of champions, the development of dedicated committees and teams, and consistent target setting and monitoring (acrp, 2016) . such processes can be challenging and costly for small airports. the technological, organisational and environmental (toe) framework, proposed by tornatzky and fleisher (1990) , has been used to explore ep adoption within small organisations. the toe framework posits that there are conceptualised factors which can encourage and/or prevent the organisational adoption of practices and innovations (tornatzky and fleischer, 1990 ). these include: (1) technological factors, (2) organisational factors and (3) environmental factors (lippert and govindarajulu, 2006; angeles, 2013 angeles, , 2014 baker, 2011) . the framework is generic and flexible, and variables can be added or removed according to context (baker, 2011) . such flexibility enables the toe framework to be used to examine the factors which affect ep adoption at small european airports. as well as enabling researchers to appreciate the factors which promote the adoption of eps, the toe framework also permits the identification of barriers to implementation. these barriers may include (but are not limited to): a lack of funding, a lack of human resources, a lack of awareness of financial support mechanisms such as grants, competing commercial priorities, and a lack of awareness of the potential commercial benefits of adoption (acrp, 2008 (acrp, , 2016 devault et al., 2009; boiral et al., 2017; jaiyeola, 2017) . while limited funding is often cited as the primary barrier to ep engagement, it is often a 'lack of human resources' which actually pose the greatest barrier to adoption (hillary, 2004, p. 568) . human resources can be limited by incumbent staff members' knowledge base and skill sets (acrp, 2008 (acrp, , 2016 boiral et al., 2017) . smaller organisations often do not have access to specialist training facilities and/or cannot afford to hire dedicated staff who have the necessary knowledge and skills to adopt eps (simpson et al., 2004; gupta and barua, 2018) . staff with less specialised training will also be less able to adopt and employ complex technologies and practices, which presents a further barrier to adoption ho, 2008, 2011; weng and lin, 2011; hwang et al., 2016; kousar et al., 2017) . at smaller organisations, staff may also have many roles and so balancing duties and responsibilities can be challenging and environmental concerns may not be a priority (chassé and boiral, 2016) . a limited understanding and awareness on the part of an organisation's senior management team can also hinder ep adoption (acrp, 2008 (acrp, , 2016 boiral et al., 2017) . if this limited awareness results in senior managers not supporting ep it is unlikely eps will be adopted (ramakrishnan et al., 2015; gupta and barua, 2018) . equally, if senior managers believe 'that making the airport's operations more sustainable is the right thing to do' this can drive ep adoption (acrp, 2015, p. 14) . technological resources can also affect the adoption of eps. the (in)compatibility of eps with existing airport operations and technologies can present another obstacle to implementation. if eps are not perceived to be easy to integrate with existing operations, ep adoption will be less likely (weng and lin, 2011; hwang et al., 2016) . although barriers to ep adoption exist, there are factors which have been shown to encourage engagement. however, there is significant debate regarding the consistency of these drivers in all operational contexts. for example, many airports' ep adoption is driven by strategic intent (lee, 2009; brammer et al., 2012; agan et al., 2013) . some eps can be advantageous for organisations as they may deliver cost reductions, improve environmental performance, enhance corporate reputation and ensure regulatory compliance (acrp, 2015 (acrp, , 2016 . however, small organisations do not (or cannot) always benefit from the rewards from ep adoption as the implementation costs can outweigh any financial or competitive benefits they deliver (hillary, 2004; simpson et al., 2004; revell and blackburn, 2007) . however, cost reduction, improved environmental performance, enhanced stakeholder relations and legislative compliance are often anticipated outcomes of ep adoption (acrp, 2015 (acrp, , 2016 . social and consumer pressures also have the potential to encourage ep adoption. an acrp (2016) survey reported that airports who had not employed eps stated that they would be more likely to do so if communities surrounding airports and passengers expressed concerns about the environment and demanded change (acrp, 2016). it has been suggested that smaller organisations are often responsive to social pressure, however, in some cases (particularly where organisations are in more rural locations) these pressures are not necessarily present and so do not act as drivers for change (darnall et al., 2010) . where drivers for the voluntary adoption of eps are ineffective, legislation and regulation can act as a powerful incentive to adoption (acrp, 2016). however, a study of small canadian airports noted that despite the introduction of new regulations governing surface runoff, staff did not have the time or resources to receive the training that was necessary for compliance (boiral et al., 2017) . many small firms are also not 'eco-literate' and often lack the resources and knowledge to appreciate how legislation affects them (hörisch et al., 2015) . in addition, legislation is often inapplicable to smaller organisations and compliance is not monitored or policed (brammer et al., 2012; agan et al., 2013) . for example, the eu environmental noise directive (which concerns the assessment and management of airport noise) does not apply to airports with fewer than 50,000 annual aircraft movements (european union, 2002) . regulation of small airports is problematic as 'frequently these airports are subject to multiple levels of policy compliance with respect to their aviation operations… environmental impacts, and relationship to other airports' (donehue and baker, 2012, p. 235) . certainly, relatively little is known about the types and range of employed eps at small airports, particularly outside of the us. there is a need for both academics and policy makers to understand the status of small airport engagement with eps and appreciate how to encourage adoption in order to mitigate the environmental impact these airports generate. an online self-completion questionnaire was developed and distributed via email to all commercial airports within the ecaa which handled under 5 million passengers in 2017 (and hence defined as 'small'). data was obtained from national reporting bodies (most commonly national aviation authorities) or, where this was unavailable, from official passenger statistics of individual airports. this provided a total population of 441 airports. airports were excluded from the study if they did not have an accessible website and/or a contact email. as a result, 28 airports were excluded, leaving a population of 413. fig. 1 displays the ecaa, divided into geographical regions of north, south, east and west (as defined by the un.) and the location of the 413 small airports. the ecaa offers an interesting and varied region of study as it is one of the largest aviation markets in the world, comprises multiple sovereign states and supports a mature aviation market which has been progressively liberalised since the mid-1990s. the focus on a mature market was deliberate as 'in general, emerging markets lag behind developed economies in environmental stewardship' (jayanti and rajeev gowda, 2014, p. 130) . the online survey was conducted in english as english is the international language of commercial aviation and international airport operations. participants were assured anonymity in exchange for their participation to encourage truthful and honest responses. ethical approval was received from the lead researcher's institution. a list of the managers and/or environmental officers' email addresses for each airport was compiled from each individual airport's website. a link to the survey was emailed on march 29th 2019. follow up emails were sent to those who had not completed the survey on april 15th and 22nd to encourage additional responses. the survey was live for 6 weeks and this enabled the whole population to be approached (wright, 2005 ). an email survey was chosen to promote a high response rate as previous research into small organisations reported low response rates on account of the limited time of staff members to complete survey requests (macpherson and wilson, 2003; gadenne et al., 2009) . the survey comprised four distinct sections. the first and second obtained information about the respondent and the airport (or airports) they worked for. the third section asked respondents to rate the extent of ep adoption at their airport/s and identify which ep practice types were currently employed across eight environmental target areas: (1) water use reduction/quality improvement, (2) emissions reduction, (3) energy-use reduction, (4) noise reduction, (5) biodiversity improvement/protection, (6) waste reduction, (7) land use management, (8) design of green buildings. for each target area, respondents selected a value on a 5-point likert scale from "not at all" to "to a great extent". the sum of these responses provided an overall value of the extent of ep adoption (see ho, 2008, 2011; weng and lin, 2011) . to encourage respondents to consider and identify all relevant practices, indicative (but not exhaustive) examples from the literature were included in each question by way of prompts. in addition, the scope of relevant practices included those environmental impact sources that the airport operator has direct control over and those where they can influence third-party operations. for instance, respondents were asked "does your airport: reduce noise from airborne aircraft (e.g.: modify descent patterns, employ noise abatement procedures)?" and "does your airport: reduce emissions from surface access traffic (e.g.: provide incentives for low emission passenger vehicles, encourage trip reduction schemes such as subsidising public transit for passengers or providing staff ride share schemes, provide infrastructure for alternatively fuelled vehicles)?" the provision of such examples encouraged respondents not only to report the practices implemented which directly affect airport operations, but also those imposed by the airport which affect third parties' operations at the airport (including airlines, concessionaires, and ground access companies). the fourth section of the survey asked respondents to indicate their level of agreement with a number of predefined statements. responses were obtained through a 5-point likert scale which offered a range of options from "strongly disagree" to "strongly agree". the statements were developed using tornatzky and fleisher's (1990) toe framework (see table 1 ). the survey was pilot tested between march 6th and march 17th, 2019, on a sample of 54 airports (13% of the total population). factors investigated in the survey (based on the toe framework). technological complexity the degree to which a new practice 'is seen as difficult to understand and use' (ruslan et al., 2014, p. 61) . compatibility the degree to which a new technology matches the existing needs, values and experiences of a firm (ramdani et al., 2013; bin ibrahim and binti jaafar, 2016) . the perception that a new practice is better than what is already in place (wang et al., 2010; weng and lin, 2011) . organisational top management support the extent to which an organisation helps and encourages staff members to use a new practice (weng and lin, 2011) . the 'learning and innovative capabilities' of staff members (lin and ho, 2011, p. 75 ). size total annual passengers 2017. environmental consumer pressure the force of 'normative pressures' on an organisation causing behaviour modification in the search for legitimacy ( hwang et al., 2016, p. 9 ). regulatory pressure 'coercive pressures, such as threats or legal sanctions' exerted from national and supranational organisations (hwang et al., 2016, p. 8) . support mechanisms such as 'financial incentives, technical resources [and] human resource training' provided by government bodies and external stakeholders (piaralal et al., 2015, p. 256) . results from the pilot survey indicated that some of the statements in the fourth part of the survey were not (based on cronbach's alpha and factor analysis) reliable indicators for the factors they intended to measure. these statements were subsequently modified to improve the construct validity of the final survey instrument. additionally, the phrasing of certain questions and statements was modified to improve their clarity and prevent confusion among respondents for whom english was not their first language. factor analysis was conducted on the measurement statements to confirm the validity of the final survey instrument (roberts and priest, 2006) . a principal components analysis with direct oblimin rotation was used as the factors were correlated. the quality of the factor analysis was assessed using the kaiser-meyer-olkin (kmo) measure of sampling adequacy and bartlett's test of sphericity; the kmo was 0.683, above the recommended value of 0.5. bartlett's test was significant (χ 2 = 3469.680, p < .001) (williams et al., 2010) . cronbach's alpha was used to test for internal consistency; as all alpha values are above 0.7, the consistency was confirmed (tavakol and dennick, 2011) . factor scores were also obtained which were used in the subsequent regression. the results of the factor analysis are presented in table 2 . as the survey employed a single informant technique it was necessary to test for common method bias. harman's single factor test was used. the results showed that a single factor accounted for only 41% of the total variance, indicating that common method bias was not an issue (podsakoff et al., 2003) . a response rate of 26.4% was achieved (northern europe = 40.2%; eastern europe = 20.9%; southern europe = 23.4%; western europe = 3.6%), which is comparable with other studies investigating environmental behaviours of organisations and small organisations (gadenne et al., 2009; sroufe, 2009; darnall et al., 2010) . given this figure, it was necessary to check for non-response bias. it is assumed that non-respondents are more similar to late-respondents than they are to early-respondents (weng and lin, 2011) . by using armstrong and overton's (1977) method, comparing the average responses of late (those who responded in the second three weeks) and early respondents (those who responded in the first three weeks) using an independent samples t-test, it was found that non-response bias was not a concern, as there were no significant differences in the responses (armstrong and overton, 1977) . the survey received 109 valid responses from airports across europe. table 3 shows the geographical location, ownership 4 and number of staff members employed at the airports who responded to the survey. the average number of passengers at the respondent our passengers require us to improve environmental performance 0.709 caring for the environment is an important consideration for our passengers 0.923 caring for the environment is an important consideration for the airlines at our airport(s) 0.861 regulatory pressure α ¼ national government sets stringent environmental regulations 0.643 the environmental regulations set by national government affect our airport(s) operations 0.748 national environmental regulations do not affect our airport(s) operations 0.983 european environmental regulations do not affect our airport(s) operations 0.965 national government provides financial support for adopting environmental practices 0.976 national government provides information for adopting environmental practices 0.466 national government provides specialist training opportunities for staff members to learn environmental practices and related skills external stakeholders (e.g.: industry associations, local companies, specialist groups) provide financial support for adopting environmental practices 0.789 4 ownership is defined in accordance with the definitions used in aci-e's airport ownership report (see aci-europe, 2016, p. 2) airports was 403,465 in 2017. within the study, respondents were asked to identify which practice types, if any, their airport had adopted. fig. 2 shows the percentage of airports addressing 5 each of the 8 target areas, by geographic region and the overall percentage. the figure also shows the mean 6 number of practice types employed to address each target. the most commonly addressed target areas were waste and noise reduction, and the least common were emissions reductions and the design of green buildings. airports in western europe employed, on average, a greater number of practice types to address noise reduction. for waste reduction, the target is addressed by a higher percentage of airports in northern and southern europe. airports in northern europe also employed, on average, a greater number of practice types to address waste reduction. in eastern europe, a higher percentage of airports have employed green buildings than other regions. airports in north and west europe tend to address more environmental target areas with more eps. there is a potential that being close geographical neighbours they have a shared environmental culture influencing their behaviour. it is possible that different population densities around the individual airports result in noise reduction being a greater focus for western europe (where the population densities in germany and the netherlands the 236.7 and 508.5 people/km 2 respectively) than in northern europe (where the population densities in norway and sweden are 14.5 and 24.7 people/km 2 respectively) (the world bank, 2017). this would suggest that fewer people are impacted by noise in northern europe than other regions. green buildings were not a common target in any region which is likely a result of the high cost associated with their design, building and certification. one respondent highlighted that buildings at their airport had been built to formal certification standards, however certification had not been pursued as the administrative costs were too high. in eastern europe, the majority of airports indicated that where green buildings had been constructed, they were done so in accordance with national guidelines, as opposed to formal certification standards. this suggests that while there is interest in designing green buildings in this region, formal recognition is not important. figs. 3 and 4 show ep employment by airport ownership type. the results show that, on average, privately owned airports employ more eps in total and across all environmental target areas, with the exception of waste reduction and land use management. this suggests that commercial involvement has a positive impact on ep adoption as ep adoption could impart potentially important reputational benefits as being a responsible company and thus attracting/retaining custom. this supports lee (2009 ), brammer et al (2012 and agan et al. (2013) who suggest that there are commercial benefits to be gained from ep adoption. publicly owned airports may employ fewer eps as they tend to be the smallest airports which are focused on regional connectivity, therefore environmental concerns may be a lesser concern for them owing to their size and primary strategic goals. however, again, further research is needed to confirm this. following the examination of the target areas, further analysis explored the practice types which are employed to address these target areas. fig. 5 displays the % of airports employing each practice type 7 and whether the practice involves the airport modifying third party operators' operations (demarked by an asterisk.) on average, airports employed eight practice types across five target areas. all respondent airports employed at least one practice type; no respondents employed all practice types, indicating that there is scope for improvement with regards to ep engagement. only six practice types were employed by over 50% of respondents. in comparison, ten practice types were employed by fewer than 10%. of the six most commonly employed practice types, three were aimed at reducing waste. almost all airports reported addressing waste; the majority of which did so by recycling waste from administrative areas and passenger terminals. a large proportion of airports also indicated that they composted organic materials; this corroborates findings from the 2018 acrp study which indicated that composting was a practice growing in popularity at airports (acrp, 2018). it is not evident from this study's results, however, for what purpose the resulting compost is used. future research may usefully explore this. recycling waste from aircraft was identified as a further, however less common, practice aimed at reducing waste. existing literature focusing on waste management at larger airports highlights that recycling waste from aircraft is not common practice as international health and safety legislation aimed at maintaining a nation's sanitary border require international catering waste to be sent to deep landfill or incinerated (pitt et al., 2002) . the survey results here showed that almost 15% of the airports reported recycling waste from aircraft; this is likely because many of these smaller airports receive domestic flights only and so international health and sanitary regulations do not apply. the remaining three most common practice types were aimed at improving water quality by managing surface run-off pollution, managing land use by avoiding operating on/remediating contaminated land and protecting/improving biodiversity by having conservation areas within the airport boundary. having conservation programmes within the boundary has the potential to increase wildlife hazards which makes them uncommon at larger airports (martin et al., 2013) . however, it is likely that at these smaller airports the risk of wildlife strike is lower and so conservation programmes can be safely pursued. practices targeting noise reduction do not feature among the most common practice types. it is frequently stated in literature that noise is the greatest environmental concern for airports (wolfe et al., 2014; grampella et al., 2017; rodríguez-díaz et al., 2017) , however, while noise reduction is a commonly targeted area for airports, very few small airports (just over 25%) indicated that they employed more than one practice type to address the issue. where noise reducing practices were employed, almost 25% of airports in this study indicated that they employed practices to reduce noise emissions which restricted or modified airlines' operations. extant research into the environmental practices of small airports indicated that such facilities were reluctant to impose operational restrictions on airlines for fear of losing custom (dimitriou and voskaki, 2010; boiral et al., 2017) . of the least common practice types (employed by fewer than 10% of respondents) the majority feature practices and technologies which are complex and/or expensive; for example collecting and reusing water (see ashford et al., 2013; couto et al., 2015) . it would be important to consider that the airports using these practice types may be situated in more remote areas in which connections to mains water supplies are limited and reuse of water may be a necessity. also uncommon is the design of green buildings. where small airports report designing green buildings, they are often built in accordance with national standards, and not to certified levels of international bodies such as leed and breeam. the limited engagement was attributed to cost by some respondents. practices which involve modifying third party operations are also not commonly implemented. while some scholars have suggested that airports have a limited jurisdiction over pollutants, others contend that airports can exert some influence over third party operators' actions (hansen et al., p. 166, 2013; ryerson, 2016) . a limited number of respondent airports indicated that they imposed practices on airlines to address noise pollution, however, such interventions were not widespread and, as such, our findings corroborate those of boiral et al. (2017) . practices targeting emissions reductions (either local air pollution or greenhouse gases) were not commonly employed. after noise, atmospheric emissions have been identified as a significant environmental concern for airports (daley, 2010; wolfe et al., 2014; rodríguez-díaz et al., 2017; gudmundsson, 2018) . however, our results show that fewer than half of small airports are addressing this target area. one respondent stated that their airport conducted regular air quality monitoring and that the results indicated that no mitigating action was required. thus, it may be the case that for many smaller airports there are limited air quality and emission issues and so minimal action is taken. however, the act of monitoring would suggest that concern and awareness exist. on average, each practice type was employed more commonly by the 'larger small airports' (those with more than 1 million passengers a year) with the exception of some practices addressing waste reduction, biodiversity management and green buildings. airports handling under 1 million passengers a year recycled waste from both terminal areas and aircraft, composted organics, fig. 6 . classification of airports by ep engagement levels. plot size representative of how many airports represented by plot point. g. harley et al. employed conservation programmes both inside and outside of the airport site, used non-lethal wildlife control methods and constructed buildings to leed, breeam and national standards more commonly than the larger airports in the sample. it is possible that recycling waste from buildings may be easier for smaller airports as there is less to manage than at larger airports; also, as discussed previously, the smaller airports tend to handle primarily domestic traffic, meaning that international food waste laws do not apply and they are able to recycle more waste from aircraft. it may also be the case that the smaller airports in the sample handle fewer aircraft annually than their larger counterparts, and so are able to employ conservation programmes as the exposure risk for aircraft strikes with wildlife is less than at airports with more annual movements. it is unclear from the results why green buildings are more commonly constructed by the smaller airports in the sample, as the cost of such projects has specifically been highlighted as a barrier to their construction. there is potential that smaller scale construction at smaller sites has a lesser cost attached and that the cost savings that green buildings can bring (e.g. from reduced heating requirements) are appealing and cost effective at smaller sites. further research would be required to confirm this. the survey enabled airports to be clustered into three groups according to the number of environmental impact target areas they addressed and how many environmental practice types they employed. fig. 6 shows that the majority of airports fall within group 2, i.e. they are 'attempting engagement' by employing a mid-range number of practice types which address a medium-to-high number of target areas. these airports appear to be attempting engagement with eps but are not engaging at the same level as the 9 'industry leaders' in group 3. airports in group 3 employ of a broad range of practice types that address a high number of target areas. this contrasts with group 1 airports who we define as 'minimally engaged' as they employ few practice types and address few of the target areas. airports within each group were then segmented by size (table 4) . results showed that, on average, the 'larger' small airports (handling 1-5 million p.p.a) employed significantly more practice types and addressed more targets than the 'smaller' small airports (which handled under 1 million p.p.a). this suggests that subgroupings by size exist within this population which impact an airport's ability or need to engage with eps. the identification of size subgroups led to an additional difference being noted between the engagement groups identified in fig. 6 . airports with more than 1 million p.p.a are found more commonly in ep engagement group 3 (and somewhat in group 2), whereas all cases in ep engagement group 1 are airports handling under 1 million p.p.a. this suggests that the size of the airport impacts either the capability or need to engage with eps. however, there are a large number of airports with less than 1 million p.p.a in group 2 and some more anomalous cases found in group 3. this would suggest that the size of the airport is not the only factor affecting ep engagement. based on the toe framework (tornatzky and fleischer, 1990) , further analysis was therefore conducted to explore the relationships between the technological, organisational and environmental factors and ep adoption. the following subsections discuss the contextual factors affecting ep adoption at small european airports. fig. 7 presents the mean responses 8 to individual statements in the survey relating to the technological context. broadly speaking, respondents did not perceive eps as being complex and challenging to learn and engage with. however, the regression analysis (discussed in section 4.4.4) revealed that where respondents did perceive practices to be complex, they were less likely to adopt eps. the results corroborate the work of hillary (2004) , simpson et al. (2004) , lee (2009) and weng and lin (2011) who suggest that increased perceived complexity results in reduced practice adoption, however the responses contradict their suggestions that smaller organisations feel that eps are too complex and challenging to adopt. in order to further encourage ep engagement, practice complexities should be kept to a minimum, as adoption is less likely when perceived complexity increases. over 40% of airports indicated that they felt that adopting practices is easier when coupled with previous experience. this supports upham and mills (2005) , who suggested that exposure to best practice and success stories makes adoption more likely. increased networking and experience showcasing opportunities would likely be the most effective approach to this, as 'airports rely on peer group learning for their most critical decision making' and, furthermore, the literature has suggested that the dissemination of 'guidebook' type materials has been ineffective (acrp, 2011 (acrp, , 2016 ryerson, p. 1, 2016) . the majority of respondents agreed that eps are compatible with existing operations, corporate values, and environmental and strategic goals. however, very few strongly agreed with these statements. even in the case of practices being compatible with the environmental goals of the airports, fewer than 14% strongly agreed with the statement. this suggests that additional research is required to establish what small airport strategic and environmental goals are, in order to design eps which best align with them. responses showed that airports generally perceived eps to bring relative advantages. over 80% strongly agreed that the practices could enhance their airport's reputation. this was not anticipated, as extant literature generally focuses on the social benefits brought about by small airports, providing connecting services to comparatively isolated communities. chassé and boiral, (2016) suggest that small organisations' environmental impacts are often overlooked, excused by the social benefits they bring, thus it was not expected that the airports would feel there was reputational advantage to be gained by appearing to be 'environmentally friendly'. it would likely be effective to further highlight the advantages which can be elicited from eps to drive practice engagement. fig. 8 presents the mean response to the individual statements relating to organisational context. generally, support provided by top management in the pursuit of eps is present. however, the regression analysis did not find the relationship between top management support and adoption to be significant. this disagrees with conclusions drawn by jenkins (2006) , walker et al. (2008) and lee (2009) however corroborates similar findings from ramakrishnan et al. (2015) , suggesting that, while beneficial, top management support is not a vital factor for adopting eps in this context. for human resources, respondents indicated that they generally agreed with the provided statements and the regression analysis found the relationship to be significant. this agrees with results from ho (2008, 2011) and weng and lin (2011) who also found the relationship to be significant. however, in previous studies, the relationship between human resources and ep adoption has not been negative when included in a regression model. further investigation would be required to explore the effect of confounding variables. airport size also has a significant relationship with ep adoption, suggesting that bigger airports are more likely to adopt practices. however, the beta weight of this variable was not large, and other variables provided much stronger weightings. this suggests that while size may play a role in affecting adoption, it does not play as significant a role as is suggested in other studies (cassells and lewis, 2011; agan et al., 2013; hoogendoorn et al., 2015) . fig. 9 displays the mean response to the individual statements in the survey relating to the environmental context. the regression analysis (section 4.4.4) revealed consumer pressure to have the largest beta weighting relating to ep adoption, suggesting that the greater the perceived pressure from consumers the more likely small airports are to adopt. respondents expressing that they generally felt that consumers demanded environmental performance improvement largely disagrees with hillary (2004) and gadenne et al. (2009) who claimed that pressures of this kind are not felt by smaller organisations. however, this result does agree with darnall et al. (2010) , who said that when smaller organisations recognise consumer pressures, they are usually responsive. regulatory pressure was found to have the second highest beta weight in the regression analysis. respondents indicated that they felt that both national and european regulations impacted their operations. regulatory pressure perceptions were also the only factor found to significantly vary 9 by geographical location. airports in northern europe had a statistically larger average overall response to regulatory pressure, compared to the other european regions (see fig. 10 ). this geographical variation in perceptions warrants further investigation to potentially identify best regulatory practices to employ in other regions. the results in the analysis do, however, largely contradict much existing literature (revell and blackburn, 2007; brammer et al., 2012; agan et al., 2013) which suggests that regulation at small organisations is either ineffective or unpoliced. this research would suggest that regulation is effective and is encouraging engagement with eps. while support was not found to be significant in the regression analysis and had an unexpected negative relationship with ep (something which, in itself, warrants further investigation) the trends shown in responses to the statements provide valuable insight. the majority of airports reported that they did not feel that their governments provided sufficient financial support to assist in the pursuit of eps; they did, however, agree that support in the form of information is provided. the majority of respondents neither agreed nor disagreed with the final two statements. this suggests that perhaps there is an opportunity to be exploited in which specialist training can be provided to small airports to assist in the adoption of eps and also that external stakeholders can provide additional support. from northern european airports, the mean overall response to support was larger than the responses from the other european regions. there is potential that with the greater regulatory pressure exuded from national bodies in northern europe comes greater support. this, again, is worthy of further investigation. to explore the relationships between the nine factors (discussed in section 4 of the survey) and ep adoption at small airports, an ols regression was conducted. ols regression was appropriate as the dependant variable was continuous and the assumptions of multicollinearity, normality and homoscedasticity were met. all nine factors were taken as independent variables and the total extent of adoption as the dependant variable (dv) (mean = 22.32; sd = 6.339). the total extent of adoption was calculated by summing the self-reported extent of ep adoption across the eight environmental target areas (indicated on a 1 -5 likert scale) as discussed in section 3. as such, it is assumed that all environmental target areas are of equal importance. the total extent of adoption is therefore an indicative measure of the relative importance an airport operator places on integrating environmental management within their operations. the minimum possible value of the dv was eight (indicating that the respondent airport was not at all engaged with any of the target areas) and the maximum possible value of the dv was 40 (indicating that the reporting airport was engaged to a great extent with all target areas). table 5 shows the results of the regression analysis. the results found that compatibility, senior management support, airport size, regulatory pressure and consumer pressure have a positive relationship with ep adoption, while complexity, relative advantage, human resources and support have a negative relationship. the analysis indicates that increased perceptions of consumer pressure, regulatory pressure and larger airport sizes will likely result in airports being more engaged with eps. it also indicates that the more complex airports perceive eps to be, the less likely they are to adopt them. this analysis also suggests that an increase in perceived relative advantage and the quality of human resources results in reduced engagement. when taken as standalone independent variables, both have a positive association with ep adoption, however when other variables are added to the model the association becomes negative (the same applies to support however this variable was not found to be significant). it is anticipated that this is the result of confounding variables and requires further investigation. this research has provided new insights into the current environmental behaviours of small european airports. it has shown that there are some types of eps which are more and less favoured by small airports, and target areas to which small airports are more and less committed to. importantly, ep adoption by small airports is identified as being different from larger airports. regulatory interventions, consumer pressure, technological complexity, airport size, the quality of human resources and relative advantage were identified as having significant impacts on the likelihood of airports adopting eps. existing literature on small organisation adoption of eps focuses on the limitations small size can impose on the adoption process. the results here show that for aviation, size may have an impact, however other factors have a more substantive effect on ep adoption. therefore, it is necessary to target more specifically these other factors to further encourage ep adoption amongst small airports. the environmental and technological contexts, which were identified thorough the toe framework, have a greater effect than the organisational context on ep adoption. therefore, it is recommended that airlines, passengers and regulatory bodies continue to demand environmental behaviour from airports and that exceptions and exclusions are not be made based on size alone. this should be coupled with increased networking and showcasing opportunities and support where required, specifically in the form of specialist staff training. with this being said, however, it is now also important to consider the impact of the covid-19 pandemic on future small airport engagement with eps. although great uncertainty surrounds the realistic impact on the aviation industry and how industry recovery will look, it is likely that airports, particularly smaller airports, will see decreased revenues and compounded financial challenges. this will likely exacerbate resource issues at small airports, limiting their ability to engage with eps. furthermore, with decreased demand for air travel, the environmental impact of airports will also decrease, lessening the imminent need to address environmental externalities. this paper makes several important contributions by adding to the limited field of study focusing on small airports, specifically focusing on their environmental behaviours and the factors affecting this behaviour. the research has revealed that some of the claims in the existing literature regarding ep adoption at airports do not necessarily hold true in the context of small european airports. this, therefore, has the potential to more effectively inform policy. existing aviation environmental policies, guided by existing literature, have been primarily based on information relevant to larger airports; this study's contribution will allow more appropriate and effective environmental policies to be designed for small airports. the exploration of environmental target areas and employed practice types in this study builds on the previously conducted acrp studies (acrp, 2016 (acrp, , 2008 , however adds to the literature by examining a new geographic area, subject to different regulatory regimes and operational boundaries. whereas acrp (2016, 2008) 10 examined only small airports in the united states, this research has provided the first examination of the european airport industry and examined small airports spanning across 36 different countries. furthermore, while the acrp studies had examined the influence of various drivers and barriers to ep engagement, they had not considered the role that airport ownership plays. this study's examination of this factor presents a further development of the previous work. in addition to presenting the first large scale, european based survey of small airports, this research also presents the first application of the toe framework and regression in an aviation context. further research is required to explore and confirm the patterns and trends of practice adoption found in this study. this should in particular focus on examining further the causal relationships indicated in this study and understanding why certain environmental target areas were prioritised over others. furthermore, the classifying of airports by ep engagement level and exploring the features of the identified groups presents an additional contribution. combining the segmented ep engagement groups 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air service sustainability: analytical approach to documenting air carrier incentive programs in airport sustainability plans environmental sustainability measures for airports environmental responsibility in smes: does it deliver competitive advantage? effects of environmental management systems on environmental management practices and operations making sense of cronbach's alpha population density (people per sq. km of land area) the processes of technological innovation environmental and operational sustainability of airports: core indicators and stakeholder communication understanding the determinants of rfid adoption in the manufacturing industry small and medium enterprises and the environment: barriers, drivers, innovation and best practice: a review of the literature determinants of green innovation adoption for small and medium-size enterprises (smes). afric exploratory factor analysis: a five-step guide for novices near-airport distribution of the environmental costs of aviation researching internet-based populations: advantages and disadvantages of online survey research, online questionnaire authoring software packages, and web survey services heathrow 2.0 the authors would like to thank the editor and the reviewers for their very helpful comments on an earlier draft of this paper. this research was financially supported by the engineering and physical sciences research council (epsrc) via the loughborough university epsrc doctoral training partnership (grant ep/r513088/1). key: cord-322364-uo49h1ku authors: button, kenneth title: the economics of africa's floriculture air-cargo supply chain date: 2020-07-06 journal: j transp geogr doi: 10.1016/j.jtrangeo.2020.102789 sha: doc_id: 322364 cord_uid: uo49h1ku this article examines the economics of africa's emerging air cargo supply chains, taking floriculture as a case study. floriculture is an important employer, and earner of foreign exchange for several regions of central/southern and eastern africa including more recently ethiopia. air transportation often plays a critical role when the supply-chain involves high-value, non-durable, relatively light-weight, and compact consignments such as flowers, and geographically when regions are difficult to access by other trunk modes. the success of air cargo chains, however, depend as much on the quality of surface modes serving various “last mile” access and egress functions, as well as efficient nodal interchange points and the availability of suitable airport and airline capacity. the last, because of the important role of belly-hold space, includes consideration of passenger as well as cargo specific services. to meet the needs of africa's floriculture sector, a variety of supply-chain models have emerged that embrace air and surface links, as well as storage at various points in the chain. the paper considers the nature of these chains, the reason d'être for their structures, and their limitations. the most dynamic trading regions are now those that have become linked into the network of global value chains. unfortunately, africa is not a significant player in these networks. drivers for the development of global value chains are considered to be low transportation costs; information and communication technologies; high quality telecommunication infrastructure; technological innovations; education and skills of the workforce; competitive labor costs; political, social, and cultural environments; stable legislation and ability to enforce contracts; proximity to supply sources; and proximity to market. in general, africa falls short in most of these. 1 the focus of this paper is on the peculiar economic challenges associated with africa's floriculture aviation supply chains. 2 the requirements of this industry differ considerably from the traditional view of supply chains in africa with their focus of bulk raw materials and cheap consumer goods. 3 the modes used differ, the organization of the various links in the supply chain differ, the perishability of the products differ, the informational needs differ, the linking of the long and the short hauls differ, and so on. and, importantly, the aviation supplychain dominates the delivery of transportation to the floriculture industry. africa has the world's worst road, railroad, and airport infrastructures in terms of both quantity and quality (gwilliam, 2011; buys et al., 2010) . it also has the least number of commercial aircraft per capita. having said this, the forecasts for aviation activities are relatively optimistic. boeing commercial airplane (2018) predicts that intra-africa revenue passenger kilometers flown will grow an average annually by 6.6% between 2019 and 2038, and those between africa and the middle east and europe by 7.3% and 4.1% respectively. physically, air cargo is projected to grow between africa and europe by 3.7% per year, between africa and east asia by 6.1%, and between africa and north america by 5.3% per year. but this is from a small base. this paper looks at the economic challenges that still confront aviation-based floricultural supply chains in africa, and how they are being confronted. this is done largely within a managerial-economics framework. 4 i am much less concerned with the other significant challenges these supply chains encounter, such as culture and ethics issues (hughes, 2000 (hughes, , 2001 , although there is some discussion of the various forms of governance and government set within williamson's (2000) new institutional economics. methodologically, the article is an exercise in what used to be called "descriptive economics"; and which should not be taken as a pejorative term. 5 it involves gathering and compiling data about the economy and entails economists making observations, noticing patterns and recording facts. descriptive economics is mainly qualitative and inductive in its nature. initially, the general characteristics africa's floriculture sector are outlined, and the aviation services available are described. i then move to the specific challenges of the floriculture supply chain. finally, attention is paid to the main african chains, with a focus on the alternative structural models in place. these chains involve the linking of short-haul domestic african routes and their interface with intercontinental, trunk-haul airline services as well as the air transportation itself. 6 africa's modern commercial flower production began in the 1960s. it has always been largely an export orientated industry. flowers are neither a major part of most african cultures nor used much in decoration. outside of africa, prior to the 1960s demands for cut flowers in europe and north america were met by local production. in europe, which still has the largest per capita consumption of stems in the world, and about eight times that of the us, production was concentrated in the netherlands. 7 with the coming of expedited movements within the eu, it also became possible to economically produce cut flowers in southern europe. the energy crisis in 1973 put producers in northern europe under further pressure because of the higher costs of greenhousing. subsequently, the supplying of cut flowers to european markets began to shift to lower cost producing regions with climates that allow continuous production without high-energy consumption. growing exportable floriculture products in africa then became concentrated in kenya and south africa, with uganda, tanzania, and especially ethiopia rising in importance over recent years. zimbabwe's output declined dramatically from the early 1980s with the country's land reforms but there has been some recent recovery (english et al., 2006) . 8 at the same time, new markets are being developed for floriculture products in east asia, the middle east, and the us. kenya's current 500 t of daily exports of flowers, for example, end up in 60 national markets. ethiopia's growers, and exporters, while continuing to encourage trade with traditional european partners, have also begun exporting to saudi arabia, qatar, and bahrain. accompanying this have been tighter controls imposed by importing markets and, in particular, on the quality of products and on the environmental implications of their cultivation (kuiper and gemählich, 2017) . this has increased costs of production, and particularly so for some of the newer regions. the traditional distribution channels, notably the flower auctions in amsterdam, are responding to this. the auction systems have been computerized and the auction houses have taken on new roles including acting as intermediaries between growers and buyers when flowers go directly to final consumers (mwangi, 2019) . competing auctions have also emerged, most notably in dubai (babalola et al., 2011) . despite these developments, africa's floriculture industry is at the micro-level, geographically specific. there are variations in the needs of the varieties of plant grown, with each depending on appropriate amounts of sunlight, a narrow temperature range, and water supply, as well as specific soil compositions. altitude can be important in some cases. there are also differences in the ideal agroecological conditions for cultivating plants and cuttings for export as opposed to stems. the regions around lake victoria are, for example, ideal for long-stemmed cut roses as are 1200 ha on lake tana in ethiopia, the source of the blue nile, and another 2000 ha on the blue nile itself. the majority of floriculture in africa is located within relatively short distances of international airports. most of ethiopia's floriculture is, for example, within a 290 kms radius of addis ababa airport. similarly, kenya's flower farms are mainly situated around lake naivasha, about 90 kms northwest of nairobi airport. from an employment perspective, however, they do not bring more farm jobs to rural areas, but rather work is focused close to major cities, reinforcing urbanization trends. one reason for this is the cost structure of the industry. although this can vary a lot according to location, climate, and product type and quality, for an 18-ha farm near lake naivasha the cost per stem was estimated in 2015 at $0.03 to $0.04 for growth and $0.05 to $0.07 for transportation. 9 a stem would sell wholesale for $0.20 to $0.30. 10 given that production costs are largely fixed -wages are often already low and most operating capital is tied up in such as irrigation systems, cold storage, and ventilating systems -transportation is major variable element in the cost function. linked to this, another key factor influencing location is the lack of durability of stems. this means production has to be close to the trunk mode and there must be appropriate intermodal transfer facilities. flowers and cuttings, for example, need be at the retail market within days of cutting; e.g. roses last for three to five days, carnations seven to ten days, standard chrysanthemums seven to 12 days, and pompon chrysanthemums ten to 14 days. on average, for every extra day spent travelling flowers lose around 15% of their vase lives. africa's surface transportation infrastructure, despite considerable investment over the past decade, is seriously deficient in both quantity and quality. physical proximity to a major airport is, therefore, important to the floriculture industry. regarding regional economic effects, floriculture's impacts are highly geographically specific. unlike many other agricultural products, floriculture workers migrated to and live in areas that have become urbanized as the flower business has developed around them. as noted earlier, this has contributed to urbanization rather than slowed it as intended with agricultural retention programs (hall et al., 2017) . the industry is important because it creates employment and development possibilities, and especially because it provides relatively steady work throughout the year unlike other agricultural activities (mitullah et al., 2017; kabiru et al., 2018) . it is also a major employer of female labor, which constitutes about 75% of workers in kenya's flower production (kuiper, 2019) . although increasing over time, along with improved working conditions, farm workers' wages are in general still low. while the majority of those employed in floriculture in kenya earn wages above the agricultural legislated monthly minimum (dettmer et al., 2014) they still often fall below local poverty lines (kazimierczuk et al., 2018) . there are also often problems of displacement. in the lake victoria 5 the approach has an established pedigree and is, for example, referred as one of several branches of economics by jevons (1871) , generally seen as the father of mathematical economics, in his seminal work on the theory of political economy. 6 in doing this there are inevitable caveats regarding the quantity and quality of data. while global bodies, such as the world bank and the african development bank, and national governments, collect some aggregate statistics, much of the information regarding specific african supply chains is piece meal, often gained from case studies or profession bodies in individual countries, and sometimes from the grey literature. additionally, up-to-dated information can be found at the website of organizations cited in the text. 7 individual cut flowers are "stems". 8 https://www.floraldaily.com/article/9016096/zimbabwe-making-flowerexports-blossom-again/ 9 https://gro-intelligence.com/insights/articles/east-african-floricultureblossoming 10 taking 100 kenyan shillings are about $1. region, for example, workers migrating to the area have led to tension with local society which has traditionally been supported by grazing. floriculture's dependence on lake waters and the need for farmland not only raises concerns over ecosystem preservation but results in competition for water access and for land with local masai herders. cultural, conflicts also exist between the herders and kikuyu flower growers (kuiper, 2019) . economic theory highlights the key market characteristics required for viable aviation networks, but africa is an awkward "shape" for any of these (scotti et al., 2017) . the us is good for hub-and-spoke systems with its contiguous states forming a virtual square embracing large populations at each corner that act as gateways for international traffic as well as large markets for domestic fights. major cities in the center act as domestic hubs. europe is ideal for discrete, short-haul, nonconnecting services emanating from bases, such as in ryanair's business model. the bulk of its population and economic activity is located a dense economic corridor stretching from north wales to northern italy; the "blue banana". china, with its concentration of economic activity in the south and west, in many ways, parallels that of europe. the linear networks found in such as norway facilitate "bus-stop routes", with planes maintaining their load factors by picking-up and dropping passengers as they move along routes. most of africa's human geography does not conform to any of these patterns. institutional structures have not helped the situation. until the 1990s, intra-africa air services were regulated on a piece-meal basis by restrictive, bilateral national agreements with nearly all carriers stateowned and lacking a commercial focus. airlines were characterized by mismanagement, political interference, high operating costs, and outdated equipment. their focus was on inter-continental traffic, with the intra-africa network taking a secondary role. the 1999 yamoussoukro decision sought to readdress this. it was a commitment to deregulate air services and to open regional air markets to transnational competition. the expected gains have yet, however, to materialize on any scale, although in those regions where yamoussoukro has been implemented, frequencies have often increased and privately funded airlines have emerged (njoya, 2016) . but the impact is patchy. the creation of a single african air transport market (saatm), which has been planned since 2018, may offer another opportunity for enlargement of air services. most analyses of africa's aviation supply chains have focused on tourism (e.g. sifolo, 2020; steyn and mhlanga, 2016) . this is not surprising given the overall economic contribution of the sector to africa's economy. the world travel and tourism council (2019) estimated that in 2018 tourism accounted for 8.5% of the continent's gdp. but, as we have also seen a number of africa's regions have the geography to grow quality flowers in volume. like tourism, floriculture has a high labor content and its localized economic impacts are often where unemployment is high and labor productivity has been rather low. further, because africa's floriculture is almost exclusively an export industry, it is a major source of foreign exchange. fig. 1 stylizes the stages in air cargo supply chains. 11 it is conceptually identical for passengers with some differences in terminology; e.g. warehousing would be hotels and integrators would be inclusive package tour operators. basically, shippers can make all or some the decisions concerning modes of movement, routing, warehousing, distribution etc., or can engage integrators or forwarders to act as agents and carry out all or some of the stages. some of these decisions are of a purely technical nature (yang et al., 2010) , but other, partly due to market uncertainties, are more subjective. the generic pattern of air cargo logistics and the branches in the decision tree are similar irrespective of whether the logistics involves developed or developing countries. the range of options, however, tends to be smaller when developing countries are involved, and some of the options may be of lower quality. this is particularly so with cold chains that require actions and equipment designed to maintain a product within a specified low temperature range from harvest to consumption. an increase in temperature beyond four degrees at any point in the cold chain, for example, compromises the quality of cut flowers. at a more macro level, there are two broad frameworks typifying aviation supply chains, or at least to significant elements of then. one consists of a series of interacting free markets involving suppliers of various services and shippers -a set of standard neoclassical economic models. looking again at fig. 1 , this does not mean that at each stage there is competition in selling services. in some cases, to minimize coasian transactions costs, or to reap various forms of economies of scale, there may be vertical integration of suppliers of logistics services. thus, as seen later, while kenya has a largely competitive chain, it falls short of the neoclassical ideal. the alternative is a more command-andcontrol approach with the government, or a quasi-state corporation, controlling the supply chain, or key links in it. this, although not completely, is the model ethiopia has adopted in its relatively recent move into floriculture. the authorities provide a considerable degree of "direction' in the chain. a challenge in developing efficient aviation-supply chains lies in the size of the market. economies of scale can be particularly pronounced, at least up to a point, in the provision of airport logistics centers (martín and voltes-dorta, 2008 ) and forwarder/integration services. economies of density, scope and other network features are relevant when providing airline services and regional distribution. in the african context, barros and wanke (2015) , for example, find economies of scope are the most important variables for explaining levels of airline efficiency, although the impact of fleet mix and public ownership are also important. this generally means that passengers fares (important when cargo is carried as a complementary revenue source in a plane's hold) and freight rates are higher for leaner markets combined with more spartan schedules. it also means that many air cargo services are indirect, collecting traffic along "bus-stop routes" rather than being direct between the flower growing regions and destinations. thinner markets also tend to be associated with less competitive airline conditions, affording users less opportunity to exercise any monopsony power they may have over fares and freight rates. there is something of a paradox here. while concentration of business in the hands of a few airlines and other actors along the aviation-supply chain can help reap the gains of various scale effects, lack of competition can lead to both allocative and x-inefficiencies, with suppliers having no incentive to minimize their rates. in this sense, the thin aviation markets found in much of africa are below the threshold required to bring about a reasonable level of competition between airlines. a recent change in africa has been the emergence of gulf and turkish carriers (pirie, 2017) . not only have these expanded dedicated freight services, but their extensive use of wide-bodied long-haul passenger jets has added belly-hold freight capacity on many corridors (heinz and o'connell, 2013) . inbound into africa, the gulf carriers have diverted traffic away from africa's airlines. this includes flying out of major european cities such as london and amsterdam, as well as their own hubs (pirie, 2017) . for example, emirates' cargo-only service flew to five african cities in 2015. in the same year qatar airways launched a specialized freighter service into djibouti when already operating freighters to accra, entebbe, johannesburg, khartoum, lagos, nairobi, and etihad increased its freighter links to africa with the launch of a twice-weekly service between abu dhabi and brazzaville, via lagos. airports council international reports that africa had none of the world's top 20 cargo airports in 2018. the main african hubs are at johannesburg, addis ababa, cairo, and nairobi, with lagos and khartoum being somewhat smaller, and with much of their activity involving aid imports. 12 other countries, such as uganda and ghana, have sought to increase their presence in the cargo market but suffer from inadequate landside facilities and poor access. most international air cargo operations confront challenges associated with asymmetric patterns of trade caused by natural market imbalances and institutional factors. these pose backhaul problems restricting maximum utilization of aircraft capacity and, given limited fifth-freedom rights, add to the risk of service withdrawal (behrensa and picard, 2011) . 13 emirates' weekly inbound service to lilongwe transporting mainly merchandise and pharmaceuticals was, for example, near capacity in the mid-2010s, but very lightly loaded outbound, calling at nairobi to load additional cargo for europe. electronic items, often for onward regional distribution, dominate emirates' cargo into kenya while outbound traffic comprises mainly flowers and fish. the airline has also long flown pharmaceuticals from india, automotive parts from germany and general cargo from china into johannesburg, taking outbound loads of manufactured goods and fresh produce (campbell, 2015) . africa's air passenger capacity, jointly supplied with belly-hold capacity, has grown. the centre for aviation (capa) estimates intra-africa business grew from about 95 million return seats in 2015, to 105 million in 2017, to 112 million in 2019. added to this has been the growth in activities of foreign carriers. much of the expansion in intercontinental capacity between 2006 and 2012 was associated with middle east airlines that roughly doubling their share to about 20% with european carriers maintaining about a third. (pirie, 2014 (pirie, , 2017 . in particular, there was growth in inter-continental connections, much of which involved traditional hubs in europe. but the middle east also enjoyed increased connectivity. 14 this has led to africa's airports becoming more dependent on a limited number of airlines which enjoy quasi-monopoly power (scotti et al., 2017) . the floriculture industry is highly sensitive to geography, and in particular to climate, water supply and altitude. unlike some more footloose industries, where transportation can have significant effects on their locations, transportation is largely a facilitator that releases the natural flower-growing potential of an area. but having an airport nearby is not sufficient, it has to be accessible and offer appropriate transit facilities. surface access to africa's airports, however, varies considerably. unlike seaports that require heavily engineered access routes, those serving flower farmers, both because of relatively infrequent truck movements and light loads, can be less-substantial and are generally built to a lower design standard. congestion and poorly maintained roads can, however, reduce the reliability of the local justin-time supply chain that floriculture relies on to connect to relatively infrequent flights. the temporal and temperature fragility of perishables normally means that a cold-supply chain is adopted. this involves rapid harvesting of the product when at the ideal stage in its life cycle, the movement of relatively small units, often in chilled containers, and storage at suitable consolidation facilities prior to long-distant movements to final customers. the perishable supply-chain, excepting capital outlays on the storage facilities, almost exclusively involves forward integration. from the perspective of economic development, this has major advantages in conservation of foreign exchange and in generating domestic jobs. the quality of the supply chain, and its associated labor, has also evolved as the floriculture sector has moved to higher value-added products. kenya, for example, has shifted away from exporting lower value to higher-value stems and onto bouquets (kuiper and gemählich, 2017) . the quality of any supply chain is dependent on its weakest link, and thus while aviation may be an important element in chains involving flowers, even good aviation infrastructure and services may not lead to successful flower production. in the case of the cold chains, the roles of large forwarders and agents are important (babalola et al., 2011) . delays often mean the loss of produce, and excessive storage time is costly in terms of ultimate shelf lives. in many cases, the trunkhaul aviation link is tied directly to local forwarders that own reefer trucks and warehouses. 15 such forwarders are often, in turn, tied to larger, international companies active in the global supply chain that generate cost economies of scope and density, as well as ensuring quality control. dettmer et al. (2014) , using south africa's international trade data, shows air transportation generally has a comparative advantage when the trunk-haul movement is over relatively long distances, the perishables involved are light weight, low volume and high value items, and especially if the shelf-life of the product is short. in many cases, the aviation supply chains can be combined with those of other goods, or passenger supply chains. in the case of landlocked countries, or those with no easy access to major markets, the air transportation supply chain has considerable advantages for the export of perishables (world bank, 2009a , 2009b . the chain is, however, expensive, with estimates by africa's flower exporters, and particularly those in kenya, that logistics represent 40% to 60% of the cost of production of stems. 16 the development of wide-bodied aircraft has produced significant economies of scope as larger planes can combine passengers and bellyhold cargo. this offers an alternative aviation product to specialized air freighters. the movement, albeit slow and incomplete towards more liberal markets, both within africa and inter-continentally, has led to passenger flights being more frequent, less expensive, and more widely available. but in the adherence to tight timetables, belly-hold cargo may get bumped at the pilot's discretion if it misses its loading time. freighters usually offer better temperature control, fewer inspections, and additional capacity, which is particularly valuable for large quantities of short-season goods. but dedicated freighters can be costlier, may fly less often and to fewer locations, and may sit until they reach capacity, endangering perishables. services with several stops are also common to increase the load factor. the aviation infrastructure in africa also often limits when and where large planes, both passenger and cargo, can operate, restricting the hubs and routes that may be served (world bank, 2009a , 2009b . being a network industry, cost minimization in cargo aviation involves consideration of economies of density as well as those of scope. this raises challenges of balancing two-way traffic flows. the majority of passengers make return journeys, whereas freight consignments are usually unidirectional. in the case of africa's trade, much of the cargo suitable for air transportation involves imports of such things as components and spare parts. these are generally higher value commodities than perishables such as flowers, less dependent on just-in-time services, and are more easily handled. in many cases, therefore, inbound freight is treated as the primary cargo, and capacity decisions based upon it, with exports of flowers seen as the marginal cargo -the return load. the development of hub-and-spoke networks has allowed consignments from diverse origins and destinations to be consolidated and transshipped to a wide range of destinations. again, however, there are trade-offs (chung and han, 2013) . trans-shipping consignments through hubs can, through help in traffic consolidation thus increasing load factors on planes and as a result, reduce costs. but consolidation and transshipment add to the time costs of a movement, increase the possibility of a consignment being damaged or mis-routed, as well as adding direct handling costs of transference. 17 finally, there are technical reasons for having both light and heavy products on a plane to ensure balance. thus, there appears to be a strong incentive for the flower and vegetable industries of a country to collaborate in developing air cargo routes and negotiate prices with the airlines. producers of floriculture products sell their stems in two main ways. many still go through a competitive, spot-auction markets and especially the amsterdam flower market (the bloemenmarkt located in aalsmeer). there are, for example, 42 floral cargo flights from kenya to amsterdam in a regular week. 18 the alternative is to sell directly to retailers and wholesalers where the price is known in advance (hughes, 2000) . the latter has the advantage of facilitating a more certain supply chain for growers, with buyers largely taking the market risk, and offers opportunities for providing value-added services, such as labelling. 19 it also avoids the costs of middlemen and usually gets the stems to the retailers more rapidly than through an auction, thus maintaining the quality of the product. in addition, if the business is regular, forwarders can arrange block space agreements with airlines that reserves capacity for the producer; this can reduce air cargo rates and guarantee capacity will be available, as well as ensuring revenue for the carriers. but direct selling may not realize the highest current price. prices are agreed before cutting. direct selling can have important cascade effects on floriculture supply chains (nolan et al., 2008; kuiper and gemählich, 2017) . in the flower industry, inter-firm coordination occurs when a supermarket chain acts as lead firm in partnering with a brand-name global consolidator-exporter. 20 the aim is to ensure a consistent, high volume supply of quality, certified flowers by simplifying the supply chain seen in fig. 1 by taking produce directly from farmers to supermarkets (riisgaard and gibbon, 2014) . more direct selling has, though, led to a wave of consolidation among farmers to counter the power of supermarkets. for the consolidator, as the main point of contact for the large supermarkets, consignment size matters. the large consolidators have developed deeply integrated, networks of growers to source from, and invested in innovative technical and logistical capabilities enabling them to meet demands consistently and on time. smaller consolidators are better suited to non-traditional markets which demand smaller quantities of niche varieties and can provide the types of relationships often desired by smaller producers and buyers. since the 1990s, the traditional african floriculture producing areas have encountered challengers from new supplying areas. some of these, however, have been handicapped by major transportation problems. rwanda, for example, has been trying to develop its flower exporting industry, but it remains small (chantal et al., 2018) . it has the natural advantage of high altitude, ranging from 1400 to over 2400 m, fertile soils, plenty of rainfall throughout the year, cheap labor, and a relatively good road network. 21 it has seen a joint venture between the rwandan government and kenya's shalimar flowers to bring kenyan expertise to rwandan undeveloped flower sector. but, along with lack of adequate quality controls and suitable labor, long-haul transportation remains a serious impediment to development. belly-hold capacity to amsterdam, brussels and dubai is available, but involves connecting flights, while the dedicated cargo capacity to amsterdam provided by martin air is via nairobi. 22 some of the smaller suppliers are seeking to circumvent air transportation limitations by increasing the self-life of their products and reducing the associated high costs of transportation. they have begun growing variatals of flowers and plant materials suitable for drying. south africa has an established record in this market, and rwanda has recently been developing such products. durability means they can be exported using standard road and air services to a global market without the need for a cold chain. in summary, the floriculture supply chains in africa are technically challenging and, in many instances, lack adequate investment in hard, soft, and orgware. there is evidence that floriculture supply chains can be inflexible and susceptible to disruption because of difficulties in adapting to emerging international protocols, certification requirements, and to regulations (mckinnon et al., 2010) . 23 the result has been, even for the more well-established growing regions, periodic squeezes on profits. the euro crises from 2009 was an example of the problem. more recently, the hoped-for pick-up in demand after the great recession did not materialized to the extent many had hoped, and the onset of covid-19 has resulted in collapses of many markets. 16 https://www.flowerweb.com/, 17 transportation damages attract "quality remarks" presented to bidders at dutch auctions that adversely affect sale prices by up to 20%. 18 https://lot.dhl.com/kenyan-flower-exports-in-full-bloom/ 19 steen and gjolberg (1999) while there are standard requirements to sustain a successful floriculture supply chain, there are several ways these requirements can be met. the role of government has been important in the choices that have been made. in particular in the role of the authorities in controlling elements of the chain and in providing public finance has proved significant. the two main growing areas have developed under somewhat different economic structures and with differing degrees and forms of government intervention in their supply chains. flower production in kenya goes back to british colonial times, and with this the application of the anglo-saxon approach to government intervention. the country's floricultural industry is largely market driven with state involvement only when this is seen to enhance outcomes. the support of the kenyan government in promoting the floriculture industry has been mixed and has not been the decisive factor in its development (kazimierczuk et al., 2018) . kenya's main comparative advantage derives from its climate and low labor costs, but it has benefitted from less stringent environmental regulation, government controls over land rights, and lower trade barriers (jaffee, 1992; rikken, 2011) . in addition, farmers utilize modern technologies including drip irrigation, fertigation systems, net shading, pre-cooling, cold storage facilities, bouqueting, recycling systems to prevent wastage, wetlands for waste-water treatment, artificial lighting, grading/ packaging sheds, and reefer trucks. the use of hydroponics reduces the water used in production and makes it independent of the soil quality (bolo, 2006) . as early as 1988, kenya's industry exported 10,946 tons of floricultural produce, climbing to 86,480 tons in 2006, 120,220 in 2010, 136,601 in 2014, but falling slightly to 133,658 in 2016. it then rose to 159,961 tons in 2017 (mwangi, 2019) . the country's flower industry employs about 100,000 people directly and up to two million indirectly, mostly women. physical quantities are not, however, the whole story. the export-oriented nature of kenya's industry makes it is vulnerable to global macroeconomic cycles and shocks. the global economic crisis of 2008, for example, led to significantly lower flower prices, and even when exports in 2008/2009 grew by 25%, the value of stems dropped by 8%. slow economic growth caused foreign consumers, and by extension their grocery stores, to encourage price wars between suppliers that depressedthe prices obtained by farmers. the problem was made worse in the short term by the higher air freight rates associated with the "icelandic ash cloud" (kazimierczuk et al., 2018) . subsequently, with eventual economic recovery, the kenya flower council estimated the country's flowers exports in 2018 contributed $1.06 billion in exports, compared with $0.77 billion in 2017. although there are some 500 commercial flower growers of all sizes, about 75% of such exports are produced by a few dozen large and medium producers. these larger farms are better equipped than rivals in other african countries to control their entire production process, allowing integration into complex, expansive product chains. as with many sectors of africa's trade, there has been a widespread adoption of thirdparty logistics service providers as part of the chains (sohail et al., 2004) . kenya is the largest external supplier to the european flower market with a 38% market share. its major competitors, colombia, ecuador, and israel each have only half this. 24 about 70% of the exports by weight are shipped to the wholesale markets in the netherlands to be sold retail in other eu countries and the uk. as noted earlier, while the dutch auctions have historically been the most important channel, changes in consumption patterns and supermarket supply chain rationalizations have led to more direct contracts. currently, about 25% of the exports to europe are sold directly to uk and germany providing an opportunity for value added at source through sleeving, labelling, and bouquet production. 25 table 1 provides an indication of the geographical spread of sales by value. lake naivashasa's location permits year-round production and facilitates the growth of the medium-sized roses that are often found in the floral sections of eu supermarkets, as well as of larger blooms favored in russia. 26 these natural advantages have been supplemented by governmental support for the sector through reduced duties and taxes on crucial imported inputs and facilitating cooperation with the industry. the availability of air freight, with nairobi airport being a regional cargo hub, and good surface transportation provides high levels of accessibility to markets. this is combined with a ready supply of workers; kenya had an unemployment rate in 2018 of about 9.3% according to the international labor organization. cut flower exports began in the late 1960s when wide-bodied jets were introduced and offered additional cargo capacity to the fresh produce industry. foreign investors and partners played a critical role in launching and expanding the floriculture industry in kenya. 27 dutch and israeli advisors, for example, were important sources of technical support. 28 although kenyans of foreign descent or members of the kenyan elite, were initially involved in developing the industry, smallholders were also present and remain so. in 2016, approximately 190 large flower farms and numerous smallholder farmers were involved in the flower production, although the former dominated output (zylberberg, 2013; kazimierczuk et al., 2018) . the latter generally cooperate with the larger producers who in turn coordinate the logistics of getting flower to market. the success of the industry is, to an extent, the result of the capacity of the private sector to develop independently from the state and its capacity to quickly adapt to changing circumstances (jaffee, 1992; tyce, 2020) . while the initial shipments were exclusively carried as belly-hold cargo, as demand grew, economies of scale made dedicated freighter services viable. the industry is well organized. in 1996, the kenya flower council was established to coordinate the efforts of independent growers and exporters and ensure implementation of acceptable international standards. its members produce over 70% of the country's flower exports. about 75% of these are rose stems which make a fast supply chain particularly important. the larger forwarders block space on flights from kenyatta airport both on passenger airlines and freighters that offer day services to europe and the middle east. a range of aviation services are available at nairobi airport, provided both by domestic and foreign airlines. as much as 90% of the shipments to the uk are carried as belly cargo on kenyan airways with lufthansa cargo and cargolux, providing dedicated cargo space to frankfurt and maastricht. about 70% of the flowers are grown around lake naivasha, some 80 to 100 km northwest of nairobi. good road links allow, for example, flowers picked in the morning to reach amsterdam by evening. the airport handles the vast majority the 24 there are few detailed comparative studies of south american floricultural supply chains. vega (2008) is an exception but it is dated. 25 https://www.voanews.com/africa/kenyas-flower-producers-eye-us-market 26 kenya grows a number of flower types. roses have the advantage of taking only 8 weeks between flower to bloom whereas, carnations take 16, alstroemeria, 52, and lilies, 12. 27 dansk chrysanthemum kultur (dck) drove kenya's flower exports during this period (english et al., 2006) . established in 1969, dck's owner reputedly gave shares in its east african subsidiary to the agriculture minister and attorney general, which helped to secure a comprehensive support package that included a low-cost long-term lease on 6000 ha of land, unlimited expatriate work permits and a 25-year guarantee against changes to taxation and profit repatriation laws. 28 for example, amiran brought consultants from israel to advise the future flower growers of kenya on the adoption of large-scale greenhouses. flowers exported. nairobi enjoys significant advantages over entebbe in terms of the scale and scope of the air services offered, its terminal facilities, and its land access. in the latter context, the main growing areas are served by the major road networks in kenya. 29 the lake naivasha region is served by nairobi -nakuru highway, the thika region by the thika road while the athi river and kitengela areas are served by mombasa road (ong'uti, 2015) . these major routes, although not always well maintained, provide easy access into the city center and into the airport. the feeder roads into the interiors of growing regions that move the flowers to the integrators and forwarders as seen in fig. 1 , are of lesser quality but went through some upgrading and improved maintenance in the 2010s. there are both charter and scheduled carriers based at the airport. as an example of global access, kenya airways' passenger services directly link nairobi with 26 african and intercontinental destinations including london and amsterdam, and together with its strategic partners provides a cargo network involving over 100 destinations (amankwah-amoah and debrah, 2011) . 30 the airport also has significant cold-chain capacity both within its perimeter and immediately outside, although rapid transfers from road to aircraft keeps down its use. where there have been issues these have been in cold-chain warehousing prior to movements to the airports. a report by tilisi developments ltd. based on 52 warehouse owners and tenants questioned in 2017 found that almost two-thirds were facing capacity shortages. 31 there were also issues of poorly ventilated spaces, leakages, power shortages, and poor structural planning. in addition, there was increased stock contamination, causing flower product deterioration during storage. added to this, a case study of equator flowers located in eldoret (150 km from nairobi) found the most significant causes of disruptions to the supply chain were natural disasters, logistics process design, labor union actions such as slow-downs and strikes, and production function mechanics (kangogo et al., 2013) . in terms of the transportation supply chain, road movements seem to pose the biggest problems, with breakdowns and congestion leading to reductions in the vase life of flowers. there can also be periodic shortages of capacity, but to facilitate market access and minimize post-harvest losses, the horticultural crops directorate has provided stand-by capacity with reefer trucks for hire by farmers, built marketing centers, and collection depots this is coupled with damage done at the packaging stage of the chain, and when there is inadequate cold-storage capacity at times of peak demand. turning to uganda, like kenya and tanzania, it has perfect conditions for commercially growing flowers. the country's cut flower business dates to 1986, with the cut rose business beginning in 1992 and shooting chrysanthemum production in 1997. it steadily built up a floricultural industry during the 1990s to become africa's fourth largest producer. 32 various forms of assistance were given to the industry including a withholding tax exemption on interest, tax exemptions on raw material, plant and machinery and on time tax refunds. in 2014, it exported nearly $100 million of cut flowers and over $56million of live plants. despite early setbacks, including growing flowers that were not suited for the climate and not meeting the quality standards of recipient countries in the eu, the industry has become a significant contributor to the national economy. in 2019 the uganda flower exporters association recognized 22 firms as involved in the flower industry. the majority of these are in the growing and exporting stages of the value chain, with two also being transporters with the rest outsourcing their transportation. one company is a broker and wholesaler while another is a grower and broker. there are no local breeders and only one freight forwarder that provide cold chain logistics forthe industry. while uganda's ten largest flower farms export about 75% of their production, worth $35 million annually as well as directly employing some 6000 workers with another 30,000 indirectly dependent through industries like transportation and storage, they are small compared to kenya. 33 the flower-growing area is about 200 ha, compared to 2000 in kenya, and there are many fewer producers. this limits the economies of scale that can be reaped in the supply chain. given the small overall size of the industry, even using forwarders to get economies from consolidation still makes it difficult to negotiate block-spaced agreements with the airlines, and there are additional risks of suitable capacity not being available when needed. the largest market for uganda's chrysanthemum shoot cuttings is the netherlands, about 90% of roses are handled by european middlemen (msogoya and maerere, 2006) , witrhretailers in norway, the uk, sweden and germany taking most of the remainder. most flower farms are located near entebbe international airport. but landing taxes and the lack of dedicated air freight for flowers mean that flying costs are around $1 per kilo of flowers higher than in neighboring kenya and tanzania where dedicated air cargo is available, as well as space on passenger airlines. 34 as a consequence, about 10% of the flowers are moved through kilimanjaro international airport which can only offer belly-hold space, with the remainder being exported through nairobi which also has easier, if longer, surface transportation access as well as significantly more air cargo capacity, south africa is the most mature producer of floriculture products in africa, with an industry dating back to the 1920s and 1930s. partly because of its historic links with the netherlands, the country has a well-established bulb exporting industry that is not reliant on a coldsupply chain and can be shipped as general cargo. the cut flower industry has just under 1000 large and medium producers of roses, chrysanthemum cuttings, carnations, gypsophila, asiatics, and irises that are mostly located within 300 km of o.r. tambo johannesburg international airport (reinten et al., 2011) . the airport is easily accessed using a high-quality road network and offers a global span of passenger and cargo airline options as well as cold storage and handling facilities. the flower export industry, however, has been in something of a plateau since 2005, at about $40 million per annum, after rapid growth following the demise of apartheid. in part this is because, despite a very good aviation-supply chain, with large capacity, good surface access, and a well-developed forwarder system, it is further from some of its markets than other producers, but mainly it is because of higher labor costs. there are also imports into south africa by both road and air from zimbabwe, kenya, and zambia of cut flowers varietals that cannot be produced locally. these amounted to about $1million in 2009. the south african industry, besides its up-to-date logistics that enables produce to arrive in good condition, maintains itself largely through the sale of its indigenous flowers. to some extent counteracting the stagnation in the cut flower business, which by value is now about 60% of floriculture exports, there has been growth in the export of higher value seedling, foliage and decorative plants. these are, however, particularly sensitive to local conditions necessitating care in the transportation supply chain. ethiopia is a relatively newcomer to the floriculture industry and, as such, has benefitted from not being a first mover. it has profited from being able to learn from the experiences of established growing regions, and in particular recognizing the importance of meeting international standards (gebreeyesus, 2015) . the development of the necessary infrastructure for a successful export industry should also be set within the broader context of national priorities to improve the country's domestic logistic systems more generally (tefera et al., 2020) . ethiopian floriculture involves more state participation and direction than similar industries of the former british colonies. the economy is not as strictly controlled as it was under the former derg regime, but there is still a very large public sector, most notably involving banking, telecommunications, and land and air transportation. floriculture was begun by the derg in 1991 with the growth of hypercium, erigrinium, gypsophilia, and carnation on state farms for export. growth accompanied assistance from the world bank and from the dutch in the case of several local flower growing companies, but wilted towards the end of the 1960s seemingly due to a lack of government interest (melese and helmsing, 2010) . the dutch program for emerging markets (psom) not only promoted the expansion of production through joint ventures but facilitated the establishment of supporting logistics; e.g. by financing the ethiopian perishables logistics company. both local and international transportation in particular has been coordinated with the development of floriculture as part of national economic planning -the state-owned national airline, for example, provides discounts to horticultural exporters -and there have been major investments in perishable handling facilities at addis ababa's international airport. the latter have been specifically designed for flower handling and largely funded by direct foreign investment. ethiopia is the second-largest flower exporter in africa, with about 120 flower growers on the 1700 ha of land in production. the industry earned $660 million from floriculture export in 2015, some 20% it's foreign trade earnings. the region's climate is ideal for several forms of floriculture, with land south of addis ababa at 2000 m above sea level providing near perfect environment for growers. the country also has the advantage of a fairly flexible labor market (mano et al., 2011) . the relatively large size of the producers, partly due to the difficulties smaller producers have in raising finance, facilitates economies of scale throughout much of their supply-chains. this has also led to consolidation with significant numbers of take-overs (mano and suzuki, 2015) . most of the growers are large enough to have their own cooled processing and packing warehouses and reefer trucks (melese and helmsing, 2010) . problems have arisen in recent years, however, with attacks on producing units and the burning of crops by groups opposed to the government. unfavorable movements in currency exchange rates have also had adverse impacts (belwal and chala, 2008) . with few exceptions, first movers and early imitators were supported by the national government and foreign aid, and involved domestically owned firms. foreign growers, either by engaging in joint ventures or through full ownership, started to enter after 2003. a significant number of the these came from other african countries, including kenya, uganda and zimbabwe, although more recently investment has come from a wider range of countries including the netherlands, the uk and india, and regional states such as nigeria, sudan and oman. to attract foreign direct investment, the government gave implicit guarantees of stability through its control of ethiopian airlines and bole airport, and initiated financial incentives including a five-year tax holiday, duty free imports, access to bank loans and farmlands, as well as a 100% exemption from payment of export customs duties (mushir and hailemariam, 2015; bekele, 2007) . the biggest market for ethiopian roses is the netherlands which takes about 90% of the country's exports, with state-owned ethiopian airlines offering in 2017 two cargo flights of flowers a day each carrying 85 tons. the airline also moves horticultural products to other destinations in europe, the middle east and other areas on more than 10 flights a week. addis's state-owned bole international airport has been through major enlargement and modernization, partly funded by chinese finance. it now has africa's largest perishable produce terminal including a 17,000 square meters cold storage unit complex that was completed in 2017. 35 the new airfreight facility can process about 600,000 tons of cargo a year mainly for transportation to europe. given the synergies in storage, the combination of floriculture and horticulture products, reduces the unit cost of pre-flight cold storage. the effects on the blue nile region's economy and population has been somewhat mixed. this was already an area with small scale farms. the arrival of the floriculture has involved taking land from established smallholders and putting it in the hands of large, often foreign owned producers. set against a typical smallholding of one hectare supporting a household consisting of five members, a hectare production of flowers can employ as many as fifty people. there are clear macro-economic benefits from the conversion, but it has the tendency to cause enclave formation and moves away from the country's objective of food selfsufficiency, or "endogenization". added to this, those displaced in recent years are among those engaged in civil unrest. one consequence of these actions has been burnings of rose crops. 36 this paper has considered the important role that air transportation plays in africa's floriculture supply chains, and the technical, geographical, institutional, but primarily, economic complexities confronting those engaged in it. there is a particular focus on the important interface between short-distance, surface transportation at africa's end of the chain and the intercontinental air-transportation haul to markets in europe and, increasingly, asia. much of the account in qualitative. not only is there a dearth of data for conducting any comprehensive econometric analysis, but in practice qualitative factors tend to dominate many decisions along the supply chain. africa's nations are among the poorest on the planet. there are signs, however, that some of their economies are growing more robustly in recent years. much of this growth is through international trade, and the gradual evolution of aviation supply chains has played a part in this. 35 https://www.cargoforwarder.eu/2019/04/22/addis-ababa-airport-onway-to-challenge-dubai/ 36 https://globalriskinsights.com/2016/10/radar-foreign-investors-attackethiopia/ the latter has been important in the growth of high export earning sectors such as tourism and "exotics", as well, as other industries that can make use of africa's abundant labor supply. the emerging problem is that other regions of the globe are also rapidly developing their tourism and flower production capacities; tourism often being a compliment to floriculture because of the belly-hold air cargo capacity it provides. generally, africa lacks competitive advantage in high export earning industries because its air transportation logistics are thin, fragile, and incomplete even for the sectors in which it has a comparative advantage in production. these weaknesses extend across hardware, software and orgware. changes are coming as foreign investment takes place, deregulation of the african aviation industries are occurring, and as the presence of non-african airlines is increasing. the emerging longterm challenge is to get sufficient investment, including human capital, into the air cargo supply chain; and to do this when unified-mega economies such as china and india, as well as some south america countries, are enjoying greater access to pertinent funding. it is also unclear at this point whether the longer-standing, free market approach to air transportation logistics pursued by traditional african supplying regions can compete with the more planned approach of emergent floriculture suppliers, notably ethiopia. while the former offers more flexibility, as well as incentives for innovation, the discrete nature of many elements in the floriculture aviation supply chain requires "chunky investments" that, even according to adam smith, are sometimes best provided with state financing. the developments around lake victoria and in ethiopia highlight some of the differences in development paths to date, but it is premature to offer conclusions as to eventual outcomes. what is also important, and still under researched, is the more general question of whether floriculture is an efficient way to expend scarce resources even if a nation has a comparative over other african countries. the market for flower production is becoming increasingly global, and perhaps africa as region has limited comparative advantages. looking forward, while the free market in african air services hoped for in 1999 has not materialized and air transportation across the continent is still far from seamless, some new impetus is promised. this comes from the signing in january 2018 of an agreement between 23 state to cooperate in a saatm and in march by 44 members of the africa union of a provisional agreement establishing the african continental free trade area. ratification, and subsequent operationalization of the agreements, would significantly improve the continents' aviation supply chains. this is a personal research paper. credits to referees etc. are contained in the paper. logistics and global value chains in africa. the impact on trade and development the evolution of alliances in the global airline industry: a review of the africa experience. thunderbird int cold chain logistics in the floral industry an analysis of african airlines efficiency with two-stage topsis and neural networks transportation, freight rates, and economic geography road and development in ethiopia catalysts and barriers to cut flower export: a case study of ethiopian floriculture industry no bed of roses: east africa's female flower workers lose jobs as coronavirus hits exports current market outlook knowledge, technology and growth: case study of lake navasha cut flower cluster in kenya, knowledge for development program road network upgrading and overland trade expansion in sub-saharan africa air freight helping 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infrastructure country diagnostic: air transportation challenges to growth air freight: a market study with implications for landlocked countries an analytic network process approach to the selection of logistics service providers for air cargo bloom or bust? a global value chain approach to smallholder flower production in kenya an earlier version of this paper was presented as the keynote lecture to the german aviation research society's workshop on aviation in africa, held at the university of applied science, bremen in june 2018. numerous useful comments for improving the paper were gratefully received. i would also like to thank both the editor of the journal and two reviewers of the paper for their views. the final product remains my responsibility. key: cord-325484-bd6ba0cp authors: johnstone, phil; mcleish, caitriona title: world wars and the age of oil: exploring directionality in deep energy transitions date: 2020-09-04 journal: energy res soc sci doi: 10.1016/j.erss.2020.101732 sha: doc_id: 325484 cord_uid: bd6ba0cp this paper explores the role of the world wars in 20th century energy transitions, focusing on the growth of oil as a major energy source which accelerated after the second world war in north america and europe. we utilise the recently developed deep transitions framework which combines techno-economic paradigms and sociotechnical transitions approaches. the first deep transition entails the long running emergence of industrial modernity since the late 18th century which culminated in the post-second world war economic ‘golden age’ underpinned by rapid and stable growth and prosperity in north america and western europe. the deep transitions framework draws attention to the increasing role of fossil fuels over this long period, and how fossil fuel consumption accelerated in the 20th century taking on a particular direction where energy, mobility, and food systems became increasingly reliant on oil while the share of coal as a proportion of the energy mix decreased. this paper integrates sociotechnical, historical and geopolitical literatures to examine how the development of the age of oil was shaped by wartime demand pressures and logistical challenges and the search for new solutions to these challenges in the united states of america and the united kingdom. the post-world war ii era saw the share of oil in energy consumption rapidly increase with abundant supplies of oil products seen as key in underpinning the so-called 'golden age' of economic development [1] . the 'golden age' constitutes a sustained period of stable economic growth, increased prosperity, and the rise of mass consumption in north america and europe, lasting until the oil crisis of 1973. while energy transitions occurring during this post-world war ii era have often been a point of focus, until recently, as evenden [2] points out, there has traditionally been a smaller proportion of studies focused on how wartime activities have influenced energy system change. in recent years however, there is a growing sub-set of literature that has focused on the importance of world war as a factor in energy transitions [2] [3] [4] [5] . elsewhere, in the fields of history and geopolitics, there has been significant attention on oil resource geographies, developments in oil technologies, its uses, industry, infrastructures, logistics, and patterns of import and export during wartime [6] [7] [8] [9] [10] . this paper contributes to emerging literatures on war and energy transitions [3, 4, [11] [12] [13] , integrating insights from historical and geopolitical literatures with sociotechnical perspectives to understand the role of world war in the 20th century development of the 'age of oil' [14] . in doing so, this paper builds on the 'deep transitions framework' (here on in "dt") introduced by schot and kanger [15] . the dt framework is relatively new and constituted by several key concepts which we discuss in more detail in section 2.2, however we will now briefly outline some key features. the dt framework combines the techno economic paradigms (tep) approach developed by carlota perez [14] , and sociotechnical transitions theories utilising the multi-level perspective (mlp) [16] . both the tep approach [17, 18] and the mlp [19, 20] have been frequently drawn upon to understand energy transitions. the tep approach builds on long wave theory which has been widely used in economics for several decades [21] , and identifies different phases of economic development referred to as 'great surges' of development. these are depicted as generally occurring over 40-60year periods, and are driven by the unleashing of particular technological innovations (such as the internal combustion engine); a paradigm of economic growth that coordinates activity (such as 'mass production'); particular patterns of financial investment; and a source of cheap energy which underpins each surge of economic growth. for the purposes of this study, the most relevant point to note is that tep framework specifically names the period from 1908 to 1971 as "the age of oil, the automobile, and mass production", where "the cheapening of oil-based fuels, electricity and road transport gave positive support to the very high growth rates of national mass markets" ( [14] : 136). the tep framework has generally focused at the 'macro' level of analysis entailing broad changes in entire economies driven by technological innovation and cycles of financial investment. analysis drawing on the mlp on the other hand, has focused at the level of 'sociotechnical systems' oriented around the provision of societal needs such as energy or mobility. different elements including technology & science, markets & users, industry, institutions & regulations, shape activities within a sociotechnical system [15] . mlp approaches tend to focus on how novel technologies and practices operating in protective environments called 'niches' can, overtime, come to destabilise 'sociotechnical regimes', which represent the dominant technological and institutional configurations through which a particular societal need is delivered. rather than the 'macro' approach of tep, the mlp's focus on individual sociotechnical systems is understood as a 'meso' level approach. the framework has been used to examine the co-evolutionary dynamics of important historical technological changes including the transition from sailing ships to steam ships [16] , as well as historical analysis focused on the long-term decline of previously dominant technologies such as the case of the uk coal industry in the 20th century [22] . however, while world wars are mentioned as relevant exogenous factors in both tep and mlp literatures, activities during world war and the sociotechnical implications of wartime have generally not been a focal point of analysis. the dt framework addresses this gap, with one of its key propositions (proposition 7) being that 'external shocks' and particularly world wars, are decisive 'turning points' in coordinating multiple sociotechnical systems (energy, food, and mobility) in a similar direction. the notion of 'directionality' is central to the dt framework. building on the work of stirling [23] , schot & kanger outline their understanding of the term as follows: "socio-technical change has a direction, choices are made between directions and actors gradually become blind to alternatives, which is a central tenet of much of the innovation studies literature" ( [14] : 1045). thus, a focus on 'directionality' recognises the plurality and diversity of potential energy transitions and is attentive to historically contingent factors whereby certain energy trajectories become dominant and alternatives are 'closed down'. the closing-down of alternative pathways occurs as technological market structures, regulations, political support, infrastructure, and user practices, align to form a particular technological trajectory that gains momentum and makes it challenging for new technologies and practices to break through [23] . to take one example, electricity grids designed around constant 'baseload' production utilising increasingly large power plants often located far from where there is most demand, made it very challenging for variable renewables and energy conservation measures to break through in many countries without concerted political pressure over several decades [24] . accordingly, energy transitions usually take several decades and are fraught with political struggles, resistance by existing energy incumbents, and usually require governmental intervention to overcome these barriers [25] . however, a key distinction with regards to the understanding of directionality in the dt framework is the focus on the co-evolution and alignment of multiple sociotechnical systems, as compared to the tendency in sociotechnical approaches to focus on single systems [26] . the notion of directionality is further refined in the dt framework through the concept of rules, which is a well-established concept used in institutional studies and a core concept of the mlp. schot and kanger define rules as "humanly devised constraints that structure human action, leading to regular patterns of practice" ( [14] : 1053). an example of a rule given by schot and kanger is an "imperative to use fossil fuels". after the second world war this rule became dominant in energy, food, and mobility and therefore constitutes a 'meta-rule' because the rule structures human action and influences regular patterns of practice in multiple sociotechnical systems rather than a single system. another meta-rule relevant to this study identified elsewhere [27] is the "imperative to maintain abundance and constancy of supply", which became particularly pronounced during the intense demand pressures of the first and second world wars, where the ability to maintain supplies of key materials to the front lines meant the difference between victory and defeat. historians have pointed out that after the second world war an era of "energy abundance" based on cheap oil emerged in the usa [28] [29] [30] , and then in many european countries as "the years of surplus" from 1955 onwards [31] . the expansion of oil and a system of energy abundance are closely linked [28] . in this paper we combine geopolitical and historical literatures with sociotechnical approaches to understand how the heightened conditions of maintaining abundant and constant supply during the first and second world wars influenced the emergence of the 'age of oil' identified as being a key element in the fourth surge by perez which forms the culmination of the first deep transition. the overall research question is as follows: what was the role of world wars in shaping the emergence of the age of oil in the culmination of the first deep transition? building on diverse literatures from geopolitics and history, it is possible to build a plausible and evidence-based narrative to address this question. in undertaking this analysis, there are two central aims. the first is to contribute to the emerging literature on energy transitions and the role of world war. the second aim is to respond to proposition 7 of the dt framework, concerning the key role of war in the coordination and alignment of sociotechnical systems. we proceed as follows: section 2 situates this paper in the wider context of the broad field of 'energy transitions' research, and specifically the emerging interest in wars and the military as key factors in energy transitions. we then discuss the dt perspective in more detail, explaining key concepts and how discussions of deep transitions align with and can contribute to energy transitions literatures. in section 3, after discussing our approach, we outline an interpretive analysis drawing on extant literatures from history and geopolitics to build an interpretive evidence-based account of the role of the world wars in the emergence of the age of oil, focusing on world war i, the inter-war years, world war ii, and the post-war period of re-orientation and reconstruction. this study focuses on the united states (usa) and the united kingdom (uk). this focus is motivated by two observations. first is the fact that core to perez's theorisation of the age of "oil and mass production" is the lead role played by the usa and how oil-dependent forms of economic activity 'diffused' to europe. second, is that historic accounts of oil developments and geopolitical struggle highlight the central role played by relations between the usa and the uk -both as a point of friction and collaboration [7, 32] -in 20th century oil developments. this focus is not to diminish the importance of oil developments in other countries, and -perhaps unsurprisingly given the nature of war and geopolitics -we do refer to the strategies of other belligerents in the analysis below. however, the main focus on usa-uk oil developments provides a necessary boundary (given the breadth of this topic) to focus more specifically on sociotechnical responses during war, and also explore international dynamics of friction and collaboration between the two countries identified as a significant factor in historical studies [7, 10, [32] [33] [34] . however, as we discuss, the changing relations between these two countries over the course of the fourth surge and after the second world war also has important implications for understanding rapid oil transitions in western europe in the context of post-world war ii reconstruction. we are aware of the geographical limitations of the present study. our focus is on breadth rather than depth (covering a time period entailing two world wars), and so there will necessarily be gaps in the analysis. entire sub-fields of historical analysis are devoted to just one war, or even a war in a particular country. however, we seek to contribute to opening up for further elaboration and testing, propositions that can contribute to emerging discussions around energy transitions and world war, through answering the question of the role of world war in influencing the directionality of the first deep transition. while history is not a guide to the future, we argue that the historical imagination [35] can contribute to enriched discussions in energy transitions on possible drivers and mobilising forces for sustainable energy transitions. we now situate the present study in the wider field of energy transitions research, and then go on to discuss the dt framework and our approach to the analysis that follows. 'energy transitions' is a broad and multi-disciplinary area of study. there is a plethora of different definitions and interpretations. in a discussion of the "emerging field of energy transitions", araujo outlines a broad definition of the term: "a shift in the nature or pattern of how energy is utilized within a system", where "an energy system is a constellation of energy inputs and outputs, involving suppliers, distributors, and end users along with institutions of regulation, conversion and trade" ([36]: 112). araujo continues that "change can occur at any level -from local systems to the global one -and is relevant for societal practices and preferences, infrastructure, as well as oversight" ([36]: 112). while some authors aim for more precision in defining energy transitions 1 , sovacool concludes that "there is no standard or commonly accepted definition of an energy transition in the recent academic literature"( [37] : 205), but rather, there are different foci of analysis and conceptual tools which form the basis for differing perspectives. thus, rather than attempting to establish a strict definition, the key question is what perspectives are being used as an entry point to understanding energy transition phenomena and what particular discussions in energy transitions does the present analysis relate to. first, this paper relates to ongoing discussions on 'historic energy transitions' as fouquet identifies [38] , which has seen more detailed examination of the historic factors influencing the speed and dynamics of transitions from the level of a single fuel or technology to the global scale [38] [39] [40] . sovacool & geels highlight that interpretations of historic transitions vary widely because there are different points of focal interest in terms of the 'multiple dimensions' of energy transitions [41] . this can include techno-economic analysis which primarily focuses on firms, sunk costs, investments, and the difficulties and long time-frames that energy transitions entail because of these economic factors, but also 'socioinstitutional analysis' which focus on political and policy interventions that influence past transitions and can trump these economic constraints leading to more rapid change. a perspective that tries to bridge these 'multiple dimensions', and that sovacool and geels identify as "a key conceptual approach" in energy studies, is 'sociotechnical transitions' [41] . sociotechnical approaches focus on the co-evolutionary changes in energy systems and examine different elements including technology & science, markets & users, industry, institutions & regulations, where these different elements interact to form a 'seamless web' to deliver a particular societal function [42] . as sovacool points out, many studies that take a sociotechnical perspective draw on the mlp which examines interactive developments between sociotechnical niches, regimes, and landscape pressures. a sociotechnical regime represents the dominant way of doing things, in terms of incumbent technologies and the rules and institutions that guide developments in an energy system. niches, on the other hand, represent the level of novelty, innovation and experimentation [43] . however, despite a plethora of work drawing on a sociotechnical perspective and the mlp, the 'landscape' level often remains underexamined in such accounts [15] . this includes wars, which in historic accounts drawing on the mlp are often used as temporal markers depicting discontinuity between different stages of development in energy transitions [22] , rather than focal points of analysis in their own right. however, recently there has been increasing attention on world wars as a factor in energy transitions. for example, samaras et al. [13] , in detailing the contemporary role of the us military in energy r&d around insulation and mini-grids, also highlight how strategic military decisions have shaped past energy developments such as the first world war transition of the british naval fleet to oil [13] . matthew evenden offers a detailed analysis of the ways in which second world war mobilisation efforts in canada played a decisive role in accelerating transitions to hydroelectric power under emergency measures to maintain adequate electricity supply to fuel industrial efforts for the allied campaign [2, 5, 11] . more recently, cohn, evenden, & landry conducted a historical analysis of canadian, german and american mobilisation during the second world war, and how this conflict played a crucial role in influencing the design of electricity systems in these countries [12] . of particular relevance to this paper, recent work by ediger & bowlus [4] moves beyond conventional commercial and technological factors outlining the importance of oil for military strategy in the build up to the first world war and its enactment, highlighting the central role of geopolitics as a driver of energy transitions. rubio-varas also focuses on the first world war, highlighting how disruptions caused by the conflict were decisive in influencing a rapid transition to oil that occurred in latin america, decades before europe [3] . the present work builds on and contributes to this sub-field, through engaging with the dt framework which we now discuss. in this section, we discuss the dt framework, its constituent conceptual elements, what it is attempting to achieve and how it can be utilised to explore energy transitions. the framework builds an understanding of long-running developments in multiple sociotechnical systems across a 250-year period from the late 18th century and culminating in the post-war 'golden age' of economic growth and prosperity [15, 44] . the first deep transition is theorised as entailing four different 'great surges' of development across this period which constitute the slow building up of industrial modernity. the focus of the present work is on the 'fourth surge' which for schot & kanger represents the culmination of the first deep transition (fig. 1) . the red circle in fig. 1 highlights the fourth surge. each surge constitutes a 'technological revolution' entailing a period of economic growth, based around a "…constellation of new inputs, products and industries, one or more new infrastructures -usually involving novel means of transport of goods, people and information-and alternative sources of energy or ways of getting access to it" ([45]: 4). the details of each surge are outlined in fig. 2 . for perez, each surge follows a pattern entailing a period of 'irruption', where a number of new technological innovations emerge; a period of 'frenzy' entailing a battle between old and new technological configurations and economic paradigms; a period of 'synergy' where there is resolution and a particular new economic paradigm becomes stabilised; and then a period of 'maturity' where the particular paradigm and its constituent technologies and economic paradigms reaches saturation point, usually ending in crisis with the absence of new 1 for example, smil outlines that an energy transition is the time that elapsed between the introduction of a new fuel and its rise to a 25% national or global market share [125] . grubler, outlining 'grand transitions' as a new fuel reaching 50% market share [126] . yet, these are not rigid definitions that should be adhered to, but particular definitions amongst a plethora of perspectives that constitute a varied and interdisciplinary field of research [37] . growth opportunities. these stages are outlined in fig. 3 : although building on the 'great surges' approach, the dt framework differs in several important ways. first, the framework emphasises continuity across these surges, where the first four surges represent a single deep transition. second, while perez identifies a fifth surge based around information communication technologies (ict) with renewable energy as the key energy input, schot & kanger propose that this period instead represents the beginnings of a second deep transition. as they outline, "through gradual accumulation and coordination, niches may contribute to a fundamental overhaul of existing socio-technical systems, introduce a new set of sustainable and just directionalities… and thereby give rise to the second deep transition"( [44] : 8). in this paper however, we are focused on the culmination of the first deep transition and more precisely, 'the age of oil' as depicted in the fourth surge. we do not discuss the second deep transition. second, the dt perspective posits that the drivers underpinning the emergence of particular surges can be understood from the perspective of the changing dynamics within sociotechnical systems. innovation in niches is driven by system builders responding to particular problems in delivering societal needs and the search for solutions and improvements. the concept of rules discussed in the introduction, is used to understand how routines and behavioural patterns within sociotechnical systems influence path dependency and form sociotechnical regimes. where the dt framework departs from most mlp-based analysis however, is it focuses on multi-system interactions and co-evolution, and how systems become increasingly aligned in a similar direction over time. that alignment process takes place when the same rule exists in multiple systems, referred to as a 'meta-rule'. an important point to also note, recognised by schot & kanger and perez, is that the time periods of surges strongly overlap. it is not the case that one surge disappears completely as another emerges. due to issues including sunk costs and resistance from incumbents, there is considerable cross-over between surges as the elements of each surge are reconfigured and compete against each other until there is a resolution at a 'turning point'. with respect to the fourth surge and the question of energy, this relates to understanding how oil rapidly gained a significantly larger share of energy consumption in the years after the second world war, in the usa, uk and europe more widely, while the share of coal (the dominant energy source of the previous two surges) decreased [17] . the present study focuses on the role of war in shaping this oil transition and how the rules of using oil and maintaining abundance and constant supply evolved in the context of the world wars. we now briefly discuss the approach taken to build our interpretive analysis. in conducting our interpretive analysis, we seek to integrate geopolitical and historical accounts of oil developments in the twentieth century with a sociotechnical perspective. we focus on four different stages to frame our analysis based around perez's depiction of the age of oil as including the stages of irruption (covering the time period of the first world war), frenzy (the interwar years), synergy (that includes the second world war), and maturity (post world war ii). in doing so, we are attentive to historical literatures which outline the key differences between the world wars and peacetime in terms of the conditions of total war [46] [47] [48] . in conditions of total war, as van creveld writes, "war itself extended its tentacles deep to the rear, spreading from the trenches into the fields, the mines, and the factories" ( [34] , p.164). during periods of total war, entire economies and societies (rather than just a dedicated military as in other conflicts) are mobilised for the war effort [49] . sociotechnical systems (including energy, food, mobility) become mobilised as part of a 'war machine' oriented around the single purpose of achieving wartime aims [50] [51] [52] . multiple sociotechnical systems are reoriented from delivering civil societal functions to also supplying vast militaries. a key mechanism of total war identified by obinger et al is the immense demand-pressures that are placed on the economy entailing often unprecedented logistical challenges that can reorient patterns of production and consumption [53] . building on the dt framework and the recognition of the key rule of maintaining abundant and constant supply during world wars [27] , we build on diverse literatures to build an interpretive account of how the exceptional demand pressures of total war influenced dynamics in multiple sociotechnical systems and the relevance these changes had for oil transitions. as rip and kemp outline, world wars provided a particular 'selection environment' for particular innovations and developments to 'break through' [42] . thus, we focus on examples of strategic openings afforded for oil as a 'solution' to a variety of demand side challenges, as well as being attentive to evidence of potential destabilising forces with regards to other technological pathways [54] . obinger and petersen also draw attention to the importance of the demobilisation phase, where soldiers and workers employed for war production have to be reintegrated back into civil economies [55] . this phase presents a particular economic challenge in warding off economic collapse once the demand-pull effects of war time cease and technological systems deployed in the war effort may also have to be reoriented back towards civil purposes. also relevant in this phase are the legacies of war as a catalyst for change, where policies can continue into peacetime. of particular relevance for our study and its focus on the usa and uk, are the legacies of policy diffusion and transfer which can be achieved in conditions of total war due to alliances between different countries and the effects of post-war reconstruction. these mechanisms of total war provide a guide to shape our narrative analysis. in doing so the analysis is interpreted around the core rule identified by the dt framework of the imperative to use fossil fuels. given our focus on the fourth surge and the recognition of the special importance of transitions from coal to oil during this period by schot & kanger [15] , for the purposes of the present analysis, we have refined this as the imperative to use oil. in integrating broad trends, geopolitical developments, and a focus on demand pressures in multiple systems, we respond to our overarching research question: what was the role of world wars in shaping the emergence of the age of oil in the culmination of the first deep transition? in this section we outline our interpretive narrative of developments in multiple sociotechnical systems in four distinct periods, following the 'age of oil, automobile and mass production' identified by perez. first, we look at events in the first world war in the uk and usa and identify broad trends and geopolitical developments before discussing illustrative examples of relevant developments related to energy, food, and mobility for considering oil transitions. we then discuss geopolitical factors related to usa-uk oil relations and sociotechnical developments in the 'frenzy' period between the wars. in the third part of our analysis we focus on the 'turning point' of the second world war in the 'synergy' phase and in the fourth part, we look at the importance of post-war reconstruction efforts and the challenges of demobilisation. drawing on literatures that analyse the role of the marshall plan in influencing technological developments in europe, we critically assess the extent to which america's role in europe shaped the wider diffusion of oil technology, infrastructures and governance. we now discuss the first world war and developments relevant to oil transitions. we expand on the existing analysis of the role of the first world war on energy transitions [3, 4] through a focus on the multisystemic demand-pull factors that influenced the enduring 'thirst' for oil and related geopolitical developments [56] . we begin with a broad overview of trends and geopolitical developments before focusing on demand pressures and logistical challenges in energy, food, and mobility relevant to oil transitions. before the first world war the use of oil was limited with the main use being kerosene lighting [8] . in 1914 coal was still king. oil provided under 5% of world energy supply while coal contributed to 74% [57] . in 1907, the value of the uk's coal trade surpassed £52 billion, while the total value of all petroleum exports from the usa amounted to some £19 million [57] . yet the first world war was a significant rupture in this pattern of development as global use of petroleum grew by 50 percent while coal production decreased in many european countries [8] . in the century prior to the war, british geopolitical dominance was secured by its steam-powered navy, and at the turn of the 20th century, the uk was the world's leading energy exporter [58] . however, the first world war interrupted this trend and concerns about access to oil would be key to these changing geopolitical dynamics [10] . the uk faced a central challenge during world war i as it had limited reserves of oil. during the war, 90% of the oil required for the british as well as french war effort was supplied by the usa [57] . the uk (along with france and italy) became dependent on the usa to fuel their military efforts during this increasingly oil-intense conflict. these dynamics intensified with the oil crisis of 1917 where, due to the everincreasing amounts of oil being consumed by militaries in europe and the disruption of oil supply routes by german submarine attack, there were significant risks of oil supply running out. influenced by these intense pressures, the usa, uk and other countries, including france and italy, were drawn closer together by the imperative to maintain constant supplies of oil. as yergin points out, the oil crisis caused by the first world war forced the united states and its european allies into tighter integration of supply activities [7] . geopolitical tensions increased in the middle east driven in part by the search for oil, with britain attempting to gain control of important oil fields in iraq. the sykes-picot agreement signed in 1916 by the uk and france carved up mesopotamia between the two countries and is understood to have been partly influenced by desires to secure strategic oil resources [59, 60] . as several authors point out, the first world war and the thirst for oil amplified the geopolitical significance of the middle east, leading to increased tensions between the usa and uk (along with france) after the war [4, 7, 33, 61] . but these broad changes and geopolitical developments to secure oil resources were rooted in specific sociotechnical challenges driving the increased demand for oil in energy, food, and mobility. we now explore the demand pressures and logistical challenges caused by conditions of total war and the implications for oil transitions. in the years preceding world war i, the advantages of oil ships had been recognised by many navies around the world. the advantages of oil included the fuel being double the thermal content of coal meaning less space was required for storage; logistics of refuelling at sea were therefore made easier; reliance on docking stations for refuelling was reduced; and there was greater flexibility in changing speeds as well as less personnel required on ships [62] . additionally, oil-based ships produced less smoke which was beneficial to gunnery operations and enabled more covert movements of naval fleets [63] . an early adopter of oil-powered ships was the british navy. the share of oil-based vessels in the british navy rose from 5% at the start of the war to over 40% by the war's end [7] 2 . prior to world war i, most shipping was steampowered, and thus the application of oil to navies was a key niche development supported by the military and accelerated by the first world war. during the conflict, the us navy which had already converted several ships from coal to oil accelerated this trend [7] . germany, on the other hand, did not use all-oil firing for surface fleets until after the war [63] . internal combustion engine-based automobiles and trucks were a niche in the mobility system before the war. however, they became increasingly used for tactical advantage during the war by the uk and usa as significant problems were experienced with rail road transportation. the first world war has been described as the pinnacle of the 'rail age' [64] dependent on coal, yet significant disruptions occurred with railroad bottlenecks on the western front disrupting the supply of weaponry and materials to troops. in allied campaigns such as the battle of verdun, the rapid construction of roads and use of motor vehicles for transportation further entrenched the importance of oil for military victory [65] . an example used by historians to exemplify a general point about the greater military dependence on the automobile and trucks is that at the beginning of the war the uk military had 823 automobiles and 15 motorcycles. by the war's end they had 23,000 motorcars, 63,000 trucks, and 34,000 motorcycles [7] . away from the front, in the usa, railroad arteries were also blocked and, under the auspices of the us high transport committee, caravans of trucks carrying important goods for the front line were initiated, "inaugurating the long-distance trucking of freight as an alternative to rail transportation and calling attention to the great need for a national system of interconnected, improved highways" ([66]: 78). during the conflict, a new reality of 'war from the air' emerged. the aeroplane, which was in its 'embryonic phase' as a niche technology at the start of the war, had consolidated as a major industry by the war's end increasing requirements for gasoline products [67] . in britain, as edgerton outlines, this created a very large aircraft industry, with increases in output accelerating through the war. monthly output increased from about ten per month at the war's beginning to 122 in 1917 and 2,688 in 1918. the number of people working in the uk's aircraft industry rose from nearly 49,00 in october 1916 to 154,000 in november 1917 to 268,000 in october 1918 [68] . in the usa, there was also considerable aeroplane construction with 10,000 constructed by the war's end [8] . this created a surplus of aircraft after the war. as responses to demand pressures in the food system also had 2 the decision had been made by winston churchill in 1911 to transition the entire british fleet from coal to oil and this is cited by historians to exemplify the general point concerning the greater dependence of militaries on oil emerging during world war i [7] . implications for oil supply. food imports became significantly disrupted and blockading food supplies became a key strategy of both the uk and germany during this war. thus, a focus on 'self-sufficiency' intensified in the uk [69] . there is evidence that the first world war also led to niche experimentation to maintain agricultural supply in response to these demand pressures. coal and steam power had not made significant inroads into the agricultural sector and farming was still mainly reliant on horse power. however, the first world war accelerated the development and marketing of tractors [70] . in the uk in 1917, the government ordered 400 british saunderson tractors and $3.2 million was invested in us models such as the fordson. ford exported 7,000 tractors to britain in an effort to boost agricultural productivity [71] . in the usa, tractor use also expanded under government loan schemes and propaganda campaigns with expos being used by government to further encourage their use [72] . we now discuss both broad geopolitical developments and relevant sociotechnical developments with regards to the inter-war years and oil transitions. the first world war created an 'oil frenzy' which significantly influenced international relations after the war [57] . the 1920s can be considered as a period of international instability with respect to global oil supplies as the heightened recognition of the strategic importance of oil created tensions between different nations. as black notes, the first world war and the emergence of oil as a 'strategic resource' [73] meant that "…new systems of negotiation and need had emerged that would eventually be referred to as "geopolitics." ( [8] : 140). before the first world war, britain controlled only 5% of the world's oil production, but by the war's end britain had acquired 50% of the world's known oil reserves [74] . france and the uk struggled for control over middle eastern oil resources, and in april 1920 the san remo agreement was reached between the two countries. here, "britain conceded a share of the oil in exchange for a general agreement, effectively granting france a 25 percent share of petroleum in exchange for mosul" ([59]: 41). this locked out foreign companies from being able to control oil production in the british empire. the usa retaliated with similar measures, using the mineral leasing act of 1920 to prevent any company from a nation that was excluding american oil companies in the middle east from gaining access to us oil fields. new oil discoveries in texas in 1924 eased this geopolitical tension. however, the new thirst for oil and wartime experiences of oil shortages had resulted in an 'exploration boom' [7, 75] . this led to low prices which risked the stability of the global oil industry. the 'red line' agreement at achnacarry in 1928 sought to control global oil prices and form monopolies around oil access. the agreement saw the creation of the 'seven sisters' oil cartel where agreement was reached to cease independent prospecting for oil in the ottoman empire by individual oil companies and instead conduct coordinated explorations as a cartel [76] . this agreement was an attempt to create stability in the global oil regime, yet tensions between the united kingdom and the usa continued as britain pursued a strategy of trying to secure its oil resource independently from america [7, 10] . however, britain did not have the industrial capacities to exploit significant amounts of oil in the middle east, and the usa maintained its focus on exploiting indigenous oil reserves. it is worth pointing out that the uk's strategy for oil independence differed in the inter-war years from germany in significant ways which would ultimately have implications for world war ii. germany was economically and politically weakened after the first world war and could not acquire oil reserves. a key part of their strategy was to pursue petroleum synthesized from coal [10] . germany established a synthetic fuels industry to meet the rising demand for oil as the country continued to industrialise during remilitarisation in the 1930s. the energy intensive process of producing synthetic oil from coal would also ensure that territorial expansion to acquire resources of crude oil would be key to german military planning and strategy in war [10] . the oil strategy of the uk also had its limitations during this period of 'frenzy' however. the uk put considerable effort into securing middle eastern oil supplies, and while in 1929 the usa produced more oil than any other country, 41% of oil production outside of the us was produced by british companies [10] . however, this strategy proved flawed in the build up to the war as routes through the mediterranean were hampered by italy in the 1930s. britain could not secure its supply routes and did not have adequate tanker capacity to transport the oil. the imperative to maintain a constant supply of oil amplified by world war i had accelerated production in the us oil industry and this presented the challenge of re-orienting to peacetime activities. as auzzanneau writes "unable to settle down and smoothly adapt its production to the new conditions of peace, the oil industry experienced an intense overproduction crisis after 1918" ([76]: 100). yet, oil production and consumption continued to steadily increase in the usa, with the rise of car culture and mass consumption during the 'roaring twenties'. however, in the uk this expanse was more modest. despite being adversely affected by world war i and facing significant economic problems, rail in the uk was not challenged by road transportation to the same extent as in the usa and its 'clash of cultures' between the automobile and rail systems in the inter-war years [77] . the significant wartime problems of bottlenecks in flows of truck freight resulting from poor road infrastructure experienced during the war gave impetus for mapping out and then funding improved road infrastructure in the usa. the federal highway act 1921 to construct a joined-up road network linking us cities was unveiled specifically citing military considerations as a reason to invest in highway construction [78] . in the uk, the ministry of transport was established in 1919 and introduced a national system of road signage, a system of grants for local authorities to construct roads, and set up a research laboratory to investigate matters of road construction [79] . several authors conclude that while ww1 had been an accelerating force for oil, coal had been negatively affected by the conflict, including through infrastructural damage, depleted labour supply and labour strikes [4, 57, [80] [81] [82] [83] . according to the official history of the british coal industry for example, british coal was an 'industry in decline' after the first world war [83] . this is reflected in the writings of trade unionist ivor thomas, who in 1934 lamented this decline stating that "whether we like it or not, we are entering -or have indeed entered -an oil age" ([84]: 43). yet in the uk, the coal industry remained powerful and what was referred to at the time as the "back-to-coal" lobby still had considerable influence ([84]: 43). 3 another impact of war relevant to oil transitions, was the emergence of new users capable of operating automobiles or aeroplanes as a result of their wartime experiences. the war popularised a product that had heretofore been viewed as elitist. automobiles, for example, moved from being niche vehicles to a more familiar form of transportation [65] . the military surplus of aeroplanes created by world war i was also significant for post-war developments in the usa: some of the 10,000 planes that had been constructed were integrated into civil aviation which was being utilised for activities including mail delivery [67] . while tractors continued to be used on both sides of the atlantic, growth was modest in both countries [68, 71, 84, 85] , although in the usa, the use of tractors increased through support for agriculture under the new deal in the 1930s. however, it would be during world war ii that the 'petrolification of agriculture' [86] would take place, as well as acceleration and innovation in the oil industry leading to the further embedding of oil in the mobility system. we now focus on the second world war, again summarising broad trends and geopolitical developments before discussing relevant sociotechnical developments with regards to the conflict. the second world war was a global conflict with a marked increased dependence on oil compared to the first world war. for example, american forces in europe used one hundred times more gasoline in world war ii than in world war i [7] . two years into the war, in 1941, oil supplies to the uk became cut off as a result of german submarines attacks [88] meaning that as the war progressed, a key challenge became sustaining constant supplies of oil to europe from the usa [7, 33, 89] . as this challenge was met, the war transformed patterns of energy imports and exports across the transatlantic zone. before the second world war, the uk was still one of the world's main energy exporters. britain's increasing reliance on the united states for supplies of oil that emerged over the course of the first world war had dissipated, and instead the uk sourced much of its oil during the inter-war years from countries including venezuela, dutch west indies, iraq, and persia. however, shipping routes from these regions were disrupted during the second world war. as edgerton points out, even as late as 1940 the british were determined to maintain their oil independence from the usa [90] . yet, as the war progressed the uk became reliant on the us for 90% of its oil supply, paying for it with assistance through the lend lease programme [91, 92] . during the course of the war, the usa began turning attention towards securing future supplies of oil for future wars and projected increases in demand in post-war society [76] . in 1944 american geologist everytt gower returned from saudi arabia to announce that the oil in the region was the "greatest single prize in all history" (quoted in yergin [7] : 393). negotiations between roosevelt and churchill took place regarding this future oil supply near the war's end. in secret meetings at the suez canal between roosevelt and abdul aziz ibn saud however, it was established that britain would not gain control over saudi's oil reserves and that saudi would exist in the american sphere of influence [76] . this moment and subsequent agreements would be decisive in fundamentally altering international energy trade and geopolitics. it is also worth pointing out, that oil had a far stronger influence on war strategy during this conflict. due to its lack of indigenous oil resource and dependence on synthetic fuels derived from coal, germany sought to acquire oil resource through territorial expansion. the german quest for oil in the caucuses is identified as a motivating factor in the invasion of the soviet union for example [9] . the allied oil campaign put significant resource into destroying german oil infrastructure and refining capacity [10, 76, 93] . waging war was now dependent on oil resources with global networks of shipping routes and refineries extended as the allied campaign sought to acquire and deliver adequate oil supplies to multiple theatres of war. we now look from a sociotechnical systems perspective at the specific demand pressures and logistical challenges that were accentuating the imperative to use oil in the energy, food and mobility systems. during world war ii the construction of oil infrastructure was rapidly accelerated. in the usa, the 'little inch" and "big inch" pipelines were constructed in under a year, between 1942 and 1943, as a means to transport oil across the us from the south to the north east [94, 95] . at the start of the twentieth century, pipe size had been standardized at eight-inches, however this could only move 125,000 barrels a day even though a refinery could produce up to 125,000 barrels. as richard rhodes points out, solutions in the form of wider pipes and 'looping' techniques were already developed but private companies were not prepared to make the requisite investment. however, during the war these innovations in pipeline technologies were put to use. as johnson notes, "in the endeavour to meet the demand for crude oil and petroleum products on the east coast, government-financed pipelines embodied technological innovations -particularly with respect to diameter of pipe -that were to have a lasting impact." ([95]: 78). the "big inch" and "little inch" pipelines stretched for 1,254 miles across the usa with pumping stations every 50 miles. the 'big inch' pipeline was capable of moving 350,000 barrels of crude daily and it was, at that time, the largest and longest pipeline ever built up [94] . an industry pipeline management committee oversaw the expansions of pipelines under the 'tulsa plan' and over 3,200 miles of new pipeline was dug and laid during world war two in the us to enable meeting the vastly increased demand during wartime [91] . in the uk, due to the threat of aerial bombardment of road infrastructure as a means to transport oil, construction began on the government pipelines and storage system (gpss) in 1940, with the first phase completed by 1942. the system connected key locations such as liverpool docks with avenmouth through underground pipelines stretching for 220 km. in 1943 the pipeline system was extended to connect up various airfields in the east of england. as the gpss system was extended further, this network of pipelines would eventually supply aviation fuel to all of england's air fields [88] . this was a significant technological breakthrough given that there was little knowledge of pipeline construction in the uk prior to the war [88, 96] . innovation in the oil sector was stimulated by the changing demand pressures and logistical challenges of war. world war ii is referred by some historians as an 'air war' [97] or 'the bombing war' [98] and during this conflict the aircraft industry was transformed. innovations in oil production methods, including perfecting 'catalytic cracking techniques', made possible the production of large volumes of 100-octane gasoline [7] . this fuel was in high demand from the once burgeoning and now mass-producing aircraft sector, with oil intensity increasing as jet engines and four engine bombers were developed. huge refineries were rapidly built to facilitate the increasing demand for different types of fuel [87] . while 100-octane gasoline and associated innovations were developed before the war there had been no market for them prior to the conflict [99] . with the 'mass mobilisation of science' during world war ii [100] , a host of other scientific endeavours led to the rapid expansion of the aero-industry further entrenching a reliance on oil. this included advancements in radar technologies, air precision, electronics, computing, and cabin pressure. meanwhile the us auto industry was redirected towards the war effort and played a central role in the mass production of tanks, trucks, jeeps, aeroplanes, bombs, torpedoes, steel helmets and ammunition under huge contracts issued by government [50, 92, 101] . the british car industry was similarly re-directed towards the production of war materiel [102] . this mass mobilisation of the auto-industry for the war effort would see the sharing of innovation and collaboration around mass production techniques with significance for increased post-war production of automobiles [101] [102] [103] in the food system, the immense pressures on agriculture to increase production in the usa and uk, accelerated the mechanization of agriculture, including the increased use of tractors and combine harvesters. for example, in 1939 there were 56,000 tractors in the uk, by 1940 this had risen to 100,000 [69] . in the usa, the number of tractors on farms rose from almost 1.6 million tractors in 1940 to 2.4 million tractors in 1945 -an increase of two-thirds. innovations took place in the design of tractors as they were mass produced: tractors got smaller, hydraulic systems were introduced, and they became more powerful. the energy intensity of us agriculture also increased and new innovations such as 'hybrid corn' and larger farm sizes accentuated the need for pesticides and insecticides which were also being rapidly developed during the war to protect troops fighting in the pacific from disease [87] . some plant protectants developed during the war were dependent on the petrochemicals industries that were consolidating as the refining of oil increased during the war [87] . these changes in agricultural practices occuring during the war were wide-ranging and were rapidly adopted. as rasmussen writes, "higher prices and a seemingly unlimited demand for farm products, combined with a shortage of farm labor and appeals from the government to increase production, led farmers to adopt technological advances" ( [86] : 588). these advances entailed increased "input of mechanical power and machinery, fertilizer and lime, chemicals, feed and seed, and other items" ( [85] : 588). thus, an increasing thirst for oil in the food system was generated by these developments. the development of plastics from petrochemical sources was also accelerated during the second world war in the usa, and would have important implications for the food system in the post-war era. in 1937, the first meeting of the society of plastics industry (spi) concluded that there was no market for these products [104] . however, during the war, demand pressures meant there was an urgent need to conserve aluminium, copper, steel and zinc for war materiel. these pressures, combined with increased oil production during the war, meant that an opening was created for oil-derived products to act as substitute for scarce resources and were used in clothing as well as acting as a solution for food preservation and storage. between 1940 and 1945 production of plastics almost tripled in the usa [105] . as black notes with regards to the burgeoning plastics industry, "petroleum became a primary component in allowing producers to overcome limits of supply and production" ([106]: 44). towards the war's end, the new condition of future us energy policy was stated by the state department's petroleum advisor: "[the central objective] …is not a rationing of scarcity, but the orderly development and orderly distribution of abundance." (quoted in yergin, [7] : 401). in 1951 oil surpassed coal as the main source of energy in the usa [107] . the second world war had been key in transforming the infrastructure associated with oil, and much of this had been achieved through government spending. after the war, the us government set about transferring government holdings of pipelines refining capacity and tankers to the private sector [91] . post-war lobbying by the us coal industry to close the 'little inch' and 'big inch' pipelines on the basis they put the coal industry at a competitive disadvantage failed [94] , and these pipelines open up east coast america to increased supplies of oil as well as natural gas [94, 108] . in 1945, after the japanese surrender, oil rationing was suspended in the united states and the stage was set for consumers to "…design[…] their post-war lives around energy decadence" ( [8] : 143). in the usa, a key challenge for the post war period, according to bonneuil & fressoz, related to the immense productive forces that had been mobilised during total war and the "…problem of productive overcapacity and its reconversion into peacetime" ( [87] : 145). the automobile industry stabilised and set about producing cheap cars in record numbers, thereby sustaining the levels of high employment achieved in the war years and working with newly refined mass production techniques perfected during the war [101, 109] . the highway expansion programmes of post-war america enabled a further rapid acceleration of the automobile culture and -similar to the programmes after world war i -were influenced by military as well as civil requirements building on wartime proposals set out by roosevelt in 1943 and the highways act 1944. the second world war had also transformed air infrastructure: the wartime development of a network of runways equipped with new air traffic control systems and standardised aircraft paved the way for the rapid expansion of domestic and international aviation. oil flowed through the food system in different ways, with plastics increasingly used in food packaging and preservation [104] . the mechanization of agriculture accelerated during the second world war continued to expand in peacetime and required increasing amounts of petroleum to power industrial farming [110] . additionally, the transportation of agricultural produce by truck became more widespread as large highways systems were constructed [78] . oil had seeped into every part of american life, forming what black refers to as a "ecology of oil" [106] . here, "oil does not just fuel americans' vehicles. oil has changed their diet, their clothes, their neighbourhoods, their jobs, their fun-in fact, everything about u.s. society" ( [106] : 41) . the situation of extreme scarcity caused by the tragic destruction of war experienced by continental europe after world war ii was very different to that of the united states. production of coal had fallen in the uk and across western europe and coal infrastructure, especially in germany, had been damaged [31] . traditional trade routes and supplies did not return to normal immediately after the war and the industry was in a state of crisis [111] . although the uk had not been as badly affected as countries on the continent, there were still grave concerns about the depleted coal industry [112] . the uk was now a net energy importer, and set about attempting to reconstruct its industries through nationalisation [113] . yet, in the early 1950s, the uk's share of oil began to rise markedly, reaching 12% in 1955 from a share of less than 5% at the war's end [31] . this trend continued and the uk's imports of oil rose rapidly through the 1950s. in 1939 the uk imported 2,201 thousand tonnes of oil. in 1946 the uk imported 2,214 thousand tonnes [114] . but by 1953 this had increased over ten-fold to 23,063 thousand tonnes, increasing year upon year to a historic maximum of 115,472 thousand tonnes in 1973. despite attempts to gain control of oil in the middle east after the second world war, the uk's oil imports were largely from middle eastern supplies under the sphere of influence of the usa [32] . the outcomes of the second world war and the nature of reconstruction have been identified by several authors as important factors influencing a rapid transition to oil that occurred across western europe in the 1950s [38, 107, 115] . the 'black gold' of saudi arabia, controlled by the usa, was not used initially to fuel american abundance but rather to facilitate the reconstruction of europe. thus, the solution to the problem of european energy scarcity was, to some extent, american abundance. the european recovery programme (marshall plan) was initiated by the usa in 1948 and 10% of marshall plan loans related to the importation of oil to europe [91, 116] . the share of petroleum products in the primary energy consumption mix of europe at the end of the war was around 10% [31] ; by 1955 it was 21% and by 1964 it was 45% [31] . in the 1950s several pipelines were built connecting europe to mediterranean supply routes from the middle east and extensive networks of pipelines were built across europe including the tap line completed in 1950, inter-provincial in 1950, and the trans-mountain in 1953 [31] . as historians of european infrastructure point out, these european pipeline projects drew on successful wartime experiences with constructing extensive pipeline networks such as the gpss in the uk [117] . historians highlight that the european oil transition was fundamentally shaped by the usa's new-found global dominance and cold war concerns about europe becoming dependent on oil from the soviet union. as boon writes, after the war "neither a distinct western european oil regime nor an integrated [european economic community] governance framework for energy materialised", rather, "…the transition to oil evolved under a global regime dominated by multinational oil companies -then at the apex of their power and closely linked to the informal empires of the us and britain" ( [118] : 83). in short, the age of oil in europe was strongly facilitated by innovations and frameworks amplified during the war in the usa that diffused to the european context as oil companies constructed pipelines and refineries underpinning a rapid transition to oil. the oil dependence of europe grew as the restoration of europe's transport infrastructure took place, particularly evidenced by increases in road mobility, automobile ownership, and trucking. there is evidence of the usa's preference for exporting trucks to europe rather than rail freight after the war, and strong lobbying by the us to push for prioritisation of road construction in europe's infrastructural recovery [119] . as seely highlights, "…the relative ease with which americanstyle highway and traffic engineering moved across the atlantic also was a product of the willingness-indeed eagerness-of american engineers, government officials, and industrial leaders to assist in this diffusion process" ( [120] : 230-231). similarly, with regards to the food system, the marshall plan is also a relevant factor to consider. the technological transfer of tractors, industrial agricultural techniques, hybrid corns requiring fertilisers and other plant protectant innovations to the uk and other western european countries was faciliated through agricultural support mechanisms as part of the marshall plan [121] . the emergence of the usa as a superpower during the second world war as the uk's geopolitical power diminished, therefore seems relevant to understanding the rapid diffusion of the imperative to use oil to europe after the conflict. the oil intensity of the us had increased markedly in multiple sociotechnical systems particularly as a result of rapid developments that had occurred in response to demand pressures in the second world war, and the embeddedness of oil in multiple sociotechnical systems underpinned a new society based on abundance, influencing the nature of the european recovery through the marshall plan. we now discuss the significance of our interpretive analysis in terms of the role of war in energy transitions, and the contribution the present work makes in responding to and developing the dt framework. we also discuss the value of the dt framework for energy transitions research. focusing mainly on the usa and uk, we have conducted an interpretive analysis of the world wars and the emergence of the oil age, integrating insights from geopolitics and historical literatures with a sociotechnical perspective on multi-system demand pressures. under the exceptional demand pressures of total war, the imperative to maintain abundance and constant supply saw the search for solutions to meeting demand challenges, and in both the first and second world wars this process deepened society's reliance on oil resources. the imperative to use oil was thus accentuated in multiple sociotechnical systems during war time. with regards to world war i, our analysis corroborates work in energy transitions that has interrogated the key role of the conflict in influencing a shift from coal to oil, where war can be seen as an extreme form of 'creative destruction' [4] . the present work also chimes with studies of the role of war on energy transitions including hydro-electricity in canada, the usa, and germany [2, 5, 11, 12] that highlight the importance of world wars as mobilising forces for energy transitions. given the limitations of our geographical focus, our broader conclusions on the role of war in energy transitions must necessarily be cautious. indeed, the pattern of the emergence of the 'oil age' at the global level does not necessarily fit the time period of the 'fourth surge' as depicted by perez. as rubio-varaz highlights in an analysis of latin american transitions to oil influenced by the first world war, these occurred at a far earlier stage than europe [3] . however, the stages of the 'age of oil' in terms of irruption, frenzy, synergy, and maturity fit with the developmental processes with regards to the usa, uk and western europe. with the existing work on energy transitions and world wars in mind, the present analysis can be used to draw out propositions about the role of war in energy transitions and the mechanisms that influence energy transitions. these are not designed as definitive conclusions but rather insights from the present research that could be tested further with different case studies, national contexts, and international dynamics contributing to the emerging literature on world wars and energy transitions. we outline three propositions as follows: 1. world war amplifies both 'sides of the coin' of sociotechnical transitions. kivimaa and kern [54] refer to the creative processes of sociotechnical niches being nurtured and the flip side of destabilisation of existing regimes as both being crucial in understanding transition processes. in this study, the demand pressures of war, and the search for solutions to these problems, saw a range of developments taking place during wartime that further embedded oil in multiple systems. this included the acceleration of automobiles and aeroplanes in the first world war, increased mechanisation and tractor use in response to labour shortages in the first world war, and petrochemical solutions to shortages of materials in the second world war. these technologies and innovations existed prior to the wars, however strategic opportunities for their use were opened up by the particular selection environment of wartime. at the same time, the coal industry, and associated industries in the mobility sector experienced destabilising consequences both in the first world war, which was compounded by the world war ii, due to severe disruption of export routes, infrastructural damage, and labour shortages. this at first seems counter-intuitive because war is of course divisive, and considerable literature has rightly drawn attention to the tendencies towards a push for greater national self-sufficiency and autarky in energy as a result of war. this is certainly true in some respects, however in the case of oil we see that the uk and other european countries became more tightly bound to the american oil regime during the first world war through the inter-allied petroleum conference. while in the period of 'frenzy' the uk attempted to forge its own path, the integration between the us and british energy systems intensified once again in the second world war. through re-orientation and reconstruction, the post-war period saw this integration continue as the uk, along with many western european countries, transitioned more rapidly to become embedded in a 'global' oil regime largely controlled by the united states. surplus and reconversion. the foundations of the oil-based society were laid during the second world war. extensive pipelines in the usa and the uk built to fuel the war effort were reconverted to supply oil and natural gas to the american east coast in the case of the usa, and aviation fuel to airports for civil aviation in the case of the uk's pipeline developments. runways, air traffic control systems, and streamlined global logistics networks shaped during world war ii for air transport were reoriented to civil aviation. the surplus of agricultural produce in the united states had to be maintained in order to ward off economic collapse and petroleumreliant industrial agricultural practices persisted and intensified to maintain this abundance. after the first world war, a surplus of planes in the us and uk were absorbed into civil airlines, then in their infancy. the first world war created hundreds of thousands of new users of oil-dependent automobiles and aeroplanes. in addition to these points, the role of war in energy transitions can be further explicated by returning to the implications of this analysis for the dt framework. through a focus on the demand pressures of world wars and the solutions that emerged to these challenges, our analysis has highlighted how in these wars the imperative to use oil was accelerated in the energy, food, and mobility systems by innovations and experimentation where reliance on oil was often a key solution. the three systemsenergy, food, and mobility -became more tightly integrated as a consequence of wartime activity. following schot & kanger, we have contributed to the dt framework in terms of "understanding how changes across multiple systems became connected and coordinated, developing a common directionality in the long run" ( [15] : 1046). while the trend towards oil use accelerated faster in the mobility system after world war i and the growth of mechanised agriculture was modest, during world war ii these systems become even more tightly integrated. pipeline infrastructure, refinery capacity, petrochemicals, plastics, pesticides, increased mechanisation of agriculture, mass production of aeroplanes, construction of runways, and a host of other concurrent developments were accelerated by war. in the language of the dt framework [15] , the role of war in deep transitions is the tighter integration and coordination of multiple sociotechnical systems in a similar direction. the world wars amplified the meta-rule of the imperative to use oil, and shaped the sociotechnical conditions to deliver abundant oil supply in numerous domains. more broadly, we argue that the dt framework can be a useful conceptual tool for energy transitions research. in focusing on multiple rather than single systems, the dt perspective analysis of the age of oil conducted in this paper, reveals the interdependencies between different systems and how they are tied together by oil infrastructure and use. these multi-systemic understandings can be of value in thinking about the shift away from an oil-based society, and the need for multiple policy interventions and policy mixes to enact a deep energy transition based around sustainable sources of energy. the focus on rules and meta-rules can assist in enhancing understandings of how broader transitions beyond one sociotechnical system occur and shine a light on the more deep-rooted unsustainable routines and patterns of behaviour associated with the age of oil that must be undone if more rapid sustainability transitions are to occur. with its focus on exogenous events like wars, the dt framework can also be utilised to explore mechanisms for deepening and accelerating renewable energy transitions beyond niche-regime dynamics, and the multi-system interactions that may need to be fostered if an 'ecology of renewable energy' rather than oil, is to be achieved. this highlights the value in further interrogating other 'landscape' events that could be influential in the directionality of renewable energy transitions. for example, the particular demand pressures of the covid-19 pandemic has had a significant impact on energy systems that could be decisive in shaping lasting change [122] . additionally, the dt framework's attention to military and wars and their historic role in accelerating particular transitions, also emphasises the importance of considering mobilising forces that can also decisively and rapidly influence the directionality of energy systems but that are not reliant on the tragedy and violence of war. indeed, given the enduring links between militaries and unsustainability [123] , a key question for sustainability transitions scholars is the extent to which rapid low carbon transition is feasible if current systems of defence, violence, and militarisation remain in place. this points to forms of 'deep incumbency' including the military that warrant more dedicated attention [124] . in this paper we have focused on the emergence of the age of oil in the twentieth century which forms the culmination of the first deep transition. we have conducted an interpretive analysis drawing on geopolitical and historical literatures to build an understanding of how the exceptional wartime demand pressures and logistical challenges experienced in multiple sociotechnical systems influenced oil transitions. the role of the two world wars in shaping the emergence of the age of oil in the culmination of the first deep transition can be summarised as follows: the exceptional conditions of total war saw the imperative to use oil being accentuated in multiple sociotechnical systems. as a consequence of war time pressures, energy, food, and mobility were coordinated in a similar direction through the meta-rule of using oil, and became more closely integrated based around an increasing dependence on oil. wars saw the rapid development of the technological, infrastructural, logistical, scientific, and institutional conditions underpinning oil-intense societies of the post-war economic 'golden age'. thus, the two world wars were decisive in shaping the directionality of the culmination of the first deep transition. the present analysis suggests that war, often discussed in mlp approaches as a residual landscape factor rather than a focal point of analysis, has an important role in shaping historic sociotechnical transitions. going forward, energy and sustainability transitions research could further unpack the landscape category examining the dynamics and mechanisms that different kinds of landscape shocks entail and the implications for sociotechnical transitions. it seems apparent that military activities and wars were influential drivers ofhistoric carbonintense and environmentally damaging energy transitions. looking towards the prospects for a second deep transition, it may be that processes of peace-making and demilitarisation deserve a more central role in ongoing struggles for a sustainable future. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the 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historical case studies of energy technology innovation coal or oil as fuel for the navy this work was supported by james anderson and baillie gifford & co. key: cord-002757-upwe0cpj authors: sullivan, kathleen e.; bassiri, hamid; bousfiha, ahmed a.; costa-carvalho, beatriz t.; freeman, alexandra f.; hagin, david; lau, yu l.; lionakis, michail s.; moreira, ileana; pinto, jorge a.; de moraes-pinto, m. isabel; rawat, amit; reda, shereen m.; reyes, saul oswaldo lugo; seppänen, mikko; tang, mimi l. k. title: emerging infections and pertinent infections related to travel for patients with primary immunodeficiencies date: 2017-08-07 journal: j clin immunol doi: 10.1007/s10875-017-0426-2 sha: doc_id: 2757 cord_uid: upwe0cpj in today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. this is never more important than for patients with primary immunodeficiency disorders (pidd). a recent review addressing common causes of fever in travelers provides important information for the general population thwaites and day (n engl j med 376:548-560, 2017). this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. . this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. this is never more important than for patients with primary immunodeficiency disorders (pidd). a recent review addressing common causes of fever in travelers provides important information for the general population [1] . this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. emerging infectious diseases are a result of a convergence of numerous factors and comprise complex interactions among multiple variables. some of those factors are human movement, land use change, encroachment and wildlife translocation, rapid transport, and climate change. several studies demonstrate that for a pathogen to persist in a population, a minimal host population size that is specific for the type of pathogen and host population. of particular relevance to emerging infections is the pattern of rapid population growth. in the tropics, before wwii, most regional ecosystems consisted of few large cities and scattered human settlements separated by large areas of cropland, pastureland, or undisturbed forest. today, the pattern is the opposite: many large cities have developed with only patches of undisturbed forest or grassland. domestic vectors have therefore expanded their population with increasing urbanization and this markedly impacts the interactions between vectors and pathogens [2] . human activities such as deforestation, use of pesticides, pollution, etc. lead to the loss of predators that naturally regulate rodent and insect populations. this contributes to emerging zoonotic diseases and explains why they occur more frequently in areas recently settled. in today's global economy and affordable vacation travel, it is increasingly important that visitors to another country and their the southern, with a reduction in the number of cold days per year, changes in rainfall (more winter precipitation and summer droughts) [4] , and together these changes increase the risk of several vector-borne diseases in new areas. climate change involves not only global warming but also changes in precipitation, wind, humidity, and the location and frequency of extreme weather events like floods, droughts, or heat waves. changes in climate produce changes in pathogens, vectors, hosts, and their living environment. increases in precipitation can increase mosquitoes for example, but heavy rainfalls may cause flooding that temporarily eliminates larval habitats and decreases mosquitoes. flooding may force rodents to look for new habitats in houses and increase the opportunities of vector-human interactions, as occurs for example in the case of epidemic leptospirosis. humidity is another very important factor of climate change in the development of vector-borne diseases. mosquitoes and ticks do not survive well in dry conditions. therefore, weather impacts infectious pathogen distribution in complex ways that are not predictable by the forecast. extreme weather events can precipitate outbreaks of infection. an increase in the frequency and intensity of natural disasters like hurricanes and tsunamis, in relation to the el niño/southern oscillation phenomenon, may result in more flooded grasslands, which favor the breeding of aedes and culex mosquitoes [5] , and impact water sanitation fostering outbreaks such as cholera. flooded areas can displace rodents leading to plague. tornados and other severe weather can stir up soil leading to infections with soil fungi leading to episodic outbreaks of invasive fungal disease such as mucormycosis such as apophysomyces trapeziformis [6] . malaria is a common disease that can vary dramatically depending on weather, and extreme weather can alter the very landscape, providing new bodies of water to support larval development. if the melting of glaciers and the polar ice caps bring coastal cities underwater, or if overpopulation and waste cause drinkable water shortages in certain regions of the world, we can expect mass migrations. these could change the patterns of infection and drive outbreaks. migrants traversing tropical forests, or feeding with meat from game or carcasses, are but two scenarios that could be envisioned for the emergence of zoonotic infectious diseases [7] . several predictive models have been developed to evaluate the impact of climate change on the emerging infectious diseases: climex, dymex, miasma models. nevertheless, it remains difficult to predict when and where pathogen behavior will deviate from its typical pattern. climate change primarily affects vector-borne diseases by increasing rates of reproduction and biting and by shortening the incubation period of the pathogen they carry. ticks have gained spread from the mediterranean basin to northern and eastern europe, as well as appearing at higher altitudes. increased survival, density, and activity have also been reported following shorter, milder winters. climate change has also resulted in more days of activity per year for mosquitoes. as temperatures rise, more parasites are viable within regions ranging from the mediterranean and tropical zones, up to the balkans, russia, scandinavia, and the uk. for some ticks and fleas, temperatures over 25°c with relative humidity of over 85% are optimal for their proliferation and activity throughout the year [4, 8, 9] . for example, dengue fever is usually limited to a tropical latitude and a low altitude, since mosquito eggs and larvae lose viability with sustained low temperatures. during unusually warm summers, however, dengue has been reported as high up as 1700 m above sea level. warmer temperatures also result in smaller adult mosquitoes, which need to bite more frequently to feed themselves and be able to lay eggs, thus increasing the rate of transmission [8] . in contrast, the incidence of malaria has followed mixed patterns of increase and decrease along recent decades, and computer models have failed to predict the spread. the explanation for this is, in part, that climate change also results in diminished survival of the vectors (warming over 34°c affects the survival of both parasites and vectors), and in part, that the effect of climate change is non-linear and complex [10] . the frequency of emerging vector-borne infections varies per changes in land use, human activity, intervention maneuvers to eradicate the vector or prevent transmission to humans, drug treatment, and vaccines. both ecologic and economic changes may bring together rodents and humans. hunting activities may change vector distribution and large-scale animal movements can impact disease distribution. impoverishment of cities and overcrowding in slums, but also reforestation, golf club development, and the urbanization of rural suburbs facilitate exposure to ticks and rodents [11] . many patients with pidd require immunoglobulin replacement. immunoglobulin products have been demonstrated to improve outcomes in hepatitis a and measles [12, 13] . at least some neutralizing antibody is present directed to rsv and group b streptococci [14, 15] . this raises three distinct issues for patients: (1) difficulty in the diagnosis of infections in travelers because locally produced immunoglobulin may have antibody titers to local infections that are not typical for other countries, (2) safety concerns about locally produced immunoglobulin, if the patient resides in the location long enough to require immunoglobulin from a local provider, (3) the decision to use locally produced immunoglobulin products to provide superior prevention of infection compared to the patient's usual product. there are limited data on each of these subjects. serologic diagnostic testing in patients on immunoglobulin therapy will be addressed below in terms of issues related to lack of specific antibody produced by the patient (potentially) after infection. the converse can also be an issue. patients arriving from countries with significant occurrences of infections unusual in their current country may have igg antibodies to those infections simply through their immunoglobulin product and not reflecting a true infectious event in the patient. this can lead to diagnostic confusion when serologic testing demonstrates the presence of antibodies due to the infusion product. patients will often ask if immunoglobulin products from other countries are held to the same rigorous standards as their home country. today, commercially produced immunoglobulin is safe and tightly regulated. all commercially produced immunoglobulin around the world has one of the time-tested viral inactivation procedures such as nanofiltration, caprylate absorption, pasteurization, solvent/detergent, vapor heating, and low ph treatment. these procedures uniformly inactivate enveloped viruses. many emerging viruses are specifically tested for their ability to withstand the purification process. much has been learned since the transmission of hepatitis c viruses through immunoglobulin products in the early 1990s [16] . nevertheless, vigilance is important. in 2009, counterfeit immunoglobulin was identified. therefore, patients should ensure that they receive only brand name products while traveling. the subject of whether a patient's interests would be best served by using a local immunoglobulin product, with antibodies to pathogens that are prevalent in the community, or have their home physician ship their usual product, for which the patient has a known tolerance is hotly debated. patients with a history of intolerance to immunoglobulin products should not switch unless necessary. however, there are compelling reasons to consider a locally produced product when patients are in a foreign country for an extended period. it is known that antibodies to west nile virus have tracked with the distribution of the virus as it has emerged in several areas [17, 18] . titers in products using donors from the usa have higher neutralizing titers to west nile virus than those using donors from europe, although there is a 400-fold difference in titers between lots from the usa [18] . similarly, protective antibodies to concerning pathogens may be optimal in locally produced immunoglobulin. it is critical to inquire where the plasma source is derived. in most countries, the utilized immunoglobulin is produced in europe or the usa. having a different name does not ensure that the plasma pool comes from a different country. most lots of immunoglobulin are produced from 3000 to 60,000 plasma donors. the infrastructure to support such an endeavor is not easy to establish in each geographic area. serologic testing is commonly used for the diagnosis of infection. this approach relies upon detection or quantitation of antibodies made by the host against specific pathogens. the presence of igm antibodies against a specific pathogen indicates recent infection, while igg antibodies against a specific pathogen indicate past infection. importantly, serologic testing can only be applied for the diagnosis of infection if the host can mount a specific antibody response to the pathogen. conversely, serology cannot be relied upon to diagnose infection in the setting of immune deficiency where there is impairment of the specific antibody response, such as in the case of primary antibody deficiencies, cellular immune deficiencies, combined immune deficiencies, and other secondary immune deficiencies affecting t and/or b cell function. in these situations, the causative pathogen must be identified by alternate means such as culture of the organism, antigen detection, or molecular approaches (nucleic acid hybridization, nucleic acid sequencing, or oligonucleotide probe arrays). molecular approaches are particularly relevant for the diagnosis of infection in patients with pidd. signal and target amplification techniques can be coupled with nucleic acid hybridization or probe assays to allow detection of pathogen dna or rna that is present in very small amounts in clinical samples. in patients with pidd, vaccines could play an important role in preventing infections with vaccine-preventable diseases. even pidd patients may generate some protective responses [19, 20] . the decision to immunize such patients or not depends on the type and severity of pidd as well as the type of vaccine to be administered (live or inactivated) ( table 1 ). in general, inactivated vaccines are safe for pidd patients while immunization with live attenuated vaccines is a known hazard to patients with serious immunodeficiencies of t cell, b cell, and phagocytic cell origin (table 1 ). in less severe pidd, the vaccine can induce adequate protection as in healthy individuals or the efficacy may be reduced [20] [21] [22] . of note, immunoglobulin replacement therapy induces passive immune protection to some vaccine-preventable infections, such as measles, mumps, rubella (mmr), and varicella. in addition, live viral vaccines have greatly reduced efficacy while on immunoglobulin replacement. therefore, vaccine administration in patients receiving regular immunoglobulin replacement treatment should be withheld until at least 3 to 11 months (depending on dose) after cessation of such treatment, if cessation and vaccination are safe. in addition, pidd patients who have received hematopoietic stem cell transplantation but have incomplete immune reconstitution or are under immunosuppression should not receive live attenuated vaccines. in general, the decision of administering live viral vaccines should be made by clinical immunology experts [23] . in developing countries where polio is still endemic and oral polio vaccine is essential for eradicating the disease, it is of utmost importance that all pidd patients and family members should not receive live oral polio (opv) because of the reported prolonged excretion of the virus for months and even years [24] . in addition, vaccine-associated paralytic polio is a real risk for some with pidd. these patients and family members should receive inactivated polio vaccine (ipv) instead of opv. similarly, the hazards of administering bacillus calmette-guerin (bcg) vaccine to pidd patients have been documented. in a series of 349 bcg, vaccinated severe combined immunodeficiency (scid) patients from 28 centers in 17 countries, 34% of scid patients developed disseminated bcg infection and had the worst outcome [25] . patients with chronic granulomatous disease vaccinated with bcg also developed local and disseminated bcg infection. recently, vaccine strains of rubella virus were found to be associated with skin granulomas in pidd patients [26] [27] [28] . siblings and household contacts of patients with suspected or diagnosed pidds should receive all the national immunization scheduled vaccines. ipv should be substituted for op in families where an antibody-deficient patient exists. yearly influenza vaccination of family members is recommended in order to reduce the risk of household-social transmission [20, 22, 29] . diseases where routine vaccination has reduced incidence can occasionally experience a resurgence in times of economic hardship with reduced attention to vaccination. diphtheria is currently seen in venezuela for this reason. war and disruption of health infrastructure are other common reasons for resurgence in vaccine-preventable diseases. in other settings, antivaccination sentiment has led to outbreaks of diphtheria, measles, and mumps. an additional consideration is that not all countries provide the same level of vaccination, and therefore, vaccine-preventable illness can still be seen regionally. these outbreaks represent a significant risk to patients with pidd. a universal consideration for patients with pidd is the concern about antibiotic resistance, which varies dramatically around the world. for certain high impact infections, the emerging antibiotic resistance patterns will be discussed below. antimicrobial resistance occurs naturally, but misuse and overuse of antimicrobials are accelerating this process. in nearly every country, antibiotics are overused and misused in people and animals leading to antibiotic resistance in every country. key resistance patterns to common bacteria include emergence of carbapenem-resistant klebsiella pneumoniae around the world with high frequency of resistance (due to different mechanisms) in the mediterranean, with greece, italy, and turkey having endemic spread of this pathogen [17] . carbapenem-resistant strains among other genera of enterobacteriaceae have also been recognized. they are particularly common in greece, but have been found widely distributed [30] . the new delhi metallo-beta-lactamasemediated resistance, which is endemic in the indian subcontinent but becoming increasingly spread worldwide, is a growing concern [30, 31] . as a common cause of urinary tract infections, colistin is the only recourse when carbapenemresistant enterobacteriaceae, and colistin resistance has recently emerged in small outbreaks throughout the world [32] . in these cases, the infection is essentially untreatable. fluoroquinolone-resistant escherichia coli, a common cause of urinary tract infections, now accounts for over half of the isolates in some asian countries [33, 34] . t he emergence of resistance to antibiotics in grampositive pathogens has become a major international problem as there are fewer, or even sometimes no effective, antimicrobial agents available for infections caused by these bacteria. methicillin-resistant staphylococcus aureus is common in many countries and in fact has spawned a nomenclature recognized by the general public: mrsa. several studies have reported resistance to the newer antimicrobial agents like linezolid, vancomycin, teicoplanin, and daptomycin [35] . thus far, these isolates appear to be uncommon and have been found in <1% of isolates in brazil, china, ireland, and italy, with nearly undetectable rates elsewhere. vancomycinresistant enterococcus (vre) is growing in frequency and can now be a cause of primary bacteremia in immunocompromised individuals [36] . a key message is that antibiotic resistance is increasing (generally) and travelers should be alerted to resistance to commonly encountered organisms, and if antibiotic prophylaxis is required, their prophylaxis is adjusted. neisseria gonorrhoeae is a specific organism for which resistance has become especially problematic. it has progressively developed resistance to virtually all antimicrobial agents since introduction of sulfonamides in mid-1930s. the current treatment guidelines recommend dual antimicrobial therapy (ceftriaxone 250-500 mg × 1 plus azithromycin 1-2 g × 1) as first-line regimen [37, 38] . although dual therapy is very effective, development of concomitant ceftriaxone and azithromycin resistance is likely to emerge [39] . the risk of untreatable n. gonorrhoeae demands better global antimicrobial surveillance system, clinical trials on combined therapy of existing drugs as well as novel agents in monotherapy, and development of a gonococcal vaccine. for pidd patients, guidance on barrier methods for the prevention of sexually transmitted diseases should be a part of any pre-travel counseling. mycobacteria tuberculosis (mtb) is an age-old pathogen with emerging resistance. drug-resistant tb, fueled by the hiv epidemic, is a global threat. in 2015, who estimated 480,000 new cases of multidrug-resistant tb (mdr-tb) and an additional 100,000 new cases of rifampin-resistant tb (rr-tb) who would also require mdr-tb treatment. treatment of mdr-tb and mycobacterium bovis disease is beyond the scope of this text and reader is referred to recent who mdr treatment guidelines [40] . regions of the world with >6% mdr tb include regions of azerbaijan, kazakhstan, russia, uzbekistan, china, georgia, and eastern europe. extensively drug-resistant tb (xdr tb) refers to mtb resistant to isoniazid, rifampin, any fluoroquinolone and at least one second-line drug. xdr tb has been reported in 105 countries. on average, 10% of patients with mdr tb have xdr tb. as is true for all types of mtb, xdr tb is contagious and small outbreaks related to person-person transmission have been reported. non-tuberculous mycobacteria (ntm) cause significant systemic infections in patients with defects of the il-12/ ifnγ/stat1 axis as well as in gata2 deficiency and can cause significant pulmonary infections in pidd patients with bronchiectasis. compared to tb, ntm is acquired from the environment and not from person-to-person transmission; therefore, acquisition of antibiotic-resistant strains is less common. however, in these individuals with pidd, ntm disease is often chronic and can be difficult to eradicate, and resistance can then easily develop during therapy. using combination of antibiotics is essential, and consultation with those familiar with treatment of treatment refractory ntm disease is recommended. aspergillus species are ubiquitous inhaled molds with worldwide distribution that cause opportunistic infections in immunocompromised patients [41] . aspergillosis also occurs in pidds associated with quantitative and/or qualitative phagocyte defects; it develops most frequently in chronic granulomatous disease (cgd) patients (prevalence,~40%), while it is seen less often in patients with gata2 deficiency, card9 deficiency, and congenital neutropenia syndromes [42, 43] . upon inhalation, aspergillus species cause invasive pulmonary disease in susceptible hosts with the exception of card9 deficiency, where aspergillosis has a predilection for extrapulmonary tissues with sparing of the lungs [44] . diagnosis is established by fungal culture and/or histopathology showing acute-angle septate hyphae and/or detection of galactomannan, an aspergillus cell wall component released during invasive infection, in serum or bronchoalveolar lavage fluid [41] . while azole-susceptible aspergillus fumigatus is still the most common infecting species in pidd patients, the emergence of azole-resistant a. fumigatus and nonfumigatus aspergillus species underscores the importance of a high index of suspicion in patients who do not respond to front-line voriconazole treatment [45] . the advent of fungal molecular diagnostics has demonstrated that patients with pidds are more prone to infections by uncommon low-virulence aspergillus species with intrinsic resistance to azole antifungal agents that do not infect patients with iatrogenic immunosuppression. these primarily include aspergillus viridinutans, aspergillus tanneri, and neosartorya udagawae, which pose major diagnostic and therapeutic challenges due to their impaired sporulation and propensity for contiguous and distant tissue spread, respectively. in addition, acquired azole resistance in a. fumigatus can be seen in patients on long-term exposure to azole drugs used as treatment and/or prophylaxis [46] . azole resistance in these strains is predominantly caused by point mutations in the lanosterol 14α-demethylase gene that encodes the cyp51a protein, the primary target of azole drugs. importantly, infection by azole-resistant a. fumigatus strains without prior exposure of patients to azole antifungals has recently emerged as an important global health concern due to the widespread use of sterol demethylase inhibitor fungicides in agriculture that results in cross-resistance with the triazole antifungals used in clinical practice [47] [48] [49] . fungicide-driven azole-resistant environmental aspergillus strains were first observed in the netherlands in 2007 and have since then been documented in other parts of europe, south and north america, the middle east, australia, africa, and asia. the prevalence of these azole-resistant aspergillus strains among clinical aspergillus strains recovered from patients in 19 european countries was reported to be 3.2%, while alarmingly in some areas >20% of recovered strains exhibited azole resistance [50] . the emergence of such aspergillus environmental strains poses serious threats to the treatment of immunosuppressed patients. mortality rates as high as 88% have been seen due to delays in diagnosis and suboptimal treatment with azole antifungals [51] . although no prospective data exist for the treatment of patients with such resistant fungi, the use of amphotericin b-and echinocandin-based regimens are preferred over azoles [52] . in the absence of azoles, the lack of alternative oral antifungal agents is particularly challenging for pidd patients such as those with cgd who require long-term suppressive antifungal treatment. candida species are commensal yeast fungi that colonize the mucosal surfaces of~60% of healthy individuals [53] . when perturbations in immunity and/or microbiota occur, candida causes opportunistic mucosal or systemic infections that depend on clearly segregated immune responses for host defense. specifically, t cells of the th17 program are critical for mucosal and phagocytes for systemic immunity [54] . indeed, a proportion of patients with cgd and complete myeloperoxidase deficiency develop systemic, but not mucosal candidiasis [42] , whereas patients with monogenic syndromes of chronic mucocutaneous candidiasis due to mutations in the il-17 signaling pathway (il17ra, il17rc, il17f, act1) or in other genes that adversely affect th17 differentiation (rorc, stat3, stat1, aire, dock8, stk4, irf8) do not develop systemic candidiasis. the only known pidd to date that results in combined mucosal and systemic candida infection susceptibility is card9 deficiency. systemic candidiasis in card9-deficient patients has a predilection for the central nervous system, associated with brain-specific impaired recruitment and effector function of neutrophils [55] [56] [57] . diagnosis of candida infections is established by culture. azole-susceptible candida albicans is still the most common infecting species in pidd patients; however, emergence of azole-resistant c. albicans is not uncommon during chronic azole use, making long-term therapy challenging due to lack of alternative oral antifungal treatment options [58] . beyond c. albicans, non-albicans candida species can rarely infect pidd patients, some of which have intrinsic resistance to azole antifungals, including candida glabrata and candida krusei [59] . most recently, candida auris has emerged as a global public health concern due to its resistance to antifungal drugs, high virulence potential, propensity for health careassociated horizontal transmission and outbreaks in health care settings, persistence in the human skin and hospital environment, inherent resilience to antiseptics, and misidentification by routine biochemical methods as other yeasts (most often candida haemulonii, but also candida famata, rhodotorula glutinis, or saccharomyces cerevisiae). c. auris was first recovered from the ear canal of a patient in japan in 2009 and has since then been reported to cause life-threatening infections and hospital outbreaks in europe, asia, africa, the middle east, and south and north america [60] [61] [62] [63] . most of the reported strains of c. auris have intrinsic resistance to fluconazole and other triazole antifungal agents, while a significant proportion of strains has elevated minimum inhibitory concentrations to amphotericin b and echinocandins, with some strains reportedly resistant to all three classes of azoles, polyenes, and echinocandins [64] . avoidance of azole antifungals is important in c. auris-infected patients, and echinocandinor amphotericin b-based regimens are preferred, guided by strain-specific in vitro susceptibility patterns. this section on vector-borne infections is a major focus of this review because the infections are often more severe in immunocompromised individuals and because there are mitigation strategies that should be considered even in the absence of defined medical treatments for infection. prevention of mosquito bites depends somewhat on the endemic species but there are generalizations. the use of a mosquito repellant such as deet, oil of lemon eucalyptus, ir3535, or picaridin is as important as using long sleeves and long pants while in an affected area. deet and picaridin are safe in pregnancy, and some data support their greater efficacy [65] . air conditioning and fans tend to keep mosquitoes away but netting at night is essential in mosquito-prone areas. light-colored clothing is less attractive to mosquitoes than dark clothing, and scented detergents and use of dryer sheets tend to attract mosquitoes, hence should be avoided. aedes species prefer to bite indoors and thrive in urban areas with small puddles of water. they bite most frequently around dawn and dusk. anopheles species have very similar behaviors. culex mosquitoes, in contrast, bite primarily at night. tick and fly bite prevention is focused on physical and chemical prevention. for ticks, physical inspection for biting ticks should also be incorporated. arthropod-borne viruses (arboviruses) are transmitted to humans through the bites of infected insects: mosquitoes, ticks, sand flies, or midges. some arboviruses can be transmitted through blood transfusion, organ transplantation, perinatal transmission, consumption of unpasteurized dairy products, or breastfeeding. there are >100 arboviruses causing human disease. most arboviral infections are asymptomatic. infectious manifestations range from mild febrile illness to severe encephalitis. arboviral infections are often categorized into two primary groups: neuroinvasive disease and non-neuroinvasive disease. tables 2 and 3 list the encephalitigenic viruses and the febrile/hemorrhagic disease causing viruses. in this section, we will highlight west nile virus, the most common of the encephalitogenic arboviruses. west nile virus is a single-stranded mosquito-borne rna virus of the family flaviviridae. the natural transmission cycle of the virus occurs in culex mosquitoes and birds. humans and horses are dead-end hosts for the virus. the most common mode of transmission to humans is through the bite of infected mosquitoes. other less common modes of transmission include blood transfusions, organ transplantations, occupational exposure in laboratories and mother-to-child transmission during pregnancy, childbirth, and breastfeeding. west nile virus has been diagnosed in >2000 people in the usa with slightly more than half having neuroinvasive disease. since 1999, >40,000 people in the usa have been infected. it is also common in africa, europe, and asia [66] . infection with west nile virus is asymptomatic in most individuals [67, 68] . the incubation period lasts for 2 to 6 days. however, it can be significantly longer in immunocompromised hosts. clinical manifestations following infection develop in 20-40% of those infected and include fever, headache, myalgia, arthralgia, vomiting, and rash. severe neuroinvasive disease leading to meningitis, encephalitis, and flaccid paralysis develops in less than 1% of infected individuals. the overall case fatality is approximately 10% which is a disproportionately high mortality in patients with encephalitis and myelitis. diagnosis of west nile virus rests on demonstration of specific antibody responses especially specific igm antibodies in the serum or csf of infected individuals by enzyme immunoassays. plaque reduction neutralization tests can differentiate cross-reactive antibodies. detection of virus in csf, blood, or tissue specimens by culture or pcr is particularly useful in immunosuppressed individuals who may have impaired serological responses. west nile virus has been reported in the context of both primary and secondary immunodeficiency. severe neurological manifestations have been reported in hiv-positive individuals, individuals receiving immunosuppressive therapy including rituximab, and individuals with pidd. infection with wnv has been reported in individuals with common variable immunodeficiency, idiopathic cd4 lymphopenia, gata2 deficiency, and a case of probable good's syndrome [69] [70] [71] . individuals with antibody defects, neutropenias, and impaired t cell responses are potentially at an increased risk of severe manifestations of wnv disease including severe neurological involvement. this section highlights the four important non-neuroinvasive arboviruses based on current geographical distribution: dengue, yellow fever, zika, and chikungunya (table 3) . approximately 100 countries/territories have reported local transmission for both chikungunya and dengue viruses [72] . dengue is due to infection with one of four dengue virus serotypes, transmitted by a mosquito (typically aedes aegypti). this febrile illness affects all ages with symptoms appearing 3-14 days after the infective bite. symptoms range from mild to high fever, with severe headache, musculoskeletal pain, and rash. severe dengue (also known as dengue hemorrhagic fever) occurs in 0.5-5% of cases and is characterized by fever, abdominal pain, persistent vomiting, bleeding, and breathing difficulty and is a potentially lethal complication [73] . paradoxically, the main risk factor for dengue hemorrhagic fever is pre-existing antibodies. early clinical diagnosis and comprehensive management by experienced clinicians increase survival. dengue is ubiquitous throughout the tropics with the highest infection rates in the americas and asia. dengue is now endemic in 100 countries, causing up to 50 million infections a year and 22,000 deaths, mainly among children. over half of the world's population inhabits areas at risk for dengue infection [74] . the presence of a. aegypti in over 125 countries potentially puts almost the whole world at risk of becoming infected with this virus. pcr is widely used as serologic methods to diagnose dengue. immunity to one serotype does not confer protection against the other three serotypes, and heterologous antibody may be a risk factor for hemorrhagic dengue [73] . the natural history of dengue has been studied in hiv patients where hiv did not appear to increase severity. there have been no reports of patients with pidd having dengue; however, dengue infection after solid transplantation has been reported [75] [76] [77] [78] with some patients having severe complications suggesting that t cell compromise in pidd could be a risk for severe disease. there are no antiviral medications utilized for dengue virus. care of patients with hemorrhagic disease requires meticulous approach to fluids and coagulation status. one dengue vaccine has been registered in several countries (cyd-tdv) for individuals from 9 to 45 (or 60) years old. it is a live attenuated recombinant tetravalent vaccine with backbone of the attenuated yellow fever 17d virus genome with the prm and e genes that encode the proteins from the four wild-type dengue viruses. the who has suggested its use in regions where seroprevalence of dengue virus of any serotype is 70% or greater, but has not recommended it to hiv-infected, immunocompromised individuals, nor pregnant or lactating women [79] . most people infected with the yellow fever virus have no illness. symptoms of yellow fever include sudden onset of fever, chills, headache, musculoskeletal pain, nausea, vomiting, fatigue, and weakness. the incubation period is typically 3-6 days, and symptoms may appear after return from travel. most people improve after the initial presentation, but 15% of cases progress to develop a more severe form of the disease, usually after a day of presumed recovery. the severe form is characterized by high fever, jaundice, bleeding, and eventually shock and failure of multiple organs [80] . yellow fever virus is an rna virus that belongs to the genus flavivirus. it is transmitted from mosquitoes after biting an infected primate. it is widely distributed in the equatorial tropics [80] . aedes species of mosquitoes are primarily responsible for transmission. large epidemics of yellow fever occur when the infection enters heavily populated areas with a high mosquito density and where most people have little or no immunity. west africa has undergone a large-scale vaccination campaign with impressive results and yellow fever is now uncommon in west africa [81] . serologic testing for yellow fever is the diagnostic standard. pcr can be performed on tissue samples. there are no published studies of yellow fever in immunocompromised people, but the elderly, very young, people with autoimmune disease, or who are post-thymectomy are at risk from the attenuated vaccine strain. thus, it seems likely that any immunodeficiency would be associated with more severe wildtype disease. currently, no specific antiviral drug for yellow fever exists. treatment of dehydration, liver and kidney failure, and fever improves outcomes. the yellow fever vaccine is highly effective; however, immunodeficient patients should not receive it. infection with zika virus is often asymptomatic. it represents a mild infection for those who have any symptoms [82] . the zika virus has been detected in urine, semen, and saliva of infected individuals, and transmission from transfusion and sexual relations has been reported. it is also detectable in breast milk, but breastfeeding-associated transmission has not been reported so far [83] [84] [85] . contact with highly infectious body fluids from patients with severe zika infection has also been suggested as a possible mode of transmission [86] . of tremendous importance is the presence of prolonged shedding of zika virus in a congenitally infected newborn [87] . the main public health risk of zika virus is microcephaly in newborns from infected mothers [88] . zika virus is capable of infecting human neural progenitor cells in vitro. infection results in disruption of cell cycle, increased cell death, and attenuated neuron growth [89] . zika is not thought to be a major risk for people with pidd (based on the experience with hiv patients, but our recognition of zika is very recent. there is no known specific treatment for zika; however, there is an important effort to develop a vaccine. chikungunya fever is an acute febrile illness caused by the alphavirus, chikungunya virus. the incubation period is usually 3-7 days after the bite of an infected aedes mosquito. there is abrupt onset of high fever, and the fevers can be biphasic [90, 91] . severe polyarthraligias develop after the onset of fever. the joint pains can affect any joint, but the pattern is usually symmetric and a true acute arthritis is not uncommon. the proportion of infected people with rash has varied across studies. when seen, the rash appears after the fever as a truncal maculopapular type of rash [92] . cervical adenopathy is another common feature of infection. death is uncommon in chikungunya, but serious complications such as myocarditis have been seen. over half of the patients report continued joint symptoms 1 year after acute illness and 12% have long-term joint symptoms [93] . chikungunya originated in central/east africa. in forests, the virus circulates in aedes mosquitoes and non-human primates. in urban centers, the virus circulates between humans and mosquitoes similar to the pattern of dengue. there have been periodic urban outbreaks in asia and africa since 1960 with an acceleration in spread since 2004 [94] . an important consideration is the periodic outbreaks with high attack rates in naïve populations. areas at risk currently are east africa, central africa, la reunion, india, and southeast asia. diagnostic testing utilizes pcr or serology. the threat to immunodeficient patients is not entirely clear. there are a few provocative cases where the immunocompromised appears to have been associated with fewer joint symptoms, but there were two patients, medically immune compromised, who had very severe disease [95, 96] . this suggests that the presentation may be atypical and the course may be severe in immunodeficient people. treatment is supportive, although chloroquine, acyclovir, ribavirin, interferon-ɑ, and steroids have limited preclinical data to support clinical trials. babesia microti (the main species in the usa) infection can be asymptomatic, but many people develop fever, chills, headache, myalgias, anorexia, nausea, or fatigue [97] . babesiosis often causes hemolytic anemia. b. microti is spread by ixodes scapularis ticks in the usa and babesia divergens (the main species in europe) is spread by ixodes ricinus. symptoms begin 1-3 weeks after a bite from an infected tick with b. divergens having a higher mortality rate and greater symptomatology compared to b. microti. the main geographic areas involved are the coastal eastern usa and cattle breeding areas throughout europe. the diagnosis is usually by inspection of a blood smear or through serology. a pcr test has just been developed. immunodeficiency, asplenia, and older age are recognized risk factors for severe disease and even death [98] [99] [100] . thus, congenital asplenia would be considered a major risk for severe disease. a combination of atovaquone and azithromycin is generally used for therapy, although clindamycin and quinine have been used with success. patients with severe illness have been treated with exchange transfusions. five different types of plasmodium (plasmodium falciparum, plasmodium vivax, plasmodium ovale, plasmodium malariae, and plasmodium knowelsi) infect humans. malaria is transmitted primarily by female anopheles mosquitoes. symptoms vary depending on the type of plasmodium involved but usually include high fever, chills, and headache. in some cases, the illness can progress to severe anemia, kidney and respiratory failure, and death. the incubation period typically ranges from 9 to 14 days for p. falciparum, 12 to 18 days for p. vivax and p. ovale, and 18 to 40 days for p. malariae. in p. vivax and p. ovale infections, relapses can occur months or even years without symptoms. p. vivax and p. ovale have dormant liver stage parasites that must be specifically eradicated through medical therapy. malaria has been a global health concern throughout history and is a leading cause of death and disease across many tropical and subtropical countries. over the last 15 years, new control measures have reduced malaria by over half [101] . the democratic republic of the congo and nigeria account for over 40% of the estimated total of malaria deaths globally. high rates of malaria are seen in india as well. nevertheless, malaria exists in most tropical regions of the americas, africa, and asia [101] . the diagnosis of malaria depends on the demonstration of parasites in the blood, usually by microscopy. the threat to immunodeficient patients is not entirely clear, but patients with hiv seem to have no additional burden of disease other than an increase in placental malaria, suggesting that t cells are not central to the defense of malaria [102, 103] . asplenia is a known risk factor for severe malaria [104] . antibodies appear to be both protective and pathologic [105, 106] . treatment and prophylaxis depend on the region of the world because the parasites and resistance are highly variable and highly dynamic. therefore, it is best to consult an infectious disease specialist familiar with the prophylaxis before travel and for treatment of acute cases. leishmaniasis is due to infection with an obligate macrophage intracellular protozoa of the genus leishmania. it causes a spectrum of disease ranging from a cutaneous ulcer to mucosal disease and the most severe form, visceral leishmaniasis (vl). the liver, spleen, and bone marrow are major sites of parasite growth and disease pathology in vl [107] . purely cutaneous leishmaniasis is most often caused by leishmania major, leishmania. tropica, leishmania aethiopica, leishmania infantum, and parasites belonging to the leishmania mexicana complex, the leishmania braziliensis complex, and the leishmania guyanensis complex. mucocutaneous disease is most often due to l. braziliensis complex, leishmania panamensis, leishmania amazonensis, and rarely by leishmania guyanensis. vl is most often caused by leishmania donovani and leishmania infantum (previously l. chagasi) [108] . cutaneous leishmaniasis can have many variations but is most often an ulcer that develops after an indolent papule. the incubation period ranges from weeks to months. the ulcer usually heals within months to years, and there can be mild adenopathy. mucocutaneous leishmaniasis follows a cutaneous ulcer and is only caused by l. braziliensis parasites. oral and respiratory mucosa are most often involved with granulomatous lesions that may be extremely destructive. vl is associated with fever, lymphadenopathy, hepatosplenomegaly, wasting, hypoalbuminemia, and pancytopenia. this picture evolves over months to years. there can be secondary immune deficiency due to the pancytopenia. the epidemiology has changed dramatically and has been impacted by climate change [109] . the sand flies that spread the parasite are affected by temperature and rainfall. in most endemic regions, leishmania has a patchy distribution due to micro-ecologic factors. poverty has been demonstrated to be a major risk factor for leishmaniasis [110] . it has been estimated that up to half a million new cases of vl occur every year, but the majority are in resource-poor countries such as bangladesh, nepal, india, sudan, ethiopia, and brazil. emergence of resistance to antimony-based drugs has also led to a major resurgence of disease. the primary reservoir for leishmania is forest rodents, but dogs are increasingly important. the growing spread of leishmania is due to a combination of factors, and now 88 countries have reported cases. immunodeficient patients are more susceptible to infection, and relapse occurs more frequently [111] . the risk of developing vl is estimated to be between 100 and 2300 times higher in hiv-infected than in non-hiv-infected individuals [112] , and these patients have higher rates of treatment failure with the illness often taking a prolonged chronic course and higher mortality rates [113] . a similar picture has been seen in patients with vl-infected post-kidney transplantation [114] . dendritic cells, t cells, and the generation of reactive oxygen species have been shown to be essential for parasite control [115] [116] [117] . pidd with impaired il-12 production have been associated with severe disease [118] . a patient with cd40l deficiency, associated with poor il-12 production, had chronic leishmania and died in spite of aggressive treatment. vl has been reported in cgd patients [119] . six cgd patients were infected by leishmania, and they developed hemophagocytic syndrome with a poor outcome for one of them [120] . the diagnosis of leishmaniasis is usually by visual inspection for parasites. immunofluorescence microscopy, direct agglutination, skin test, and pcr have been used. treatment is long-term and difficult. emerging resistance to first-line treatment is increasingly problematic. pentavalent antimonials are the mainstay of treatment in most countries, but liposomal amphotericin is widely used where resistance occurs. newer drugs with more favorable side effect profiles have been used in certain geographic settings: miltefosine, paromycin, and sitamaquine. rickettsiae are small gram-negative bacteria. they are obligate intracellular parasites, and the primary target in humans appears to be endothelial cells with subsequent thrombosis and clinical presentation of vasculitis [121] . the rickettsiaceae family, originally defined by non-specific phenotypic characteristics, was reclassified into different strains and subspecies based on gene sequencing and genetic phylogeny ( table 4 ). the clinical presentation of rickettsial disease can vary, but the classic triad of fever, rash, and headache still provides major clues for the diagnosis [122] [123] [124] . however, rash is not an obligatory sign, and the incidence of rash can range between 100% for rickettsia conorii infection,~90% for rickettsia rickettsii, 30% for rickettsia africae, and less than 10% in the case of anaplasma phagocytophilum infection. therefore, fever in patients with exposure to a potential vector should raise a concern for a rickettsial disease, especially if there is also evidence of rash, inoculation eschar, or localized lymphadenopathy. additional supporting laboratory findings can include neutropenia, thrombocytopenia, and increase in liver transaminases. the geographic distributions of rickettsioses and ehrlichioses are mostly dependent on their vector distribution [125] . as such, louse-borne and flea-borne are worldwide, reflecting the worldwide distribution of lice and fleas, with a tendency to parasite poor people in cold places and, characteristically, during wars. ticks, on the other hand, depend on their environment and most do not have a worldwide distribution. with the exception of the dog tick, vector for r. conorii in asia and north africa, r. rickettsii in the usa, rickettsia massiiae and erhlichia canis worldwide, most other tick-borne diseases are restricted to areas of the world correlating with the distribution of their vector [126] . for that reason, it should be anticipated that climate and environmental changes will affect vector distribution and its reservoir host and, hence, the geography and epidemiology of tick-borne diseases [10, 127, 128] . diagnosis presents a challenge, as it is extremely difficult to grow these organisms in culture. immunohistochemistry and pcr can be helpful. the severity of rickettsial disease varies with the causative agent and the host. r. rickettsii, rickettsia prowazekii, and orienta tsutsugamushi are considered most pathogenic. as for host factors, although severe and fatal cases have been described in healthy immunocompetent hosts [129, 130] , there is evidence to suggest that children under the age of 10 [130] and immunocompromised hosts either secondary to hematologic malignancies, immunosuppressant treatment for organ transplantation, or hiv infection are at a greater risk to develop more severe disease with higher case fatality rates [131, 132] . all rickettsiaceae are intracellular pathogens, and one could expect an increased risk for severe disease in pidds with abnormal t cell function. five to 7 days of doxycycline is the preferred treatment for non-pregnant adults and children. treatment should not be delayed while awaiting diagnostic testing [133] and can be given to children despite a minimal risk for dental staining. alternative treatments include azithromycin for mild disease [134] and chloramphenicol for pregnant women. anaplasma is an intracellular bacterium that infects wild and domestic mammals, including man. a. phagocytophilum was formerly known as human granulocytotropic ehrlighiosis but is now known as human granulocytotropic anaplasmosis [135] . e. chaffeensis infects monocytes and causes human monocytic ehrlichiosis [136] . anaplasma and ehrlichia have historically cycled within non-human enzootic hosts, and man has become infected through increasing interactions with the environment. ehrlichia and anaplasma are transmitted by ixodes species of ticks, and their ranges include the eastern usa, south central usa, and scattered regions of europe, as far north as sweden. these infections have not been seen in humans in the southern hemisphere, but there are reports of organisms being identified [137] . a less common mode of transmission is through transfusions. the symptoms of ehrlichia and anaplasma infections are similar [136] . abrupt onset of an influenza-like illness occurs about 12 days after a tick bite. ehrlichia can cause a mild rash (30% of adults and 60% of children), but rash is uncommon in anaplasma infections. highly suggestive laboratory features are leukopenia and thrombocytopenia. mortality in the general populations appears to be <5%, but icu admission is not uncommon. hemophagocytosis has been described with anaplasma [138] and ehrlichia [139] . both infections are more severe in any setting of immune compromised, including asplenia [129, 135] . the diagnosis is typically made by pcr, and doxycycline is the recommended treatment. intracellular inclusions can be seen on cbc smears (more often in anaplasma than ehrlichia). an uncommon but well described facet of these infections is that the tick vector can also transmit borrelia burgdorferi and babesia microti, and simultaneous infection with multiple organisms can occur. c. burnetii is a highly pleomorphic gram-negative coccobacillus and the causative agent of q fever. q fever is a zoonosis, and the most common reservoirs are cattle, sheep, and goats but many other animals can be infected by c. burnetii [140, 141] . when infected, these domestic animals can shed the organism in urine, feces, milk, and especially birth products. the pathogen survives within the phagolysosome of host cells, and a spore stage has been described. this spore stage explains the ability of c. burnetii to survive in unfavorable environmental conditions, and it can be an environmental risk for months to years after shedding from an infected animal. q fever is considered an occupational disease affecting people with direct contact with infected animals; however, indirect contact through exposure to contaminated animal products has also been described to cause disease outbreaks. humans are infected by inhalation of contaminated aerosols. following an average incubation period of 20 days, infected patients can present with severe headache, fever, chills, fatigue, and myalgia. other signs and symptoms depend on the organs involved. in contrast to rickettsial diseases described above, rash rarely occurs in the early stages of the disease. c. burnetii can cause a range of clinical symptoms. a self-limited febrile illness is probably the most common form of q fever. pneumonia, either atypical or severe, is also common and can be a part of acute q fever syndrome. in contrast, a variety of manifestations can be recognized in chronic q fever, including endocarditis, endovascular infection, osteomyelitis, hepatitis, interstitial pulmonary fibrosis, prolonged fever, and purpuric vasculitic rash. q fever diagnosis is based on serologic testing with indirect immunofluorescence being the best for differentiating between acute and chronic q fever (high antiphase i antigen titer). the treatment of choice for acute q fever is doxycycline, with co-trimoxazole, chloramphenicol, or rifampin being an accepted alternative. there is no agreement on the treatment for q fever endocarditis, and a combination of doxycycline with either fluoroquinolone or hydroxychloroquine is recommended. there is also controversy regarding the duration of treatment, ranging from 2 years to indefinite treatment. old evidence suggests that q fever is more common in immunocompromised patients. a french study showed higher incidence of antibodies to c. burnetii in hiv positive compared to hiv-negative patients (10.4 vs 4.1%). in addition, 5 out of 68 hospitalized patients were hiv positive (7.3%), suggesting a more frequent symptomatic disease [142] . a smaller similar study performed in central africa failed to show increased incidence of seropositivity in hivpositive patients [143] . two case reports describe severe disease in immunocompromised patients. the first was a case of fatal q fever disease in an 11-year-old male with cgd [144] . the patient was treated with broad spectrum antibiotics, but without coverage for q fever. the second case was a 53-yearold asplenic male who presented with fever, jaundice, and encephalopathy and was diagnosed with acute q fever [145] . the patient was successfully treated, but the two case reports could suggest susceptibility in cases of phagocytic disorders. the bartonellaceae are fastidious, facultative intracellular gram-negative bacilli (table 5 ). most species infect primarily non-human animals, and in most cases, human are considered incidental hosts. the documented common human pathogens include bartonella bacilliformis, bartonella henselae, and bartonella quintana, and it is believed that humans are the primary mammalian reservoir of b. quintana. infection occurs through inoculation of bartonella-infected arthropod feces into breaks in the skin. the epidemiology of bartonella infection in humans follows the distribution of the vector. as such, infection with b. bacilliformis follows the distribution of the sand fly vector (lutzomya) and is confined to the andes mountain in peru, ecuador, and colombia at heights of between 500 and 3200 m. the human body louse pediculus humanus is the vector of b. quintana, which explains the global distribution of this pathogen and worldwide outbreaks of trench fever, mostly in conditions of poor sanitation and upon exposure to body lice. trench fever was responsible for over a million infections during world war i. fever, either abrupt or indolent in onset, with a maculopapular rash, conjunctivitis, headache, myalgias (most often affecting legs), and splenomegaly was described. urban b. quintana infections occur most often among homeless and have a distinct clinical picture with fever as the most common manifestation. endocarditis occurs in many [146] . bartonella henselae is globally endemic, and domestic cats are a major reservoir. the major arthropod vector of b. henselae is the cat flea, which is responsible for cat-to-cat transmission. human infection, called cat scratch disease, is assumed to involve inoculation of bartonella-infected flea feces into the skin during a cat scratch. b. henselae causes primarily adenopathy and neurologic symptoms [147] . b. bacilliformis causes a condition with two phases: the acute phase with fever, anemia, and transient immunosuppression followed by nodular dermal eruption [148] . recently appreciated are the ongoing systemic features during the eruptive phase such as arthralgias, adenopathy, and anorexia [149] . diagnosis of bartonella-associated diseases can be achieved by direct examination of clinical material, bacteriologic culture methods, serologic and immunocytochemical studies, pcr-based assay, or combination of these methods. bartonella infection can present differently in immunocompromised hosts [150] . in addition to higher prevalence of bartonella infection in hiv patients [151] , both b. quintana and b. henselae can induce neovascular proliferation which might involve the skin, lymph nodes, and a variety of internal organs including the liver, spleen, bone, brain, lung, bowels, etc. these neovascular lesions, known as bacillary angiomatosis/peliosis (ba/bp), were initially described in hiv-infected patients with advanced disease and was later described in other immunocompromised hosts secondary to immunosuppressant treatment for solid organ transplantation or hematologic malignancy [152] [153] [154] [155] . cutaneous ba lesions can vary in presentation and can be subcutaneous, dermal nodules, single or multiple papule that can be flesh colored, red, or purple. lesions may ulcerate and bleed. they can change in number and size (millimeters to centimeters; few to hundreds) and can involve mucosal surfaces or deeper soft tissues. similar variation can be seen with visceral involvement. histologically, lesions consist of lobular proliferation of small blood vessels and neutrophilic predominant cell infiltration. the term bacilliary peliosis is used to describe bloodfilled cystic spaces mostly involving the liver, spleen, and lymph node. pathogenic bacteria can be isolated from vascular lesions. while both pathogens were associated with cutaneous lesions, only b. henselae was associated with visceral bp [156] . based on hiv literature, it is reasonable to expect an unusual presentation of bartonella infection especially in pidds involving t cell dysfunction. bartonella infection was described as a cause for hepatitis in a single cd40l deficiency patient [157] . in addition, since cases of granulomatous disease due to bartonella infection [158] [159] [160] have been described, it should be considered in the differential diagnosis of pidd with granulomatous inflammation. borrelia spp. the genus borrelia belongs to the spirochaetaceae family. it includes b. burgdorferi which causes lyme disease and species that cause relapsing fever. the latter are further divided into tick-borne species and louse-borne species. louse-borne relapsing fever (lbrf) is caused only by borrelia recurrentis and is spread by human body louse. the disease was epidemic in the early twentieth century, and it is estimated that more than 50,000 died of lbrf during world war ii. with sanitation improvement lbrf is now found only in the horn of africa and among homeless people in europe. more recently, cases of lbrf in refugees and migrants were described [161, 162] . tick-borne relapsing fever (tbrf) is caused by a group of pathogens which are maintained by and survive in softticks (orinthodoros genus). each tbrf borrelia species depends on one specific species of soft-body tick. except for australia and antarctica, tbrf species can be found in all continents. the animal reservoir includes small animals and rodents. since the spirochetes persist in the tick salivary gland, disease transmission occurs when humans intrude the tick's environment. tick bites are painless, and history of a tick bite is often missing. therefore, a history of potential exposure can be valuable. the major clinical symptom is relapsing fever. after a median incubation period of 7 days, patients present with febrile episode that can last 2-7 days, followed by afebrile period of 4-14 days. patients with tbrf can have up to 30 febrile relapses, while lbrf is usually associated with only one relapse. other symptoms include myalgia, arthralgia headaches, and vomiting, and physical findings include lymphadenopathy and splenomegaly with rash occurring only in third of the patients. a range of neurologic complications as well as systemic inflammatory response syndrome also have been described [163] . diagnosis is based on identifying the spirochetes on blood smear. sensitivity of blood smear is higher during febrile period (about 70%), and a negative blood smear does not exclude rf. in lbrf, the spirochete load can be low and specific stains can be helpful. other diagnostic methods include serologic testing, pcr, and mouse inoculation. doxycycline, tetracycline, and penicillin are the preferred treatment, with most patients treated with 7-10 days of doxycycline. jarisch-herxheimer reactions with high fever and leukopenia occur in half of the patients following the first antibiotic dose and can develop into a severe reaction with hypotension, respiratory distress, and death [163] . without treatment, tbrf carries a mortality rate of up to 10% with even higher 40% mortality rate for untreated lbrf. two cases of meningoencephalitis with borrelia miyamotoi in heavily treated immunocompromised patients have been described [164, 165] . lyme borreliosis is the most common vector-borne disease in the northern hemisphere caused by a group of at least 13 genospecies. lyme disease is a multisystem illness affecting the skin, joints, nervous system, and heart. human infection is caused mainly by three species: b. burgdorferi is the most common cause in north america but also found in europe, and borrelia afzelii and borrelia garinii which cause the disease in europe and asia. emerging infections in the mid-western usa with borrelia mayonii cause a condition similar to lyme disease. most tick species do not carry borrelia species. the vectors of all borrelia species are the ixodid tick species; this includes the deer tick, i. scapularis, in the northeast and midwest of the usa, ixodes pacificus in the west, the sheep tick, ixodes ricinus, in europe and the taiga tick, ixodes persulcatus, in asia. the ixodid tick demonstrates a complex vector ecology with preferences for different hosts in different geographical regions and at different stages of its development. more than 300 different species, including deer, rodents, birds, and reptiles, have been described. infection rates also show seasonal variation with highest rates during lyme disease follows several stages starting with localized disease at the site of inoculation, followed by dissemination stage and, later, persistent infection [166] . however, an individual patient can show highly variable disease progression with different patterns of organ involvement and disease severity. erythema migrans (em) is often seen at the site of the tick bite after 3-30 days of incubation. regional lymphadenopathy can be seen. secondary skin lesions represent hematogenous dissemination. at this stage, constitutional symptoms of general fatigue, fever and headaches, migratory musculoskeletal pain, conjunctivitis, and cardiac involvement occur. in total, 15% of untreated patients can develop frank neurologic manifestations of meningitis, encephalitis, and variable forms of neuritis with fluctuating symptoms. persistence can occur in untreated (on inadequately) patients. antibiotic refractory arthritis is well described. however, even without treatment, intermittent or persistent attacks usually resolve completely within several years. co-infection with a. phagocytophilum and b. microti can cause diagnostic confusion [167, 168] . the diagnosis of lyme disease is established based on clinical symptoms, history of potential exposure, and serologic studies. although positive culture can confirm the diagnosis, it can usually be obtained only from early em lesions. pcr testing is superior to cultures and can be performed on joint fluid samples [169] . cdc recommendations for the diagnosis of lyme disease are based on serology which might be impossible in pidd patients with abnormal humoral response. cdc guidelines require both an elisa (or comparable test) to be positive and a western blot (2 out of 3 bands (23, 39, or 41 kd) on the igm or 5 out of 10 bands on the igg (18, 23, 28, 30, 39, 41, 45, 58, 66, 93 kd) . most lyme manifestations can be treated with oral antibiotics, while patients with neurologic abnormalities and some patient with lyme arthritis require intravenous therapy [170] . doxycycline is the treatment of choice for early and disseminated disease, with amoxicillin as the second-line choice. jarisch-herxheimer-like reactions can appear in the first 24 h in about 15% of the patients. for patients with clear neurologic symptoms, 2-4 weeks of iv ceftriaxone is the most commonly used therapy. few cases of neuroborreliosis and hiv have been described with a good response to treatment. descriptions of lyme disease in pidd patients are lacking. zoonoses are infectious diseases that pass between animals and humans and span the spectrum of pathogens including viruses, bacteria, fungi, and parasites. zoonoses are very common and range from mild such as certain forms of tinea to lifethreatening infections such as rabies. some of the zoonoses that are vector-borne will be covered in other sections. risk mitigation strategies for zoonoses include patient education, proactive advice about risk scenarios, and avoidance of infected animals. several zoonoses are associated with contact with mammals such as rodents or domestic farm animals through direct contact or through contact with their feces. for instance, hantavirus infections are often associated with exposures to mouse droppings when staying in cabins in the western usa. occupational exposures can occur with buffalopox or parapoxvirus (causing orf infection) through direct contact with buffalo and goats/sheep, respectively [171] [172] [173] [174] . in general, there are very few cases of pidd with zoonotic infections acquired from mammals. however, there are a few special considerations. for instance, lymphocytic choriomeningitis virus is acquired through exposure to house mice primarily, with hamsters being a less common source of infection. both domestic and wild mice can carry the infection without exhibiting symptoms. although infection is rare, there have been severe cases in patients with t/ nk cell dysfunction, such as a case in xlp1 and cases in solid organ transplant recipients [175] . therefore, in patients with severe t/nk defects, consideration should be given to whether small rodents are appropriate household pets. tularemia is a disease of animals and humans caused by the bacterium francisella tularensis. rabbits, hares, and rodents are the main reservoirs. humans become infected through direct contact, ingestion of contaminated water, or inhalation of organisms. ticks and deer flies can also transmit the disease through bites. fever is universal, but other features depend on the mode of transmission. a patient with cgd had a complex course suggesting myeloid defects are a risk for more severe disease [176] . rabies is an almost universally fatal infection caused by contact with oral secretions from infected mammals, typically raccoons, bats, or foxes, and there is no suggestion that pidd or immune compromised modifies the prognosis. for individuals with high-risk exposures, such as those working with wildlife or traveling in endemic areas, pre-exposure prophylaxis is given with vaccination, and if an exposure occurs, rabiesspecific immunoglobulin is provided as well as vaccination. however, for those with humoral immunodeficiencies who cannot respond to the typical pre-exposure vaccination, there needs to be counsel on the additional risk without vaccination. in table 6 , several of the bacterial and viral zoonoses are summarized with their typical endemic areas, which is somewhat limited by diagnostic abilities and reporting, as well as the typical clinical scenarios, known cases in immunodeficiency and an approach to diagnosis and therapy. nipah virus causes a range of infectious phenotypes ranging from asymptomatic infection to acute respiratory distress and encephalitis. nipah virus was identified in 1999 on pig farms in malaysia, leading to identification of 257 human cases, including 105 human deaths and the culling of one million pigs [177] . the natural host is the fruit bat: pteropodidae pteropus. symptoms of infection from the malaysian outbreak were primarily encephalitic in humans, but later, outbreaks have caused respiratory illness, increasing the likelihood of human-to-human transmission. fever, headache, cough, abdominal pain, nausea, vomiting, weakness, problems with swallowing, and blurred vision were common. seizures were seen in 25% and coma in 60%. relapses of encephalitis have been described [178] . increasing infections due to nipah virus is thought to be due to an increasing overlap between bat habitats and pig sties in malaysia. all outbreaks thus far have been in india, bangladesh, or malaysia. the diagnosis of nipah virus relies on pcr of fluid samples, serology in convalescent samples, and immunofluorescence of tissue. there have been no infections of immune compromised patients reported. therapy is largely supportive, although preliminary reports of ribavirin use have been encouraging. a vaccine is under development. severe acute respiratory syndrome coronavirus (sars-cov) and the middle east respiratory syndrome coronavirus (mers-cov) are two zoonotic coronaviruses. the sars pandemic in 2002-2003 resulted in 8096 reported cases in 27 countries. no further sars cases were reported after the pandemic except isolated cases linked to laboratory accidents. patients usually presented with fever and respiratory symptoms, but occasionally had diarrhea and vomiting. about 20-30% of sars patients required mechanical ventilation, with a case fatality rate of about 9% [179] [180] [181] . mers was first noted in saudi arabia in 2012, and countries around the arabian peninsula are now endemic for mers-cov. patients usually present with fever, cough, chills, sore throat, myalgia, and arthralgia rapidly progressing to pneumonia with over 50% of patients requiring intensive care. about one-third of patients present with diarrhea and vomiting, and acute renal impairment is a striking feature of mers. risk factors for poor outcome include diabetes, hypertension, and renal and lung disease. cases have been exported to at least 26 countries with travel occasionally causing cluster of secondary outbreaks. one such example is the mers-cov outbreak involving 82 patients in south korea, and the median incubation period was estimated to be 7 days with a range of 2 to 17 days [182] . at the end of 2015, there were 1621 confirmed mers with a 36% mortality rate [179] [180] [181] . bats are the natural reservoirs of both sars-cov and mers-cov. sars-cov crossed the species barrier into palm civets and other animals in live animal markets in china, which then infected human, while a mers-cov ancestral virus crossed species barrier into dromedary camels. abundant circulation of mers-cov in camels results in continuous zoonotic transmission of this virus to human, while sars-cov was not found to circulate in the intermediate reservoirs, explaining sars being a one-off outbreak and mers a continuing zoonotic disease [179] . aerosolgenerating procedures such as intubation were associated with increased viral transmission of both covs resulting in nosocomial outbreaks [179] . super-spreaders are responsible for large and prolonged outbreaks [181] . the diagnosis for sars and mers include both serological tests and pcr assays that can quantify viral loads [183] . functional genetic polymorphisms leading to low serum mannose binding lectin (mbl) are associated with susceptibility to but not severity of sars in both southern and northern chinese [184] [185] [186] . mbl was shown to bind to sars-cov and inhibit the infectivity [184] , suggesting its role as first-line defense against sars-cov. although no patients with primary immunodeficiency infected with sars-cov or mers-cov were identified, likely due to the limited number of such infections, patients with t cell defect and type 1 interferon pathway defects could suffer a more severe disease course [187, 188] . virus-based and host-based treatment strategies are largely experimental with uncertain benefits. ribavirin, type 1 interferons, small molecules, and monoclonal antibodies that block covs entry have been explored [183] . passive immunotherapy and multiple candidate vaccines have been tested in various animal models. convalescent plasma immunotherapy has been considered, but clinical trials are lacking in mers [189] , while for sars a systematic review concluded convalescent serum may reduce mortality and appear safe [190] . the filoviridae family contains three known genera, the ebolaviruses, marburgviruses, and cuevavirus. ebolavirus and marburgvirus cause hemorrhagic fever syndromes in primates and humans, with high fatality rates. cuevavirus infects only bats. the ebolavirus genus contains five species, with two of the species (zaire ebolavirus and sudan ebolavirus) being responsible for the majority of cases of human disease, while marburgviruses contain two species (marburg virus and ravn virus). filoviruses are capable of replicating in a number of cell types (with the exception of neurons and lymphocytes). upon entry into the body of the host (via breaks in the skin, parenterally, or through mucosal surfaces), filoviruses employ a variety of mechanisms to evade the activity of the immune system [191] . the incubation period (interval from infection to onset of symptoms) varies from 2 to 21 days. symptoms begin abruptly, with high fever, severe headache, malaise, myalgia, diarrhea, nausea, and vomiting. a rash can occur between 2 and 7 days after onset of symptoms. hemorrhagic manifestations occur between 5 and 7 days, and fatal cases usually have some form of active bleeding. in an outbreak setting, the symptoms are unmistakable but confusion with malaria can occur early in the disease or in sporadic cases. since their original descriptions in 1967 and 1976, respectively, for marburg and ebola, there have been a number of sporadic cases and several major outbreaks. the largest marburg virus outbreak occurred in angola in 2005 (with a fatality rate of >80%), while the largest ebola epidemic happened between 2014 and 2016 in west africa (sierra leone, guinea, and liberia) and claiming over 11,000 lives (fatality rate > 40%). although not definitively proven in the case of ebola, bats are believed to be the natural animal reservoir for these viruses [192, 193] . these viruses are transmitted via contact with blood or body fluids from an infected host; notably, certain body fluids can harbor virus for weeks to months after resolution of disease. given the recent outbreak in west africa, there has been renewed interest in understanding the pathogenesis of filovirus infections and possible therapies. literature regarding how the pathogenesis of disease may be altered in patients with pidd is lacking. however, the assumption is that in the absence of an intact cellular and/or humoral immune response, the patient with a pidd may be at increased risk of mortality in the setting where mortality is already high. these viruses induce apoptosis of lymphocytes and macrophages, and there is therefore a profound secondary immune compromised [194, 195] . filoviruses can be detected in multiple body fluids via pcr. although practiced for decades, a study in guinea in 2015 failed to show a decrease in mortality among patients receiving convalescent plasma from previously infected donors [196] . a number of additional compounds (e.g., tkm-ebola, bcx4430, and gs-5734) and biologics (zmapp) have been shown to offer protection in animal models of ebola, but to date, no controlled and appropriately powered clinical trials have addressed their efficacy in humans. finally, a number of vaccines for ebola are undergoing clinical studies (including four in phase iii trials). importantly, in late 2016, the rvsv-zebov vaccine was shown to have displayed high efficacy in protecting immunized adults during the 2015 guinea ebola outbreak, and the data also suggested that the vaccine may even offer bherd immunity^to unimmunized persons in proximity to recipients of the vaccine [197, 198] . hepatitis e virus is a single-strand rna virus of the hepeviridae family. it is an important zoonotic disease in asia and africa, and fecal-oral spread is the usual route of transmission [199] . handling of pig or boar meat is a risk factor, and 2-10% of pig livers sold in grocery stores in japan and the usa are infected [200, 201] . swine represent the major reservoir, although antibodies to the virus have been found in many species [199] . the incubation period is 2 weeks to 2 months, and viremia disappears with the onset of symptoms. the mortality rate is 1-4% and can reach 20% in pregnancy [202] . acute hepatitis usually resolves but can lead to liver failure in severe cases. patients with hepatitis e posttransplant have had severe courses in some cases [203] . in immune compromised patients, the course can become chronic [204] [205] [206] . in these cases, cirrhosis develops. the diagnosis is by serology or pcr, and the treatment is supportive. prevention modalities for infections transmitted by humans are conceptually different than infection prevention for vector-borne infections. hand hygiene is extremely important, and avoidance of clearly infected people can be helpful. recognition of infections with fecal-oral transmission and the importance of water purity are critical for patients with pidd. in contrast, infections transmitted by aerosols require prevention strategies related to droplet precautions. in outbreak scenarios, if the risk to the patient is high, specific chemoprophylaxis may be considered. influenza viruses type a and b cause annual epidemic influenza, while type c causes sporadic mild influenza-like illness. patients present with sudden onset of fever, chills, and myalgia, followed by sore throat and cough. other less common features include diarrhea, acute myositis, and encephalopathy [207, 208] . co-infection with bacteria such as pneumococci results in more severe disease [209, 210] . influenza pandemics occur yearly around the world. influenza viruses infect 5 to 15% of the global population, resulting in~500,000 deaths annually [211] . the viruses circulate in asia continuously and seed the temperate zones, beginning with oceania, north america, and europe, then later seeding into south america [212] . diagnosis of influenza includes direct/ indirect immunofluorescent antibody staining for antigens in nasopharyngeal aspirates and pcr. a patient with compound heterozygous null mutations of the gene encoding irf7, a transcription factor for amplifying ifn-α/β, was reported to have life-threatening influenza during primary infection [213] . fatal influenza-associated encephalopathy in both chinese and japanese children has been reported to be associated with genetic variants of thermolabile carnitine palmitoyltransferase ii [214] . patients with scid will have prolonged viral shedding [215] . severe pandemic influenza a virus (h1n1) infection has been associated with igg2 and igg3 subclass deficiency [216, 217] . in addition, influenza infection can be more severe in pidd patients with underlying lung disease, such as bronchiectasis, and antibiotic coverage of chronic colonizing bacteria (such as pseudomonas) in this setting may be helpful. inactivated seasonal influenza vaccine should be given to pidd patients even those with humoral deficiencies as their t cell response to influenza could be normal and offer protective immunity against severe influenza [218, 219] . antiviral drugs include neuraminidase inhibitors (oseltamivir and zanamir) and adamantanes (amantadine and rimantadine), but resistance to adamantanes is widespread. measles is a single-stranded, negative-sense, enveloped (nonsegmented) rna virus of the genus morbillivirus. measles is highly communicable, transmitted by droplets, and less commonly by airborne spread. patients present with fever, cough, coryza conjunctivitis rash, and koplik spots. complications include pneumonia, acute encephalitis, and subacute sclerosing panencephalitis (sspe) [220] . diagnosis of measles includes serological tests, virus isolation, and pcr. in an outbreak, the clinical features may be sufficient for diagnosis. measles vaccine has caused severe measles in children with stat2 and ifn-α/β receptor deficiency [187, 188] , demonstrating the importance of type 1 interferon pathway in controlling measles. immune compromised of nearly any type is associated with severe disease and higher mortality [221] . t cell deficiency states are the most strongly associated with the development of giant cell pneumonia and inclusion body encephalitis, the most feared complications of measles. sspe is a slow encephalitis due to persistence of replication defective measles virus in the cns. it is most frequently seen when young infants are infected with measles and 6-10 years later, sspe becomes evident. there are case reports supporting the immune compromised as increasing the risk of sspe [222] . treatment of sspe with ribavirin has shown some improvement, but the prognosis in general with sspe is very grave. patients with cgd have defective memory b cell compartment, resulting in lower measle-specific antibody levels and antibody-secreting cell numbers, but severe disease has not been reported [223] . pidd patients may harbor the virus latently for longer than usual, leading to complications at the time of transplant [224] . specific antiviral therapy is lacking, but ribavirin has been given to severely ill and immunocompromised children. for measles post-exposure prophylaxis, intravenous immunoglobulin (ivig) is recommended for severely immunocompromised patients without evidence of measles immunity [225] . this would likely include patients with scid and hypogammaglobulinemia who are not yet on regular ivig. measles vaccine, given in a two-dose regimen, has brought down incidence enormously worldwide and the who is planning for eradication globally. enteroviruses (evs) are among the most common viruses infecting humans worldwide. evs are small non-enveloped, single-stranded rna viruses of the picornaviridae family. human evs are categorized into seven species that include hundreds of serotypes, such as polioviruses (pv), coxsackie viruses a, and b (cv-a and b), echoviruses, and human rhinoviruses (hrvs). of these species, many important serotypes are known to infect human such as pv1-3, cv-a16, cv-b3, ev-a71, ev-d68, and hrv (table 7) . non-polio enteroviruses (npevs) have a worldwide distribution. infants and young children have higher incidence of infection and a more severe course of illness than adults. the mode of transmission is mainly through fecal-oral and respiratory routes. infection occurs all around the year in tropical and subtropical regions, while in temperate climates the peak incidence of infection is during summer and fall months [226] . npevs are associated with diverse clinical manifestations ranging from mild febrile illness to severe, potentially fatal conditions. most cases are asymptomatic or have mild symptoms including fever with or without rash; symptoms of hand, foot, and mouth disease; herpangina; acute hemorrhagic conjunctivitis; upper respiratory infection; and gastroenteritis. more severe symptoms occur in infants and young children [227, 228] . acute flaccid paralysis [229] , neonatal enteroviral sepsis [230] , myocarditis/pericarditis [231, 232] , hepatitis, pancreatitis, pneumonia, and atypical hemolytic uremic syndrome [233] are severe manifestations seen in immunocompetent people. chronic infections have been seen in immunocompromised patients [234] . each virus may produce one or more of the aforementioned manifestations; however, some serotypes are often associated with particular features ( table 7) . the definitive diagnosis of npev infection relies on pcr or virus isolation from the cerebrospinal fluid, blood, stools, urine, or throat swab [229, 235] . treatment of npevs is mainly supportive since most infections are self-limited. high doses of intravenous immunoglobulin (ivig) are recommended in patients with severe symptoms. the efficacy of some new antiviral drugs (pleconaril, vapendavir, and pocapavir) is still under investigation [236] . no vaccine has been licensed yet for npevs. however, phase 3 clinical trials of inactivated monovalent ev-a71 vaccines manufactured in china showed high efficacy against ev-a71 in infants and young children [237] . patients with a variety of pidds are unusually susceptible to ev [238] . the most susceptible groups are patients with primary antibody deficiency such as xla, cvid, and hyper-igm syndrome (higms) as well as those having scid and major histocompatibility class ii deficiency [239, 240] . the most severe form of infection has been described in patients with xla due to the profound deficiency of immunoglobulins essential for viral neutralization during infection. affected patients usually present with indolent but relentlessly progressive non-necrotizing meningoencephalitis. regression of cognitive skills, flaccid quadriplegia, and deafness has been described. the reported non-neurologic presentations in xla include septicemia, dermatomyositis-like disease, hepatitis, and/or arthritis [238, 241] . the incidence of npev meningoencephalitis in large registries of xla cases is 1-4% [242] . unpublished data from the kuwait national pidd registry, which includes 271 pidd patients, showed that nine patients had documented npev infections and two died from these infections. the two deaths were seen in scid patients (personal communication with prof. waleed al-herz, md). in addition, npev meningoencephalitis and/or septicemia were reported in few cases with either primary b cell deficiency such as b cell linker (blink) protein deficiency [243] or acquired b cell deficiency following the administration of anti-cd20 (rituximab) [244, 245] . in all reports, better outcome was attributed to the early administration of high doses of ivig during npev viremia [246] . npev infection in pidd diseases remains a major threat to patients. also, the possible prolonged viral excretion and the emergence of resistant strains runs the risk of spreading infection to the surrounding community. oral polio vaccine (opv) consists of a mixture of three live attenuated poliovirus serotypes. opv induces production of neutralizing antibodies against all three serotypes, in addition to a local intestinal immune response. opv can result in vaccine-associated paralysis (vap) secondary to reversion of the vaccine strain to the neurovirulent wild-type strain. an example for such an event was demonstrated by the 2000-2001 outbreak in the dominican republic and haiti [247] , believed to be driven at least in part by undervaccination of the population, which allowed the spread of the reverted vaccine strain [248] . although rare, patients with pidd have a higher risk to develop vap. reports have shown that pidd patients with antibody deficiency can have prolonged viral replication which can persist for years and therefore theoretically increase the risk for a spontaneous reversion within the immunodeficient host [249] [250] [251] [252] . cases of vap were shown in patients with antibody deficiency and combined immunodeficiency syndromes [248, 253, 254] . therefore, opv is contraindicated in patients with pidd, and this contraindication extends to their household contacts [22] . beyond the obvious risk for the pidd patient, prolonged virus shedding also increase the risk for spreading vaccine-derived paralytic strain in the general population. bacterial infections have molded human behavior and altered societies over human history. today, largely ignored due to antibiotic susceptibility, they continue to cause misery and disease around the world. three infections are highlighted, and additional commonly encountered infections are listed in table 8 . pertussis is a respiratory infection caused by bordetella pertussis that begins after a 7-to 10-day incubation period as a minor upper respiratory infection that progresses with cough. initially intermittent, it evolves into paroxysmal coughing spells usually followed by vomiting in infants and young children. it lasts 6 to 10 weeks and can have many complications such as syncope, weight loss, rib fracture, and pneumonia. infants under 6 months are more severely affected, developing pneumonia, pulmonary hypertension, hypoxia, subdural bleeding, and seizures. death can occur, especially in young infants [255, 256] . adults typically have a prolonged cough with fewer complications [257] . it is transmitted via aerosolized droplets during close contact. people are most contagious during the catarrhal stage and the first half of the paroxysmal phase, totaling 5 to 6 weeks [258] . the introduction of whole-cell pertussis vaccine (dpt) in the 1940s in the usa reduced the incidence of the disease from 250,000 cases to around 1000 cases per year in the 1970s. a resurgence in 2012 was associated with the substitution of the whole-cell vaccine by the acellular pertussis vaccine (dtap) [258] . new strategies such as boosters with acellular pertussis for adolescents and adults with tdap and use of tdap during pregnancy seem to be effective in partially reducing the incidence of the disease [259] ; however, pertussis cases in the usa remain higher than the 1970s. the lack of persistence of antibody in the adult population means adults not only represent a reservoir for the disease but also do not provide sufficient titers to immunoglobulin products prepared from adult plasma pools. a relatively recent requirement in some countries is vaccination of adults every 10 years to maintain immunity. this should, over time, improve titers in immunoglobulin products. culture of specimens obtained by nasopharyngeal swabs is the gold standard of laboratory diagnosis due to the 100% specificity, but polymerase chain reaction (pcr) is gaining prominence due to its higher sensitivity and speed of results; serodiagnosis can be used in the late stages of the disease [259] . filamentous hemagglutinin (fha) and pertussis toxin (pt) antibodies were detected at peak measurements in pidd patients on regular ivig, although some of them had pt antibodies below the protective level as trough measurements [260] . severe pertussis cases have not been reported in pidd patients, but severe disease has been seen in malignancies [261] . antimicrobials such as azithromycin, erythromycin, and clarithromycin, if given during the catarrhal stage, may ameliorate the disease and shorten the contagious period. to avoid cases of pertussis, it is also worth emphasizing the importance of good vaccine coverage rate among the whole population, but especially among healthcare workers and family members of patients with pidd. neisseria meningitidis the onset of neisserial meningitis is associated with sore throat, headache, drowsiness, fever, irritability, and neck stiffness [262, 263] . purpuric lesions are very characteristic. this pathogen can also present with sepsis which has a 20% mortality rate as opposed to 11% mortality with a meningitic presentation. this bacterium can also cause a chronic condition referred to as chronic meningococcemia. this condition is characterized by intermittent fevers lasting 1 week to 3-4 months [264] . a non-purpuric rash is common which may evolve into purpura. arthritis, similar to that seen with gonococcus, is common. meningococcal disease primarily affects children under 5 years of age. n. meningitidis is a global pathogen [265] . there are 12 serogroups, but the majority of invasive meningococcal infections are caused by organisms from the a, b, c, x, y, or w serogroups. the annual number of invasive disease cases worldwide is estimated to be at least 1.2 million, with 135,000 deaths related to invasive meningococcal disease. serogroups b and c are responsible for most infections in europe. serogroup a has historically been the major organism in africa; mass vaccination has led to some improvement, but the emergence of group x disease is worrisome. the hajj in the middle east has seen epidemics of w-135, and vaccination is now required for hajj travelers. b and c serogroups are the most common through the americas. n. meningitidis cases occur at a rate of about 1 case per 100,000 people throughout the world [266] , but across the sahel of africa and in china, epidemics can lead to case rates of 500 per 100,000 [267] . the bacterium is a natural human commensal, with carriage rates of about 10%. diagnosis can be by clinical examination in epidemics or by gram stain and culture. complement-deficient individuals have an increased risk of neisserial disease, but not necessarily increased mortality. hiv is associated with increased disease, suggesting that t cells are also important for defense. thirdgeneration cephalosporins are typically used for treatment. penicillin, ampicillin, aztreonam, and chloramphenicol are alternatives. there is great inter-individual variability in the development of tb disease. roughly, 5% of infected individuals develop clinical disease within 2 years of infection (mostly during childhood). about 90% became latently infected without clinical disease, and the remaining 5 to 10% develop pulmonary tb later in life, either from reactivation of latent infection or reinfection. molecular epidemiology studies from high burden areas suggest more disease results from recent transmission than from reactivation of latent tb, particularly in people living with hiv [268] . acquired or inherited host factors may at least partially account for the variable disease course, resulting in increased susceptibility to mycobacteria infections [269] . pidd associated with tb and ntm infections include t cell deficiencies, gata2 deficiency, cgd, anhidrotic ectodermal dysplasia with immunodeficiency, x-linked (xl) recessive cd40 ligand deficiency, autosomal recessive (ar) stat1 deficiency, ar irf8 deficiency, and ar tyk2 deficiency. in addition, a group of disorders with a strong susceptibility to ntm, named mendelian susceptibility to mycobacterial diseases (msmd), have been recognized since the 1990s. these are rare inborn errors of ifn-γ signaling pathway that present with isolated predisposition to infections caused by weakly virulent mycobacteria such as bcg vaccine and environmental ntm, in otherwise healthy patients. the genetic defects involve impairment in the production of interferons (ar il12rβ1, ar il12p40, autosomal dominant (ad) irf8, ar isg15, xl recessive nemo) or response to interferons (ifn-γr, ad stat1, ad irf8, cgd) [270] . an acquired form exits: adults with ntm infection in thailand and taiwan were found to have high-titer anti-interferongamma antibody [271] . these individuals from southeast asia were found to have hla-drb1*1502/16:02 and dqb1*05:01/05:02. patients suspected of having pulmonary tb should have acid-fast bacilli (afb) smear microscopy and culture performed in three sputum samples. pcr for mtb can be performed [272] . the use of rapid tests facilitates early diagnosis, and the who has recently recommended their use. the only recommended rapid test for detection of tb with and without rifampicin resistance is the xpert mtb/rif assay (cepheid, sunnyvale, ca). the who recommends the xpert test for those suspected of having drug-resistant tb or in hiv; however, culture is still the mainstay and is not replaced by the xpert test. tb skin testing (mantoux testing) uses a purified protein derivative injected under the skin. its advantages are that it can be used for large-scale screening and it is cost effective. skin testing does have several disadvantages when used as a diagnostic test. reading the induration requires training and immunodeficiencies can alter the magnitude of the induration. immunosuppressed patients (hiv, organ transplant) are considered positive if the induration is ≥5 mm. some immunodeficiencies may completely ablate the response. other causes of false-negative tests are malnutrition, concurrent infection, recent live viral vaccine administration, renal failure, malignancy, medical stress, very elderly, young infants, or with a very recent infection with mtb. conversely, the results may be falsely positive if bcg has been administered. interferon gamma release assays can be used in any setting where skin testing would be done but are considered superior in settings where the patient has had bcg vaccination and, in some cases, where skin testing has been sown to have high false-negative rates. in general, tb treatment for patients with impaired immune response, including pidd, hiv infection, and immunosuppressive therapy, is based on the standard 6-month regimen consisting of a 2-month intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin. decisions regarding treatment duration can be individualized, taking into account disease severity, organs involved, and response to treatment. significant pharmacological interaction can occur between rifampin-based mtb regimens and immunosuppressive drugs, such as calcineurin inhibitors or rapamycin, requiring strict monitoring of drug plasma concentrations [273] . therapy for ntm is complex with highly variable drug resistance patterns and a need for biological augmentation to effectively clear the organism. aspergillus fumigatus (see above), cryptococcus gattii, histoplasma capsulatum, coccidioides immitis (or c. posadasii), blastomyces dermatitidis, paracoccidioides brasiliensis, emmonsia pasteuriana, and penicillium (talaromyces) marneffei are environmental fungi that are endemic in certain parts of the world (table 9 ). with the exception of penicillium marneffei and emmonsia pasteuriana that only cause disease in profoundly immune compromised individuals, these fungi can cause infection in healthy individuals, ranging from mild, self-limited pulmonary disease to infection that requires antifungal therapy for eradication. on the other hand, patients with acquired defects in cell-mediated immunity such as those infected with hiv, and patients with specific monogenic disorders, particularly those involving the il-12/ ifn-γ/stat signaling pathways, scid, and gata2 depends on underlying state of immunosuppression and magnitude of environmental exposure icl idiopathic cd4 lymphocytopenia, aids acquired immune deficiency syndrome, stat1 signal transducer and activator of transcription 1, gata2 gata binding protein 2, scid severe combined immunodeficiency, cvid common variable immune deficiency, pidd primary immunodeficiency, il12rb1, interleukin-12 receptor subunit beta 1, ifngr1 gamma interferon receptor 1 deficiency, are at high risk of developing life-threatening disseminated infections by these endemic fungi following environmental exposure [42, [274] [275] [276] [277] [278] . diagnosis relies on culture of the corresponding fungus, histopathological demonstration of the fungus-specific characteristic morphologies, and/or surrogate serological and fungal antigen tests. treatment of clinical disease (as opposed to colonization) typically involves an initial induction phase with amphotericin b, followed by long-term azole maintenance therapy and secondary prophylaxis, and prognosis varies significantly depending on the fungal pathogen and underlying pidd. melioidosis is caused by b. pseudomallei, a gram-negative bacteria found in soil and water, in tropical climates of southeast asia and northern australia [279, 280] . melioidosis is an emerging, potentially fatal disease (20% mortality). b. pseudomallei can be transmitted by inhalation, ingestion, or direct contact (through open skin) with contaminated soil or water. animals (sheep, goats, swine, horses, cats, dogs, and cattle) are also susceptible to infection and cases of zoonotic transmission through direct contact of skin lesions with infected animal meat or milk have been described [280] . b. pseudomallei infections are endemic in northern australia and southeast asia. approximately 75% of reported infections occur during the rainy seasons. cases have also been reported in south pacific, africa, india, and the middle east. in temperate areas, infection is extremely rare and is predominantly imported by travellers or immigrants [281] . the incubation period of melioidosis is variable from 1 day to years, although common symptoms develop between 2 and 4 weeks after exposure. melioidosis presents most frequently in adults 40-60 years of age, but can occur in all ages, with one study reporting 5% of cases occurred in children [282] . in australia, the average annual incidence in 2001-2002 was reported as 5.8 cases per 100,000 people [279] . the incidence in indigenous australians was higher at 25.5 cases per 100,000. a case-cluster in an australian community was associated with post-cyclonic flooding. a recent review suggests that b. pseudomallei is increasingly prevalent in the americas, with a mortality rate of 39% [283] . infection in healthy individuals is uncommon, and more than 70% of cases occur in the setting of underlying conditions such as chronic renal disease, diabetes, chronic lung disease, and alcoholism. a recent review of melioidosis in travelers found that 46% of cases were acquired in thailand. symptoms usually started at 23 days (range 1-360 days) after leaving the endemic area. traveller infections were less often associated with predisposing risk factors (37.5%), diabetes mellitus being the most common (21%). melioidosis in travelers had lower mortality (17%) than infection in autochthonous cases in southeast asia [284] . pneumonia (~50-55%) is the most common presentation in adults. there is usually high fever, headache, anorexia, and myalgia. b. pseudomallei infection may also present as localized skin infection, septicemia, or disseminated infection. localized infection results in an ulcer, nodule, or skin abscess. this usually occurs from the bacterium breaching through a break in the skin. patients with renal disease and diabetes are more susceptible to sepsis. in disseminated infection, abscesses may develop in the liver, spleen, lung, and prostate. in children, primary cutaneous melioidosis is the commonest presentation (60%). bacteremia is less common in children than in adults, but brainstem encephalitis has been reported [282] . difficulties in laboratory diagnosis of melioidosis may delay treatment and affect disease outcomes [285] . diagnosis of melioidosis is primarily by isolation of the organism. identification of b. pseudomallei can be difficult in clinical microbiology laboratories, especially in non-endemic areas where clinical suspicion is low. although various serological tests have been developed, they are generally unstandardized bin house^assays with low sensitivities and specificities. pcr assays have been applied to clinical and environmental specimens but are not widely available and sensitivity remains to be evaluated. cases of melioidosis have been reported in patients with acquired or inherited immune deficiency. melioidosis was the presenting complaint in several patients with cgd. bacteremic melioidosis was recently reported in two patients with prolonged neutropenia, who succumbed despite appropriate antibiotics [286] . it is likely that there is increased susceptibility in situations where innate or adaptive immunity is compromised. treatment is with intravenous antimicrobial therapy for 10-14 days, followed by 3-6 months of oral antimicrobial therapy. intravenous therapy with ceftazidime or meropenem is usually effective. oral therapy may continue with trimethoprim-sulfamethoxazole or doxycycline. free-living amoebas (fla) are protozoa found worldwide that do not require hosts to survive. fla do not employ vectors for transmission and are not well adapted to parasitism in humans. however, there are four genera/species that can cause human disease: naegleria (n. fowleri), acanthamoeba (multiple species), balamuthia (b. mandrillaris), and sappinia (s. pedata). all of these amoebae are capable of inducing cns disease in humans, but acanthamoeba species also cause various extra-cns infections, especially in immunocompromised hosts. the fla that are pathogenic in humans are reviewed below. naegleria are a diverse group of fla flagellate protozoans with a large number of distinct species. only one species, n. fowleri, has been shown to cause infection in humans. n. fowleri has a multi-stage life cycle with amoeboid and trophozoite-infective forms as well as a cyst form [287] . n. fowleri is found commonly in warm freshwater around the world including lakes, rivers, and hot springs. humans become can become infected when swimming or diving in contaminated water. in rare circumstances, infections have also been attributed to exposure from contaminated tap water sources when utilized for religious cleansing of the nose or irrigation of the sinuses. thus, tap water should not be used for nasal and sinus irrigation. it is not possible to become infected from drinking contaminated water or from contact with an infected person, and the amoeba is not found in salt water. after entry to the nasal cavity, the amoeba travels through the cribiform plate to the olfactory bulbs and migrates to the cerebellum, resulting in primary amoebic meningoencephalitis (pam), a rapidly fatal brain infection characterized by the destruction of brain tissue. in its initial presentation, pam can mimic bacterial meningitis, further delaying accurate diagnosis and initiation of therapies that may save the patient. overall, n. fowleri infections are rare. worldwide, most cases are reported in the usa, australia, and europe; however, in developing countries, it is suspected that a large number of cases go unreported. between 2006 and 2015, there were only 37 infections reported in the usa with 33 of the cases attributed to contaminated recreational water, 3 infections following nasal irrigation with contaminated tap water, and 1 case where a person was infected following use of a backyard slipn-slide utilizing contaminated tap water [288] . the fatality rate associated with n. fowleri infection is over 95%, and between 1962 and 2015, only 3 of the 138 infected persons in the usa have survived infection. initial symptoms of pam start 1 to 9 days after infection and can include headache, fever, nausea, or vomiting [288] . progressive symptoms can include stiff neck, confusion, lack of attention, loss of balance, seizures, and hallucinations. cardiac arrhythmias have also been observed. the infection progresses rapidly after initial onset and causes death within 1 to 12 days after exposure (mean of 9.9 days). since infection often progresses rapidly to death, there is often insufficient time to mount a robust immune response. however, both the innate (neutrophils, macrophages, and complement system) and the adaptive (both t and b cells) arms of the immune system have been shown to participate in the immune response to n. fowleri [289] . patients with pam have csf with elevated pressure that is often cloudy or hemorrhagic, with neutrophil-predominant pleiocytosis, elevated protein levels, and very low glucose. wet mounts from centrifuged csf will show motile mono-nucleated trophozoites measuring~10-25 μm in size. additionally, trophozoites can be identified with giemsa and wright stains of csf smears combined with an enflagellation test [289] . confirmation can be achieved via a variety of timeconsuming methods including an immunofluorescence assay [290] , culture of csf [291] , or pcr-based methods [292] . the optimal therapy for n. fowleri pam is still debated. the use of intravenous amphotericin b and fluconazole followed by oral administration of rifampin resulted in survival of a 10year-old child with pam [293] . another child was shown to survive following intravenous and intrathecal amphotericin b and miconazole as well as oral rifampin [294] . most recently, an adolescent girl was successfully treated with the combination of azithromycin, rifampin, fluconazole, and miltefosine [295] . prevention is critical for this highly fatal infection and warning pidd patients not to use tap water for nasal irrigation is important. since its original description in 1986, over 200 cases of b. mandrillaris infections have been described worldwidewith most cases occurring in south america and the usa. balamuthia are found in soil, and acquisition of disease has been associated with agricultural activities, dirt-biking, gardening, and swimming in contaminated water sources. b. mandrillaris is thought to enter the body of the host through breaks in the skin and or via inhalation. the organism is believed to access the cns through hematogenous spread, resulting in a chronic, insidious, but often fatal granulomatous amoebic encephalitis (gae), which has been documented in both immunocompetent and immunocompromised hosts [291, 296] . the incubation period from exposure to development of clinical symptoms is not well established and experts believe that this may occur between 2 months and 2 years. finally, an alternative mode of transmission via solid organ transplantation has also gained attention [297] [298] [299] . in many cases, gae is diagnosed post-mortem, due to delayed diagnosis or unawareness of the clinical entity. following infection by b. mandrillaris, two clinical patterns of presentation have been described. in the first pattern, patients initially develop a skin lesion that may resemble a painless plaque that may evolve into subcutaneous nodules and rarely ulcerations [300] . these patients may develop neurologic manifestations weeks to months later. histopathologic examination of these lesions typically reveals granulomatous reactions in the reticular dermis, associated with lymphocytic and plasma cell infiltrates as well as multinucleated giant cells, without distinct epidermal changes. skin lesions will harbor trophozoites, but these are scarce and often easily overlooked as they resemble histiocytes. it is believed that early diagnosis of b. mandrillaris infections in those presenting with skin lesions may prevent subsequent development of cns disease, but there have also been cases in which patients presenting with skin lesions have progressed to developing gae despite treatment. in the second pattern, patients present with cns involvement without a previously recognized skin lesion. patients presenting with gae may initially display fever, malaise, headache, nausea and vomiting, and frank lethargy. later, these symptoms evolve into visual abnormalities, cranial nerve palsies, seizures, focal paresis; as intracranial pressure builds, coma, and eventually death with tonsilar or uncal herniation ensue within 2-3 weeks [301] . upon infection with b. mandrillaris, brain endothelial cells produce the proinflammatory cytokine il-6, thereby initiating an inflammatory response [302] . moreover, the amoebic trophozoites infiltrate blood vessel walls. degradative enzymes, vessel wall infiltration, and the host inflammatory responses result in tissue necrosis and infarctions in the cerebral hemispheres, cerebellum, and the brainstem. in a mouse model of b. mandrillaris infection, cd4+ t cells were shown to be protective [303] , suggesting that patients with lowered number or dysfunction in cd4+ t cells may be more susceptible to disease by this amoeba. however, b. mandrillaris infections have been described in a variety of human hosts [304] , ranging from the young, healthy, and presumably immunocompetent to the elderly, and those with hiv, chronic corticosteroid exposure, on post-transplant immunosuppression and even patients with cvid. as such, further research is necessary to fully delineate the susceptibility of pidd patients. in patients who develop the characteristic skin lesions, recognition, testing, and treatment for b. mandrillaris may prevent subsequent gae. as such, obtaining tissue and looking for granulomas and trophozoites is quite helpful. skin biopsies can be stained via immunofluorescence or immunoperoxidase techniques to identify b. mandrillaris [305] . additionally, a pcr technique that identifies mitochondrial 16s ribosomal rna from b. mandrillaris is also available through the cdc [306] . in patients in whom the diagnosis is confirmed via skin biopsy, wide resection and medical treatment appears to prevent development of cns disease in at least a proportion of patients. in patients presenting with cns involvement, lumbar punctures reveal csf with lymphocytic pleiocytosis, low-to-normal glucose, and mildly to significantly elevated protein levels. trophozoites are not typically found in the csf, but pcr analysis may be performed. ct or mr imaging may show multiple nodules with ring enhancement; some of these nodules may also contain focal areas of hemorrhage. biopsies of brain tissues typically reveal granulomas and foamy macrophages and multinucleated giant cells surrounded by lymphocytic infiltrates. additionally, there will be areas of necrosis filled with neutrophils, multinucleated giant cells, and lymphocytes, with balamuthia trophozoites and cysts interspersed with macrophages [16] . as with the skin biopsies, immunofluorescent and immunoperoxidase stains may aid diagnosis and should be performed. unfortunately, the optimal medical management of cns disease is unknown. in the usa, a few patients have been successfully treated with a combination of fluconazole, flucytosine, pentamidine, a macrolide antibiotic (either clarithromycin or azithromycin), and one of the following agents: liposomal amphotericin b, miltefosine, sulfadiazine, or thoridazine [307] [308] [309] ; others in peru have been treated successfully with fluconazole (or itraconazole), albendazole, and miltefosine [307] . based on these case reports, most experts recommend treatment with a combination of medications (along with partial or complete resection of nodules) for a prolonged period of time to prevent further deterioration and death [307] [308] [309] [310] . acanthamoeba spp. the genus acanthamoeba contains at least 24 morphologically distinct species that live in a diverse array of habitats, including soil, salt, brackish, and fresh water. acanthamoeba spp. have also been found in humidifiers, heating and cooling unit components, jacuzzis, hot water tanks, bathrooms and drains, eye wash stations and dentistry irrigation systems, and more. acanthamoeba spp. have been isolated from reptiles, birds, and other non-human mammals, suggesting a broad distribution in the environment. acanthamoeba trophozoites feed on bacteria, but have also recently been shown to harbor a number of bacteria (including legionella and burkholderia spp., e. coli, listeria monocytogenes, vibrio cholerae, mycobacteria spp., chlamydophila, and others) and at least one virus (mimivirus) as endosymbionts. acanthamoeba infections in humans can present in a variety of ways. of primary importance are cns infections. like b. mandrillaris, acanthamoeba spp. can induce gae (described above). there is a high predilection for gae in those with hiv/aids, patients on chemotherapy, and those receiving broad spectrum antibiotics [301] . acanthamoeba are rarely found in csf, but some case reports indicate isolation of amoebae by culturing csf on bacterized agar plates. similar to gae seen with b. mandrillaris, cns histopathology may reveal edema, multiple areas of necrosis and hemorrhage, and occasional findings of angitis and blood vessel cuffing by inflammatory cells, as well as occasional trophozoites or cysts. cns disease treatment is not standardized, but several patients have been successfully treated with pentamidine, fluconazole, flucytosine, sulfadiazine, as well as miltefosine. acanthamoeba can rarely cause cutaneous infections; these lesions, like gae, are also predominantly seen in immunocompromised hosts. these lesions can start as nodules or papules on the lower extremities and develop into necrotic ulcers. histopathologic examination may reveal granulomatous dermal lesions in immunocompetent hosts, with histiocytes, as well as neutrophils and plasmacytes; trophozoites are typically visible [311, 312] . the optimal management of cutaneous disease is not known, but typically involves combinational therapy with topical (e.g., chlorhexidine, gluconate, or ketoconazole) and systemic (miltefosine, sulfadiazine, flucytosine, liposomal amphotericin b, azole antifungals, etc.) drugs. additionally, nasopharyngeal and sinus infections have been seen in people with severe compromise in immunity [313, 314] . patients typically present with purulent nasal discharge, and examination may reveal erosion of the nasal septum. nasopharyngeal disease can present concomitantly with cutaneous disease. treatment of nasopharyngeal or sinus disease is difficult and involves surgical debridement and combinations of systemic drugs. disseminated disease is also seen in immunocompromised hosts and typically involves concomitant pulmonary and cutaneous disease in the presence or absence of cns infection. keratitis readily occurs in immunocompetent hosts-with the major risk factor being contact lens wearing without proper adherence to recommended cleansing protocols. this infection less commonly presents as a result of direct inoculation with trauma. one of the most common reasons for contact lens wearers to acquire disease is due to the use of non-sterile tap water in preparing contact lens saline solutions [315] , although contaminated solutions from manufacturers have also been identified. patients will have pain and photophobia. physical exam reveals conjunctival injection and epithelial abnormalities (including pseudodendritic lesions) and stromal infiltrates [316] . the proper diagnosis can be made by staining corneal scrapings with calcofluor or wright-giemsa stains and examined by confocal microscopy, culture, or pcr analysis. prompt therapy with a combination of polyhexamethylene biguanide (or biguanide-chlorhexidine) and propamidine or hexamidine [317, 318] is indicated, but misdiagnosis and delayed therapy are common. more severe cases may also require debridement. the use of topical steroids before administration of combinational therapy may result in worse outcomes and should be avoided; however, if scleritis ensues, it may be necessary to use immunosuppressants to reduce the need for enucleation. severe and/or refractory cases may result in the need for cornea transplantation. phenotypes seen in pidd like hsv-1 and candida [337] . patients with ifnar2 deficiency seem highly susceptible to cns disease caused by mmr vaccine, an otherwise extremely rare phenomenon [187] . recently, a case of noroviral cns disease was described associated with a novel, yet unpublished pidd, suggesting that some pidds may lead to susceptibility of the cns to viruses that normally do not exhibit neurotropism (casanova jl, personal communication) . this again favors metagenomic approaches in the study of cns sequelae in pidd patients. in pidds, the cns is also more vulnerable to virally induced immunodysregulation [325] . conditions like primary hemophagocytic lymphohistiocytosis (hlh) may present as isolated cns disease or relapse only in the cns [338] [339] [340] . almost 20% all human malignancies are associated with chronic infections by hbv, hcv, hpv, ebv, hhv8/kshv, htlv-i, hiv-1, hiv-2, jcv, merkel cell polyomavirus (mcpv), helicobacter pylori, schistosomes, or liver flukes [341] . accordingly, pidd patients' malignancies are often associated with chronic infections. mcpv-associated merkel cell carcinoma has now been described in gata2 and tmc8 (ever2) deficiencies as well as other forms of pidd [330, [342] [343] [344] [345] [346] . large follow-up cohorts are needed to refute or confirm associations between novel pidds and malignancies, such as hyperactivating pik3cd and ovarian dysgerminoma or gata2 deficiency and leiomyosarcoma [329, 347] . recently, hymenolepis nana was found to have driven malignant transformation in an hiv patient. likely, other novel pidd-and pathogen-associated malignancies will be found in the future by those with an open and inquisitive mind [348] . understanding the specific infection susceptibility for each pidd allows not only a better understanding of host defense, but also allows the clinician to collaborate with the microbiology laboratory to make definitive diagnoses and provide the best therapy. reviewing all of the infections for each pidd is not within the scope of this article, but there are several infections that are unique for specific pidds and require special attention from the microbiology laboratory. three examples are provided below. g. bethesdensis is a gram-negative bacterium that was identified to cause disease in patients with cgd in 2006 [349] . g. bethesdensis is a member of the methylotroph group of bacteria, which are able to use single-carbon organic compounds as their only source of energy. they are widespread in the environment, but are rare human pathogens, and infections with g. bethesdensis have been limited thus far to patients with cgd. the organism was first detected in an adult patient with indolent and recurrent necrotizing lymphadenitis [349] . subsequently, g. bethesdensis was isolated from nine patients with cgd, primarily causing lymphadenitis, but there have been two fatalities [350] . treatment has been most effective with intravenous ceftriaxone. the microbiology laboratory should be alerted when there is concern for g. bethesdensis infection to allow for proper culture media. charcoal yeast extract (cye) agar and lowenstein jensen (lj) media are appropriate culture media. mycoplasma and ureaplasma spp. as molecular techniques are becoming more widely used to detect pathogens, the spectrum of infections that were previously only detected through serologic assays and research laboratories will increase. this is important especially for patients with pidd who have unique susceptibility to infection and may not have the ability to mount a serologic response. examples of infections in this group are those caused by mycoplasma and ureaplasma [351, 352] . these pathogens have been known to cause osteoarticular infections for those with antibody deficiency, such as xla and cvid. recently, mycoplasma orale, typically an oral commensal, has been isolated from two patients with defects in the activated pi3k delta syndrome, as chronic lymphadenitis in one and chronic splenic abscess in the other (sm holland personal communication). defects in pi3kcd and pi3kr are frequently associated with hypogammaglobulinemia and therefore would fit in the pattern of mycoplasma infections in those with humoral immunodeficiency. mycoplasma orale has also previously been reported as causing bone disease in a patient with cvid [353] . in patients with xla, helicobacter, camplyobacter, and the related flexispira bacteria that are typically isolated to the gi tract can disseminate and often lead to chronic bacteremia, ulcers, and bone infections [354] [355] [356] . xla patients have higher susceptibility than other humoral pidd and are thought to be due to the role that igm is playing in controlling the dissemination of these pathogens and potentially iga in providing mucosal immunity. these bacteria can be fastidious to grow, and therefore, when there is suspicion, identification needs collaboration with the microbiology laboratory. for instance, the blood culture media may allow growth (although with a longer incubation period), but then the organisms may need molecular techniques for identification, such as 16 s sequencing, as they will not grow on the agar plates. treatment is often difficult, requiring combination antimicrobials for prolonged periods (such as 1 year), and relapse is common. this review provides an important perspective for practicing immunologists, namely that we are a part of a global community as are our patients. this overview of emerging infections and infectious concerns for travelers serves as a foundation for practical considerations for clinicians and patients. using prevalence data, an estimation of the number of infected patients with pidd (table 10) can be developed [25, 130, [357] [358] [359] [360] . thus, the concerns addressed in this review are not theoretical but impact a considerable number of patients already. the landscape of emerging infections is by its nature highly dynamic. during the preparation of this manuscript, a mumps outbreak in the usa occurred, a new bunyavirus outbreak causing an hlh picture was reported (severe fever with thrombocytopenia syndrome), a new outbreak of the hantavirus seoul virus occurred, and an enlarging demographic of the h7n9 influenza virus was reported. this review lists several resources, many of which are updated in real time to support efforts to provide information to patients. doctor's guide alerts can be sent weekly to provide updates on current outbreaks around the world. approach to fever in the returning traveler potential changes in disease patterns and pharmaceutical use in response to climate change climate change 2014: 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verruciformis merkel cell polyomavirus detection in a patient with familial epidermodysplasia verruciformis merkel cell polyomavirus-positive merkel cell carcinoma in a patient with epidermodysplasia verruciformis merkel cell polyomavirus in merkel cell carcinoma from a brazilian epidermodysplasia verruciformis patient association of gata2 deficiency with severe primary epstein-barr virus (ebv) infection and ebv-associated cancers malignant transformation of hymenolepis nana in a human host granulibacter bethesdensis gen. nov., sp. nov., a distinctive pathogenic acetic acid bacterium in the family acetobacteraceae methylotroph infections and chronic granulomatous disease osteoarticular infectious complications in patients with primary immunodeficiencies increased susceptibility to mycoplasma infection in patients with hypogammaglobulinemia disseminated mycoplasma orale infection in a patient with common variable immunodeficiency syndrome relapsing campylobacter jejuni systemic infections in a child with x-linked agammaglobulinemia bacteremia and skin/bone infections in two patients with x-linked agammaglobulinemia caused by an unusual organism related to flexispira/helicobacter species successful approach to treatment of helicobacter bilis infection in x-linked agammaglobulinemia prevalence and morbidity of primary immunodeficiency diseases, united states epidemiological characteristics of spotted fever in israel over 26 years complications of bacille calmette-guerin (bcg) vaccination and immunotherapy and their management acknowledgements the authors would like to thank thomas krell for information regarding ivig safety and david peden for recognizing global warming as central to medical knowledge. conflict of interest the authors declared that they have no conflict of interest. pidds display wide genetic and phenotypic heterogeneity [319] . similar disease phenotypes may be caused by multiple genes, while patients' phenotypes caused by the same gene and even by the same mutations vary between individuals. importantly, after a novel pidd has been described, subsequent reports often reveal a wider variation in associated infections and cellular findings, often without clear genotype-phenotype correlations [320] [321] [322] [323] [324] . variation may be caused by mechanisms such as other contributing genes or geographical variation in infectious exposures. geographic differences seem most pronounced in intracellular and often chronic infections. while the numbers of described pidd patients increase, at first seemingly rarely pidd-associated infections turn out to be found in a significant subset of pidd patients [325] [326] [327] . for example, patients with cd40l deficiency living in endemic areas display susceptibility to bartonellosis and paracoccidioidomycosis, infections not described in european and us cohorts [157, 328, 329] .often, an infectious phenotype previously only described in secondary immunodeficiencies may reveal the possibility of an underlying primary immunodeficiency [327, 330, 331] . increasing numbers of genetic defects causing early-onset, severe, and recurrent susceptibility to commonly circulating pathogens like pneumococci, tuberculosis, herpes simplex, and influenza viruses as well as endemic protozoans like trypanosomes and fungi are being recognized, and thus, infections with unusual pathogens require a high index of suspicion for pidd [332] . in contrast, pidds may also manifest as suspected infection but sterile inflammation. for example, in inflammatory lesions like granulomas and necrotizing fasciitis where no clear pathogens are found, one needs to rule out aberrant host responses due to pidd [333] .chronic viral and fungal infections may also display novel phenotypes never or rarely seen in secondary immunodefic i e n c i e s . i n f e c t i o n s l i k e d e r m a t o p h y t o s i s a n d phaeohyphomycosis deeply infiltrating the skin and lymph nodes, occasionally extending to bones and central nervous system (cns) as well as predisposition to primary cns candidiasis and extrapulmonary aspergillus slowly revealed the full phenotypic spectrum of card9 deficiency [44, 324, 334] . chronic skin ulcers caused by hsv-1 and severe molluscum contagiosum suggest dock8 deficiency or gain-of-function mutations of stat1 [320, 323] . chronic mucocutaneous candidiasis has revealed a large group of monogenic diseases (il17ra, il17rc, il17f, stat1 (gof), rorx, act1), which may also be associated with recurrent bacterial infections or syndromic features [335] . while novel diseases by newly described viruses are being discovered, one needs awareness to suspect these in pidd patients [336] .interestingly, most novel forms of infectious disease in pidd patients have been described either in easily accessible sites like the skin or in immunologically privileged, normally sterile sites like the cns. this suggests that with the increasing use of invasive sampling and sensitive metagenomic approaches, we might find more novel infectious phenotypes. pathogens highly suggestive of certain pidds, like chronic enteroviral cns infections in xla patients are reviewed above. in hypomorphic mutations, cns seems to be especially vulnerable to chronically active and/or recurrent novel infectious bsmoldering^focal encephalitis lesions by pathogens key: cord-288183-pz3t29a7 authors: mckibbin, warwick j.; wilcoxen, peter j. title: chapter 15 a global approach to energy and the environment the g-cubed model date: 2013-12-31 journal: handbook of computable general equilibrium modeling doi: 10.1016/b978-0-444-59568-3.00015-8 sha: doc_id: 288183 cord_uid: pz3t29a7 abstract g-cubed is a multi-country, multi-sector, intertemporal general equilibrium model that has been used to study a variety of policies in the areas of environmental regulation, tax reform, monetary and fiscal policy, and international trade. it is designed to bridge the gaps between three areas of research – econometric general equilibrium modeling, international trade theory, and modern macroeconomics – by incorporating the best features of each. this chapter describes the theoretical and empirical structure of the model, summarizes its applications and contributions to the literature, and discusses two example applications in detail. from the trade literature, g-cubed takes the approach of modeling the world economy as a set of autonomous regions e 12 in the version used in this paper e interacting through bilateral trade flows. 3 following the armington approach (armington, 1969) , goods produced in different regions are treated as imperfect substitutes. 4 unlike most trade models, however, g-cubed distinguishes between financial and physical capital. financial capital is perfectly mobile between sectors and from one region to another, and is driven by forward-looking investors who respond to arbitrage opportunities. physical capital, in contrast, is perfectly immobile once it has been installed: it cannot be moved from one sector to another or from one region to another. in addition, intertemporal budget constraints are imposed on each region: all trade deficits must eventually be repaid by future trade surpluses. drawing on the general equilibrium literature, g-cubed represents each region by its own multisector econometric general equilibrium model. 5 production is broken down into n industries and each is represented by an econometrically estimated cost function. unlike many general equilibrium models, however, g-cubed draws on macroeconomic theory by representing saving and investment as the result of forwardlooking intertemporal optimization. households maximize an intertemporal utility function subject to a lifetime budget constraint, which determines the level of saving, and firms choose investment to maximize the stock market value of their equity. 6 finally, g-cubed also draws on the macroeconomic literature by representing international capital flows as the result of intertemporal optimization, and by including liquidityconstrained agents, a transactions-based money demand equation and slow nominal wage adjustment. unlike typical macro models, however, g-cubed has substantial sector detail and many of its parameters are determined by estimation rather than calibration. this combination of features was chosen to make g-cubed versatile. industry detail allows the model to be used to examine environmental and tax policies which tend to have their largest direct effects on small segments of the economy. intertemporal modeling of investment and saving allows g-cubed to trace out the transition of the economy between the short run and the long run. slow wage adjustment and liquidityconstrained agents improves the empirical accuracy with which the model captures the transition. overall, the model is designed to provide a bridge between computable general equilibrium models, international trade models and macroeconomic models by combining key features of each approach. the cost of this versatility is that g-cubed is a fairly large model. it has over 10000 equations holding in each year, is typically solved annually for 100 years in each simulation, and has over 100 intertemporal costate variables. nonetheless, it can be solved using software developed for a personal computer. the key features of g-cubed are summarized in table 15 .1. there are several different versions of g-cubed that have been developed, depending on the question being analyzed. versions have been built with two sectors (macroeconomic issues), six sectors (trade and growth issues), 12 sectors (energy and environmental issues), 21 sectors (india) and 57 sectors (australia). there are also a large number of different country disaggregations. however, all versions of g-cubed are global: each represents the economic activity of all countries in the world, either modeled individually or aggregated into regions. developed and developing countries are modeled in detail, including all trade and financial links between countries. 2 a full menu of financial assets is included and the valuations of those assets are driven by the real economy. 3 international flows of financial capital are modeled. an important distinction is made between the stickiness of physical capital within sectors and within countries and the flexibility of financial capital, which quickly flows to where expected returns are highest. this important distinction leads to a critical difference between the quantity of physical capital that is available at any time to produce goods and services, and the valuation of that capital as a result of decisions about the allocation of financial capital. 4 households and firms are represented as mixtures of two types of agents: one group which bases its decisions on forward-looking expectations and a second group which follows simpler rules of thumb which are optimal in the long run, but not necessarily in the short run. 5 the model allows for short-run wage rigidity (varying in degree across countries) and therefore allows for significant periods of unemployment depending on the labor market institutions in each country. this assumption, when taken together with the explicit modeling of money and other financial assets, gives the model more realistic macroeconomic properties than conventional general equilibrium models. the most frequently used model and the version most relevant for environmental and energy questions is the 12 sector model. in this paper we will focus on the structure and specification of this version of g-cubed. within each region, production is disaggregated into 12 sectors: five energy sectors (electric utilities, natural gas utilities, petroleum refining, coal mining, and crude oil and gas extraction) and seven non-energy sectors (mining, agriculture, forestry and wood products, durable goods, non-durable goods, transportation and services). this disaggregation, summarized in table 15 .2, enables us to capture the sector level differences in the impact of alternative environmental policies. each economy or region in the model consists of several economic agents: households, the government, the financial sector and the 12 production sectors listed above. we now present an overview of the theoretical structure of the model by describing the decisions facing these agents. to keep our notation as simple as possible we have not subscripted variables by country except where needed for clarity. throughout the discussion all quantity variables will be normalized by the economy's endowment of effective labor units. thus, the model's long-run steady state will represent an economy in a balanced growth equilibrium. regions (codes shown in parentheses) 1 us (u or usa) 2 japan (j or jpn) 3 australia (a or aus) 4 western europe (e or euw) 5 rest of the oecd (o or oec) 6 china (c or chi) 7 other developing countries (l or ldc) 8 eastern europe and the former soviet union (b or eeb) 9 oil exporting countries and the middle east (p or opc) sectors 1 electric utilities 2 gas utilities 3 petroleum refining 4 coal mining 5 crude oil and gas extraction 6 other mining 7 agriculture 8 forestry and wood products 9 durable goods 10 non-durables 11 transportation 12 services we assume that each of the 12 sectors can be represented by a price-taking firm, which chooses variable inputs and its level of investment in order to maximize its stock market value. each firm's production technology is represented by a tier-structured constant elasticity of substitution (ces) function. at the top tier, output is a function of capital, labor, energy and materials: where q i is the output of industry i, x ij is industry i's use of input j, and ij parameters reflect the weights of different inputs in production; the superscript 'o' indicates that the parameters apply to the top, or 'output', tier. without loss of generality, we constrain the ds to sum to one. at the second tier, inputs of energy and materials, x ie and x im , are themselves ces aggregates of goods and services. energy is an aggregate of goods 1e5 (electricity through crude oil) and materials is an aggregate of goods 7e12 (mining through services). the functional form used for these tiers is identical to (1) except that the parameters of the energy tier are a i e , d e ij and s i e , and those of the materials tier are a i m , d m ij and s i m . the goods and services purchased by firms are, in turn, aggregates of imported and domestic commodities, which are taken to be imperfect substitutes. we assume that all agents in the economy have identical preferences over foreign and domestic varieties of each commodity. we represent these preferences by defining 12 composite commodities that are produced from imported and domestic goods. each of these commodities, y i , is a ces function of inputs domestic output, q i , and imported goods, m i . 7 for example, the petroleum products purchased by agents in the model are a composite of imported and domestic petroleum. by constraining all agents in the model to have the same preferences over the origin of goods we require that, for example, the agricultural and service sectors have the identical preferences over domestic oil and oil imported from the middle east. 8 this accords with the input-output data we use and allows a very convenient nesting of production, investment and consumption decisions. finally, the production function includes one additional feature to allow the model to be used to examine the effects of emissions quotas or tradable permit systems: each input is used in fixed proportions to the use of an input-specific permit. the permits are owned by households and included in household wealth. permit prices are determined endogenously by a competitive market for each type of permit. to run simulations without a permit system, the supply of permits can be set large enough so that the price of a permit goes to zero. in each sector the capital stock changes according to the rate of fixed capital formation ( j i ) and the rate of geometric depreciation (d i ): following the cost of adjustment models of lucas (1967) , treadway (1969) and uzawa (1969) , we assume that the investment process is subject to rising marginal costs of installation. to formalize this we adopt uzawa's approach by assuming that in order to install j units of capital a firm must buy a larger quantity, i, that depends on its rate of investment ( j/k): where f is a non-negative parameter. the difference between j and i may be interpreted various ways; we will view it as installation services provided by the capital-goods vendor. the goal of each firm is to choose its investment and inputs of labor, materials and energy to maximize intertemporal risk-adjusted net of tax profits. for analytical tractability, we assume that this problem is deterministic (equivalently, the firm could be assumed to believe its estimates of future variables with subjective certainty). thus, the firm will maximize: 9 z n t ð1 à s 2 þp i e àðrðsþþm ei ànþðsàtþ ds; (15.4) where m ei is a sector-and region-specific equity risk premium, s 2 is the effective tax rate on capital income, and variables are implicitly subscripted by time. the firm's profits, p, are given by: (15.5) where s 4 is an investment tax credit and p ) is the producer price of the firm's output. r(s) is the long-term interest rate between periods t and s: as all real variables are normalized by the economy's endowment of effective labor units, profits are discounted adjusting for the rate of growth of population plus productivity growth, n. solving the top-tier optimization problem gives the following equations characterizing the firm's behavior: where l i is the shadow value of an additional unit of investment in industry i. equation (15.7) gives the firm's factor demands for labor, energy and materials, and equations (15.8) and (15.9) describe the optimal evolution of the capital stock. by integrating (15.9) along the optimum path of capital accumulation, it is straightforward to show that l i is the increment to the value of the firm from a unit increase in its investment at time t. it is related to q, the after-tax marginal version of tobin's q (abel, 1979) , as follows: (15.12) in order to capture the inertia often observed in empirical investment studies we assume that only fraction a 2 of firms making investment decision use the fully forward-looking tobin's q described above. the remaining (1 e a 2 ) use a slowly-adjusting version, q, driven by a partial adjustment model. in each period, the gap between q and q closes by fraction a 3 : as a result, we modify (15.12) by writing i i as a function not only of q, but also the slowly adjusting q: a global approach to energy and the environment: the g-cubed model this creates inertia in private investment, which improves the model's ability to mimic historical data and is consistent with the existence of firms that are unable to borrow. the weight on unconstrained behavior, a 2 , is taken to be 0.3 based on a range of empirical estimates reported by mckibbin and sachs (1991) . so far we have described the demand for investment goods by each sector. investment goods are supplied, in turn, by a 13th industry that combines capital, labor and the outputs of other industries to produce raw capital goods. we assume that this firm faces an optimization problem identical to those of the other 12 industries: it has a nested ces production function, uses inputs of capital, labor, energy and materials in the top tier, incurs adjustment costs when changing its capital stock, and earns zero profits. the key difference between it and the other sectors is that we use the investment column of the input-output table to estimate its production parameters. households have three distinct activities in the model: they supply labor, they save, and they consume goods and services. within each region we assume household behavior can be modeled by a representative agent with an intertemporal utility function of the form: where c(s) is the household's aggregate consumption of goods and services at time s, g(s) is government consumption at s, which we take to be a measure of public goods provided, and q is the rate of time preference. 10 the household maximizes (15.15) subject to the constraint that the present value of consumption (potentially adjusted by risk premium m h ) be equal to the sum of human wealth, h, and initial financial assets, f: 11 human wealth is defined as the expected present value of the future stream of aftertax labor income plus transfers: (15.17) 10 this specification imposes the restriction that household decisions on the allocations of expenditure among different goods at different points in time be separable. 11 as before, n appears in (15.16) because the model's scaled variables must be converted back to their original basis. where s 1 is the tax rate on labor income, tr is the level of government transfers, l c is the quantity of labor used directly in final consumption, l i is labor used in producing the investment good, l g is government employment, and l i is employment in sector i. financial wealth is the sum of real money balances, mon/p, real government bonds in the hand of the public, b, net holding of claims against foreign residents, a, the value of capital in each sector and holdings of emissions permits, q i p : solving this maximization problem gives the familiar result that aggregate consumption spending is equal to a constant proportion of private wealth, where private wealth is defined as financial wealth plus human wealth: however, based on the evidence cited by campbell and mankiw (1990) and hayashi (1982) we assume some consumers are liquidity-constrained and consume a fixed fraction g of their after-tax income (inc ). 12 denoting the share of consumers who are not constrained e and choose consumption in accordance with (15.19) e by a 8 , total consumption expenditure is given by: the share of households consuming a fixed fraction of their income could also be interpreted as permanent income behavior in which household expectations about income are myopic. once the level of overall consumption has been determined, spending is allocated among goods and services according to a two-tier ces utility function. 13 at the top tier, the demand equations for capital, labor, energy and materials can be shown to be: ; i˛fk; l; e; mg; (15.21) 12 there has been considerable debate about the empirical validity of the permanent income hypothesis. in addition the work of campbell, mankiw and hayashi, other key papers include hall (1978) and flavin (1981) . one side-effect of this specification is that it prevents us from computing equivalent variation. since the behavior of some of the households is inconsistent with (15.19), either because the households are at corner solutions or for some other reason, aggregate behavior is inconsistent with the expenditure function derived from our utility function. 13 the use of the ces function has the undesirable effect of imposing unitary income elasticities, a restriction usually rejected by data. an alternative would be to replace this specification with one derived from the linear expenditure system. a global approach to energy and the environment: the g-cubed model where x ci is household demand for good i, s o c is the top-tier elasticity of substitution and the d ci are the input-specific parameters of the utility function. the price index for consumption, p c , is given by: the demand equations and price indices for the energy and materials tiers are similar. household capital services consist of the service flows of consumer durables plus residential housing. the supply of household capital services is determined by consumers themselves who invest in household capital, k c , in order to generate a desired flow of capital services, c k , according to the following production function: where a is a constant. accumulation of household capital is subject to the condition: we assume that changing the household capital stock is subject to adjustment costs so household spending on investment, i c , is related to j c by: thus, the household's investment decision is to choose i c to maximize: ðp ck ak c à p i i c þe àðrðsþþm z ànþðsàtþ ds; (15.26) where p ck is the imputed rental price of household capital and m z is a risk premium on household capital (possibly zero). this problem is nearly identical to the investment problem faced by firms, including the partial adjustment mechanism outlined in equations 15.13 and 15.14, and the results are very similar. the only important difference is that no variable factors are used in producing household capital services. we assume that labor is perfectly mobile among sectors within each region but is immobile between regions. thus, wages will be equal across sectors within each region, but will generally not be equal between regions. in the long run, labor supply is completely inelastic and is determined by the exogenous rate of population growth. long-run wages adjust to move each region to full employment. in the short run, however, nominal wages are assumed to adjust slowly according to an overlapping contracts model where wages are set based on current and expected inflation and on labor demand relative to labor supply. this can lead to short-run unemployment if unexpected shocks cause the real wage to be too high to clear the labor market. at the same time, employment can temporarily exceed its long-run level if unexpected events cause the real wage to be below its long run equilibrium. we take each region's real government spending on goods and services to be exogenous and assume that it is allocated among inputs in fixed proportions, which we set to 2006 values. total government outlays include purchases of goods and services plus interest payments on government debt, investment tax credits and transfers to households. government revenue comes from sales taxes, capital and labor taxes, and from sales of new government bonds. in addition, there can be taxes on externalities such as carbon dioxide emissions. the government budget constraint may be written in terms of the accumulation of public debt as follows: where b is the stock of debt, d is the budget deficit, g is total government spending on goods and services, tr is transfer payments to households and t is total tax revenue net of any investment tax credit. we assume that agents will not hold government bonds unless they expect the bonds to be paid off eventually and accordingly impose the following transversality condition: lim s/n bðsþe àðrðsþànþs ¼ 0: (15.28) this prevents per capita government debt from growing faster than the interest rate forever. if the government is fully leveraged at all times, (15.28) allows (15.27) to be integrated to give: thus, the current level of debt will always be exactly equal to the present value of future budget surpluses. 14 the implication of (29) is that a government running a budget deficit today must run an appropriate budget surplus as some point in the future. otherwise, the government would be unable to pay interest on the debt and agents would not be willing to hold it. to ensure that (15.29) holds at all points in time we assume that the government levies a lump sum tax in each period equal to the value of interest payments on the outstanding debt. 15 in effect, therefore, any increase in government debt is financed by consols and future taxes are raised enough to accommodate the increased interest costs. other fiscal closure rules are possible, such as requiring the ratio of government debt to gdp to be unchanged in the long run or that the fiscal deficit be exogenous with a lump sum tax ensuring this holds. these closures have interesting implications but are beyond the scope of this paper. the nine regions in the model are linked by flows of goods and assets. flows of goods are determined by the import demands described above. these demands can be summarized in a set of bilateral trade matrices which give the flows of each good between exporting and importing countries. there is one nine by nine trade matrix for each of the 12 goods. trade imbalances are financed by flows of assets between countries. each region with a current account deficit will have a matching capital account surplus, and vice versa. 16 we assume asset markets are perfectly integrated across regions. 17 with free mobility of capital, expected returns on loans denominated in the currencies of the various regions must be equalized period to period according to a set of interest arbitrage relations of the following form: where i k and i j are the interest rates in countries k and j, m k and m j are exogenous risk premiums demanded by investors (possibly zero), and e j k is the exchange rate between the currencies of the two countries. 18 however, in cases where there are institutional rigidities to capital flows, the arbitrage condition does not hold and we replace it with an explicit model of the relevant restrictions (such as capital controls). 15 in the model the tax is actually levied on the difference between interest payments on the debt and what interest payments would have been if the debt had remained at its base case level. the remainder e interest payments on the base case debt e is financed by ordinary taxes. 16 global net flows of private capital are constrained to be zero at all times e the total of all funds borrowed exactly equals the total funds lent. as a theoretical matter this may seem obvious, but it is often violated in international financial data. 17 the mobility of international capital is a subject of considerable debate; see gordon and bovenberg (1994) or feldstein and horioka (1980) . 18 the one exception to this is the oil-exporting region, which we treat as choosing its foreign lending in order to maintain a desired ratio of income to wealth. capital flows may take the form of portfolio investment or direct investment but we assume these are perfectly substitutable ex ante, adjusting to the expected rates of return across economies and across sectors. within each economy, the expected returns to each type of asset are equated by arbitrage, taking into account the costs of adjusting physical capital stock and allowing for exogenous risk premiums. however, because physical capital is costly to adjust, any inflow of financial capital that is invested in physical capital will also be costly to shift once it is in place. this means that unexpected events can cause windfall gains and losses to owners of physical capital, and ex post returns can vary substantially across countries and sectors. for example, if a shock lowers profits in a particular industry, the physical capital stock in the sector will initially be unchanged but its financial value will drop immediately. we assume that money enters the model via a constraint on transactions. 19 we use a money demand function in which the demand for real money balances is a function of the value of aggregate output and short-term nominal interest rates: where y is aggregate output, p is a price index for y, i is the interest rate, and 3 is the interest elasticity of money demand. following mckibbin and sachs (1991) we take 3 to be e0.6. on the supply side, the model includes an endogenous monetary response function for each region. each region's central bank is assumed to adjust short-term nominal interest rates following a hendersonemckibbinetaylor rule as shown in the equation below. the interest rate evolves as a function of actual inflation (p) relative to target inflation (p t ), output growth (dy) relative to growth of potential output (dy t ) and the change in the exchange rate (de) relative to the bank's target change (de t ): the parameters in (32) vary across countries. for example, countries that peg their exchange rate to the us dollar have a very large value of b 3 . to estimate g-cubed's parameters we began by constructing a consistent time series of input-output tables for the us. the procedure is described in detail in and can be summarized as follows. we started with the detailed benchmark us input-output transactions tables produced by the bureau of economic analysis (bea) and converted them to a standard set of industrial classifications and then aggregate them to 12 sectors. 20 then, we corrected the treatment of consumer durables, which are included in consumption rather than investment in the us national income and product accounts (nipas) and the benchmark input-output tables. third, we supplemented the value added rows of the tables using a detailed dataset on capital and labor input by industry constructed by dale jorgenson and his colleagues. 21 finally, we obtained prices for each good in each benchmark year from the output and employment data set constructed by the office of employment projections at the bureau of labor statistics (bls). this dataset allowed us to estimate the model's parameters for the us. to estimate the production side of the model, we began with the energy and materials tiers because they have constant returns to scale and all inputs are variable. in this case it is convenient to replace the production function with its dual unit cost function. for industry i, the unit cost function for energy is: the cost function for materials has a similar form. assuming that the energy and materials nodes earn zero profits, c will be equal to the price of the node's output. using shephard's lemma to derive demand equations for individual commodities and then converting these demands to cost shares gives expressions of the form: where s e ij is the share of industry is spending on energy that is devoted to purchasing input j. 22 a i e , s i e and d ij e were found by estimating (15.33) and (15.34) as a system of equations. 23 estimates of the parameters in the materials tier were found by an analogous approach. 20 converting the data to a standard basis was necessary because the sector definitions and accounting conventions used by the bea have changed over time. 21 primary factors often account for half or more of industry costs so it is particularly important that this part of the data set be constructed as carefully as possible. from the standpoint of estimating cost and production functions, however, value added is the least satisfactory part of the benchmark input-output tables. in the early tables, labor and capital are not disaggregated. in all years, the techniques used by the bea to construct implicit price deflators for labor and capital are subject to various methodological problems. one example is that the income of proprietors is not split between capital and imputed labor income correctly. the jorgenson dataset corrects these problems and is the work of several people over many years. in addition to dale jorgenson, some of the contributors were l. christensen, barbara fraumeni, mun sing ho and dae keun park. the original source of the data is the fourteen components of income tape produced by the bureau of economic analysis. see ho (1989) for more information. 22 when s e is unity, this collapses to the familiar cobbedouglas result that s ¼ d and is independent of prices. 23 for factors for which the value of s was consistently very small, we set the corresponding input to zero and estimated the production function over the remaining inputs. the output node must be treated differently because it includes capital, which is not variable in the short run. we assume that the firm chooses output, q i , and its top-tier variable inputs (l, e and m) to maximize its restricted profit function, p: where the summation is taken over all inputs other than capital. inserting the production function into (15.35) and rewriting gives: where k i is the quantity of capital owned by the firm, d ik is the distributional parameter associated with capital, and j ranges over inputs other than capital. maximizing (15.36) with respect to variable inputs produces the following factor demand equations for industry i: this system of equations can be used to estimate the top-tier production parameters. the results are listed in . much of the empirical literature on cost and production functions fails to account for the fact that capital is fixed in the short run. rather than using (15.37), a common approach is to use factor demands of the form: this expression is correct only if all inputs are variable in the short run. in we show that using equation (15.38) biases the estimated elasticity of substitution toward unity for many sectors in the model in petroleum refining, for example, the fixed-capital estimate for the top tier elasticity, s 3 o , is 0.54 while in the variable elasticity case it is 1.04. the treatment of capital thus has a very significant effect on the estimated elasticities of substitution. estimating parameters for regions other than the us is more difficult because timeseries input-output data is often unavailable. in part, this is because some countries do not collect the data regularly and in part it is because many of g-cubed's geographic entities are regions rather than individual countries. as a result, we impose the a global approach to energy and the environment: the g-cubed model restriction that substitution elasticities within individual industries are equal across regions. 24 by doing so, we are able to use the us elasticity estimates everywhere. the share parameters (the ds in the equations above), however, are derived from regional input-output data taken from the gtap version 7 database and differ from one region to another. in effect, we are assuming that all regions share a similar but not identical production technology. this is intermediate between one extreme of assuming that the regions share common technologies and the other extreme of allowing the technologies to differ in arbitrary ways. the regions also differ in their endowments of primary factors, their government policies, and patterns of final demands. final demand parameters, such as those in the utility function or in the production function of new investment goods were estimated by a similar procedure: elasticities were estimated from us data and share parameters were obtained from regional input-output tables. trade shares were obtained from 2009 un standard industry trade classification (sitc) data aggregated up from the four-digit level. 25 the trade elasticities are based on a survey of the literature and vary between 1 and 3. 26 g-cubed is implemented via three software components. the first consists of a sequence of programs written in the ox language that construct g-cubed's dataset from raw data. 27 the second component consists of a set of files specifying the model's economic structure in a portable, general-purpose language we developed called 'sym'. sym is a set-driven matrix language that descends from gams and gempack. it imposes rigorous conformability rules on all expressions to eliminate a broad range of potential errors in the design and coding of the model. a useful consequence of these rules is that subscripts are generally unnecessary and the model can be expressed very concisely and clearly. the third component is a suite of ox programs that are used for setting up simulations and solving the model according to the two-point boundary value algorithm described in mckibbin (1986) . 28 . it allows models with large numbers of forwardlooking costate variables (g-cubed has more than 100) to be solved quickly on computers with limited resources. 24 for example, the top-tier elasticity of substitution is identical in the durable goods industries of japan and the us. this approach is consistent with the econometric evidence of kim and lau (1994) . this specification does not mean, however, that the elasticities are the same across industries within a country. 25 a full mapping of sitc codes into g-cubed industries is contained in mckibbin and wilcoxen (1994) . 26 for a sensitivity analysis examining the role of the trade elasticities and several other key parameters, see . 27 ox is available from www.doornik.com and described in doornik (2007) . 28 for a more detailed description of the algorithm, see mckibbin and sachs (1991, appendix c) . because g-cubed is an intertemporal model, it is necessary to calculate a baseline, or 'business-as-usual', solution before the model can be used for policy simulations. in order to do so we begin by making assumptions about the future course of key exogenous variables. we take the underlying long-run rate of world population growth plus productivity growth to be 2.5% per annum and take the long-run real interest rate to be 5%. we also assume that tax rates and the shares of government spending devoted to each commodity remain unchanged. our remaining assumptions are listed by region in table 15 .3. as these assumptions do not necessarily match the expectations held by agents in the real world, the model's solution in any given year, say 2006, will generally not reproduce that year's historical data exactly. in particular, it is unlikely that the costate variables based on current and expected future paths of the exogenous variables in the model will equal the actual values of those variables in 2006. this problem arises in all intertemporal models and is not unique to g-cubed, but it is inconvenient when interpreting the model's results. to address the problem we add a set of constants, one for each costate variable, to the model's costate equations. for example, the constants for tobin's q for each sector in each country are added to the arbitrage equation for each sector's q. similarly, constants for each real exchange rate are added to the interest arbitrage equation for each country, and a constant for human wealth is added to the equation for human wealth. 29 to calculate the constants we use newton's method to find a set of values that will make the model's costate variables in 2006 exactly equal their 2006 historical values. after the constants have been determined, the model will reproduce the base year exactly given the state variables inherited from 2005 and the assumed future paths of all exogenous variables. 30 one additional problem is to solve for both real and nominal interest rates consistently since the real interest rate is the nominal interest rate from the money market equilibrium less the ex ante expected inflation rate. to produce the expected inflation rate implicit in historical data for 2006 we add a constant to the equation for nominal wages in each country. 31 finally, we are then able to construct the baseline trajectory by solving the model for each period after 2006 given any shocks to variables, shocks to information sets (announcements about future policies) or changes in initial conditions. 29 one interpretation of these constants is that they are risk premiums; another is that they are simply the residuals left between the actual data and the econometrically fitted values calculated by the model. 30 in general, these constants affect the model's steady state, but have little or no effect on the transitional dynamics. 31 one way to interpret this is as a shift in the full employment level of unemployment. in that case this approach is equivalent to using the full model to solve for the natural rate of unemployment in each country. a global approach to energy and the environment: the g-cubed model originally developed to evaluate climate change policies, g-cubed has been used to analyze trade policy, monetary and fiscal policy, financial crises, projections of global economic growth, the impacts of pandemics, and global demographic change. 32 it has been used by agencies within the governments of the us, japan, canada, australia and new zealand, as well as in reports by the intergovernmental panel on climate change, the un, the organization for economic cooperation and development (oecd), the world bank, the international monetary fund, the asian development bank, and a number of corporations. academic users can be found in the us, the uk, germany, austria, australia, indonesia and japan. the remainder of this section outlines key applications of g-cubed in the six areas: climate and energy policy, trade policy, analysis of financial crises, macroeconomic policy, the analysis of pandemics, and global demographic change. g-cubed was designed to contribute to the debate on environmental policy and international trade, with particular emphasis on climate change. it has been used for that purpose since 1992 and work using the model has roughly fallen into two areas of focus. one has been on generating projections of the future evolution of the world economy and exploring the sensitivity of these projections to a variety of assumptions. the second focus has been on evaluating the impacts of a variety of policy changes on these projections. these two strands of research will be dealt with separately below. in a study for the united nations university, bagnoli et al. (1996) found that over a 30year horizon, assumptions about productivity growth and structural change are crucial for understanding an economy's energy intensity. using the model, the authors made two projections of the world economy from 1990 to 2020. the first scenario assumed that all sectors in a given region experienced a uniform rate of technical change characteristic of that region. however, the rate varied across regions based on their historical performance, with higher rates in particular developing economies such as china. the second scenario allowed technical change to be heterogeneous at the sector level. within each region, sectoral technical change followed historical patterns, but scaled so that each economy had the same average economy-wide gdp growth rate as in the first scenario. the two scenarios produced dramatically different projections of world energy intensity by 2020. countries had approximately the same gdp growth rates in both scenarios (by construction), but energy use was far lower in the second scenario. sectorlevel differences in technical change caused structural changes that reduced economywide energy per unit of gdp by around 1% per year independent of any autonomous energy efficiency improvement (aeei). this difference was purely due to the changing structure of economies over time in response to relative price changes induced by different sectoral rates of technical change. the difference was shown clearly in the carbon taxes required for stabilizing emissions: in the second scenario the taxes were typically half those for the first scenario. this study and subsequent papers by emphasized that a simple projection of gdp growth was insufficient for projecting carbon emissions. although overall gdp growth matters, sectoral-level differences in productivity are critical for future emissions. 33 the other issue that was emphasized in this study and related studies, is that the effect of small changes in low-level growth rates over 20 or more years can have enormous effects on composition of the economy. the large range of possible outcomes from small changes in growth rates is always a sobering reminder of the degree of uncertainty underlying climate policy. in particular, there is empirical evidence to suggest that many economic variables have a unit root or a stochastic trend. if this is correct, or even approximately correct, then standard errors for projected levels of variables would quickly become large. g-cubed has been used for a range of studies of alternative greenhouse policies. carbon taxes are examined in mckibbin and wilcoxen 1993 , 1994 . these studies all highlight that a surprise carbon tax leads to a reduction in real output with the greatest losses occurring in the short run. show that the adjustment of capital flows are important for the impacts of climate policy. an increase in the price of energy inputs makes goods produced using energy relatively more expensive in world markets. the conventional view is that the current account of a country would deteriorate as a result of a carbon tax. in mckibbin and wilcoxen (1994) we showed on the contrary that the current account could improve if the revenue from the tax was used to reduce the fiscal deficit (i.e. holding government spending and transfers constant in spite of the rise in tax revenue). the rise in saving and fall in investment could easily lead to an improvement in the overall current account balance reflecting a capital outflow. the composition of the trade account would reflect the simple partial equilibrium reasoning but the economy-wide general equilibrium effect could go the other way. this paper also illustrated that the way in which the revenue from a carbon tax is used can have important consequences for the costs of the carbon abatement policy. if the revenue is used to reduce another tax in the economy, then the costs of abatement can be reduced. for example, in the us if the revenue is used to reduce the fiscal deficit, there can be a fall in interest rates which stimulates economic growth and reduces the costs of the carbon abatement. however, this effect does not occur in a country like australia because it is not a major participant in global capital markets and has very little impact on world interest rates. nonetheless, using the revenue to reduce taxes on capital can help to offset the negative effects of a carbon abatement policy in australia. the trade implications of environmental policy are the focus of mckibbin and wilcoxen (1993 . these papers show that changes in environmental policy are unlikely to lead to major changes in trade flows through relocation of industry because the costs of environmental policy are generally small relative to the cost of relocating production facilities. this does not mean that environmental policies lead to small losses in economic output, but that policies are unlikely to be fully offset by substitution toward goods that are not subject to the same environmental regulation. in the context of us climate policy, the papers above have shown that for every 100 tons of reduction in us emissions, global emissions fall by 80e90 tons; only 10e20 tons are offset due to higher emissions elsewhere. a key insight from this research is that a significant part of energy use is for domestic transportation which is largely non-traded and therefore is unlikely to move overseas. in mckibbin and wilcoxen (1997) we found that many aggressive permit trading scenarios were infeasible in g-cubed because of the instability they caused in the global trade system. the main problem was the extent of stabilization proposed in the scenarios, which implied very high prices for emission permits. the result was wild fluctuations in real exchange rates and consequently in patterns of international trade. this pointed to a fundamental flaw in the global emission permit trading schemes frequently proposed, such as the kyoto protocol. these regimes could generate large transfers of wealth between countries. supporters of a global permit system regard this as an advantage, because it would allow developed countries to compensate developing countries for reducing their emissions. however, g-cubed suggests that such an approach would put enormous stress on the world trade system depending on the tightness of the emission targets, the extent to which the allocation of permits was different from the permits required to meet the targets, and the marginal cost of abatement in different countries, amongst other things. a developed country importing permits would see its balance of trade deteriorate substantially. equally serious problems would be created for developing countries. massive exports of permits would lead to exchange rate appreciation and a decline or collapse in traditional exports. in the international economics literature this is known as the 'dutch disease' or in australia as the 'gregory thesis'. it occurs because the granting of permits has an impact on the wealth of the receiving countries, which changes their consumption patterns and comparative advantage. in international capital flows are shown to play an important role in the adjustment process to emissions policies. a rise in the price of carbon leads to a fall in the return on capital in carbon-intensive economies and to capital outflow from carbon-intensive economies into large economies and less carbon-intensive economies. although developing countries are generally less carbon intensive, they cannot absorb a large capital inflow because of the adjustment costs in physical capital formation. there is, therefore, much less carbon leakage in g-cubed than in other trade models because of the impact of capital flows and adjustment costs in developing countries. the appeal of an international permit program is strongest if participating countries have different marginal costs of abating carbon emissions. the analysis in mckibbin et al. (1999) . suggests that abatement costs are quite heterogeneous and international trading offers large potential benefits to parties with relatively high mitigation costs. the analysis also highlights that in an increasingly interconnected world in which international financial flows play a crucial role, the impact of greenhouse abatement policy cannot be determined without attention to the impact of these policies on the return to capital in different economies. to understand the full adjustment process to international greenhouse abatement policy it is essential to explicitly model international capital flows. an important but often neglected issue in climate policy design is the effect that the climate policy regime has on the transmission of economic shocks within a country and between countries. mckibbin et al. (2009d) explore potential interactions between climate policy, unanticipated macroeconomic events, and carbon emissions. they examine two kinds of unanticipated macroeconomic shocks under two global climate policy architectures and pay special attention to outcomes that could undermine individual countries' incentives to remain party to the global agreement. they find that a regime of fixed emissions targets strongly propagates growth shocks between regions while price-based systems do not. under a quantity-based policy, a positive growth shock in developing countries can raise the global price of permits enough that gdp in some economies actually contracts, creating an incentive for such countries to withdraw from the arrangement. they also find that in a global downturn, a price-based system exacerbates the economic decline. overall, quantity-based policies perform badly during unexpected economic booms and price-based policies perform badly during downturns. they argue that a hybrid policy would be superior e performing like a price-based policy during a boom and like a quantity-based policy in a downturn. g-cubed also has been used to explore the characteristics of particular international agreements such as the kyoto protocol in and wilcoxen (2004, 2007) , and the copenhagen accord in mckibbin et al. (2010) . in the latter paper, the authors used g-cubed to convert a heterogeneous set of commitments by countries at copenhagen into comparable policy effort by calculating the 'carbon price equivalence' of policies. among other results, they showed that china's intensity targets, which some observers at the time regarded as insignificant, are actually a commitment to very significant reductions relative to the expected trajectory of chinese emissions in the absence of the policy. india's intensity targets, on the other hand, are essentially non-binding. g-cubed also has been used for evaluating national carbon policy proposals such as the carbon pollution reduction scheme in australia by the australian government (2008) and various national schemes in the us by mckibbin et al. ( , 2009c . in addition, we examined border tax adjustments for embodied carbon in mckibbin and wilcoxen (2009a) . border taxes are calculated based on the carbon emissions associated with production of each imported product, and would be intended to match the cost increase that would have occurred had the exporting country adopted a climate policy similar to that of the importing country. we estimated how large such tariffs would be in practice, and then examined their economic and environmental effects. we found that the tariffs would be small on most traded goods, would reduce leakage of emissions reduction very modestly and would do little to protect import-competing industries. the benefits produced by border adjustments would be too small to justify their administrative complexity or their deleterious effects on international trade. a consistent theme in analyses of climate policies using g-cubed is that climate policy design should be robust to uncertainties about future economic conditions. the sensitivity of longer run projections to small changes in assumptions as shown in suggests that policies that rely heavily on precise forecasts about the future are likely to be vulnerable to collapse. this experience led to the development of a 'hybrid' policy of taxes and permit trading set out in mckibbin and wilcoxen (2002a , 2002b , 2004 , 2007 . a policy that is able to manage uncertainty is key in the climate policy debate. 34 in a study for a report by the us congressional budget office (cbo), g-cubed was used to assess the north american free trade agreement (nafta) (congressional budget office, 1993; mckibbin, 1994; manchester and mckibbin, 1994) . at the time nafta was being evaluated, many studies suggested that it would lead to a flood of cheap goods into the us economy and a loss of jobs in the us. g-cubed, however, showed the opposite. in these studies, the key aspect of nafta was not only the removal of us tariffs on mexican goods, but the impact of the agreement on expected future productivity in mexico and the reduction in the risk premium attached to mexican assets by international investors. in the studies we followed the empirical link between closer economic integration and productivity growth surveyed in the case of europe by catinat and italianer (1988) . the risk premium shock was based on estimates by the congressional budget office (1993a) that on average investment in mexico required roughly a 10% higher return than investments in the us. we assumed that the risk premium which drove this differential was eliminated in three years from the announcement of nafta. g-cubed predicted that nafta would lead to a large flow of financial capital from the rest of the world into the mexican economy in response to a rise in the expected return to capital and a reduction in the mexican risk premium. the mexican real exchange rate was predicted to appreciate, crowding out net exports and leading to a rise in the mexican current account deficit. the short-term impacts of nafta were consistent with g-cubed predictions. the medium to long-run predictions from g-cubed were more consistent with the majority of studies at the time. the additional insight from g-cubed was the short-run adjustment process was largely driven by capital flows driving trade adjustment. the model predicted a large impact from expected long-term productivity improvements, and showed how, through the operation of intertemporal forces, this stimulated shortterm capital inflows to mexico. in the short term, this completely dwarfed the static effect (i.e. changing the composition of trade) of the tariff changes that was the focus of other studies. the scale of economies, as well as the sectoral adjustment within economies, can change significantly in dynamic models. financial markets contain important information about absolute and relative returns to current and future activities. g-cubed has also been applied to the free trade agreement of the americas (ftaa) e a proposed extension of nafta. that analysis is discussed in detail in section 15.4. the six-sector version of g-cubed has been used to explore the impact of trade liberalization under alternative regional and multilateral arrangements 35 as well as unilateral trade liberalization in china. 36 in many of these studies, which are based on actual agreements, the trade liberalization is generally announced to be phased in over time. in this case, the key dynamic adjustment to the various trade policy changes is the instantaneous change in rates of return to capital and asset prices in the liberalizing economies. changes in the return to capital change financial capital flows which cause exchange rate adjustments. these exchange rate adjustments then drive trade adjustment in the short run, even before substantial tariff reductions are implemented. mckibbin (1998a, 1998b) examined different regional groupings for trade liberalization. countries were assumed to reduce tariff rates from 1996 levels to zero by 2010 for developed countries, and by 2020 for developing countries figure 15 .1 shows the impact on australian real gdp of liberalization in alternative groupings. liberalization within the regional groupings that include australia (world, apec and australia) results in short-term losses as the tariff reductions are phased in. over time however there are significant medium to long-term gains relative to the base scenario. there are significant additional benefits to joint liberalization in the short run but the majority of medium to long-term gains occur through own liberalization. liberalization by other countries (asean) results in only small gdp gains for australia. the adjustment path to phased liberalization can therefore exhibit short-run costs as resources begin to be reallocated before the trade reforms are implemented. once the liberalization is announced, the return to capital in some sectors rises and capital flows in, appreciating the real exchange rate. this further dampens demand for exported goods as they temporarily become more expensive. liberalization by other countries at the same time can help to reduce these short-run adjustment costs and real exchange rate changes. in the long run, own reforms give larger gains than foreign reforms and there is little benefit from a policy of free riding. the key insight provided by g-cubed is the short-run adjustment process. the impact of a policy change can be perverse in the short run in the sense that capital flowing into a liberalizing economy can cause such a large real exchange rate appreciation that there is a significant deterioration in the trade account as real resources flow into the economy. if the adjustment process is poorly understood, policy makers can become disaffected or can implement inappropriate policy responses such as tightening macroeconomic policy in order to improve the external balance thus slowing down economic activity. however, the capital inflows are needed to build future capacity in expanding sectors. the appreciation of the real exchange rate and worsening of the trade balance is not a loss of underlying competitiveness because of a bad policy change. the reallocation of resources is driven by the signals in financial markets of where expected returns are highest after the reforms are implemented. g-cubed has been used in a number of studies to explore the role of macroeconomic policies and shocks in generating trade imbalances between regions of the world. in g-cubed the trade deficit of a country not only represents a excess of imports of goods and services over exports of goods and services. a trade deficit also reflects a excess of investment over savings in a country. lee et al. (2006) used the model to explore the sensitivity of the trade flows between the us and asia. they found the fundamental cause of trade imbalance since 1997 is changes in savingeinvestment gaps, attributed to the surge of the us fiscal deficits and the decline of east asia's private investment after the 1997 financial crisis. in exploring the impact of nominal exchange rate realignment the results from g-cubed show that a revaluation of east asia's exchange rates by 10% (effectively a shift in monetary policy) cannot resolve the imbalances. they also found that a concerted effort by east asian economies to stimulate aggregate demand can have significant impacts on trade balances globally, but the impact on the us trade balance is not large. us fiscal contraction was estimated to have large impacts on the us trade position overall and on the bilateral trade balances with east asian economies. these results suggest that in order to a global approach to energy and the environment: the g-cubed model improve the transpacific imbalance, macroeconomic adjustment will need to be made on both sides of the pacific. an antecedent of g-cubed called the mckibbinesachs global (msg) model was originally designed to explore macroeconomic policy issues. g-cubed has similar macroeconomic properties and has been used to explore a wide range of issues in macroeconomics. monetary and fiscal regime design in europe has been explored using g-cubed by allsop et al. (1996 allsop et al. ( , 1999 , gagnon et al. (1996) , haber et al. (2001) , mckibbin and bok (2001) , and neck et al. (2000 neck et al. ( , 2005 . in these papers the key insight was that the fixed exchange rate regime of the euro zone would be under serious stress if fiscal policies in europe were not coordinated in the face of various economic shocks. macroeconomic policy issues in japan have been examined using g-cubed by mckibbin (2002) and callen and mckibbin (2003) where the experience of japan during the 1990s was captured by the model as a serious of policy errors particularly in announcing fiscal expansion and generating crowding out through asset markets, but then not delivering the fiscal spending causing a persistent downward drop in gdp; in india by mckibbin and singh (2003) where nominal income targeting was shown to be a far better monetary regime than inflation targeting given the prevalence of supply side rather than demand-side shocks in the indian economy; in china by mckibbin and tang (2000) and mckibbin and huang (2000) where financial reforms where found to have profound effects on economic growth and the balance of payments adjustment but that a loss in confidence in china could devastate economic growth; and in asia in mckibbin and le (2004) and mckibbin and chanthapun (1999) where flexible exchange rate regimes were found to be far better at insulating east asian economies against global economic shocks that pegging to either the us dollar or a common asia currency. theoretical issues in monetary policy design are investigated using g-cubed in henderson and mckibbin (1993); . trade imbalances caused by macroeconomic policies and shocks are explored in lee, mckibbin and park (2006) . the impacts of the end of the cold war and large shift in military spending on the global economy are explored by mckibbin and thurman (1995) , and congressional budget office (1996b); the spillover of macroeconomic policies between countries are explored in mckibbin and bok (1995) and mckibbin and tan (2009) ; and theoretical issues in the design of models for policy analysis are explored in mckibbin and vines (2000) and pagan et al. (1998) . global fiscal consolidation is explored in mckibbin and stoeckel (2012) which examines the direct impact of a large-scale reduction in government outlays on economies as well as the implications that a global fiscal adjustment might have on country risk premia. one key result in this paper is that substantial fiscal consolidation by high-income economies (in proportion to the size of their debt problem) has the temporary effect of lowering economic activity in those economies, but has a positive effect on developing countries and a few high-income economies not undertaking fiscal consolidation. the reason is that the negative flow-on effects through trade linkages by high-income economies reducing imports and stimulating exports with the developing world are offset by favorable financial flow-on effects, which provides capital for developing countries to increase gdp. secondly a credible phasing in of fiscal cuts can reduce expected future tax liabilities of households and firms which dampens the negative direct effects of cuts in government spending. the paper also explores the outcome if all countries coordinate their fiscal adjustment except the us. a coordinated fiscal consolidation in the industrial world that is not accompanied by us actions is likely to lead to a substantial worsening of trade imbalances globally as the release of capital in fiscally contracting economies flows into the us economy, appreciates the us dollar and worsens the current account position of the us. the scale of this change is likely to be sufficient to substantially increase the probability of a trade war between the us and other economies. in order to avoid this outcome, a coordinated fiscal adjustment is clearly in the interest of the global economy. in mckibbin and martin (1998) , the six-sector version of g-cubed was used to simulate the asian currency and economic crisis. data from the key crisis economies of thailand, korea and indonesia were used as inputs for simulations to see if the model could generate the scales of adjustment in asset markets as well as the sharp declines in economic activity that occurred. the study considered three key factors in explaining the qualitative and quantitative events that unfolded in the crisis economies: (i) revisions to growth prospects, (ii) changes in risk perceptions and (iii) policy responses in individual countries. the role of asset markets and financial flows was critical. downward revision in expected growth led to falling asset prices, which reduced current income and wealth. combined with increased risk premia, calibrated to generate an exchange rate depreciation of the size being observed in real time in these economies, meant investment and growth collapsed. the extent to which financial markets responded through intertemporal arbitrage was crucial to the risk shocks. finally, the ability to model the anticipated policy responses, both through price-setting and asset-market adjustments, was crucial to understanding the subsequent outcomes. mckibbin (1999) focuses on the second of these factors: the impact on asian countries of a jump in the perceived risk of investing in these economies. this paper argued that a financial shock can quickly become a real shock because of the interdependence of the real and financial economies. too often policy makers and modelers a global approach to energy and the environment: the g-cubed model ignore this interdependence. the reaction of policy makers directly, and in the implications for risk of their responses are crucial to the evolution of the crisis. both mckibbin (1999) and mckibbin and martin (1998) conclude that the risk shock was crucial to understanding the asian crisis. the results for a risk shock are similar to the results for a fall in expected productivity. the shock leads to capital outflow from crisis economies and a sharp real and nominal exchange-rate depreciation. this reduces the value of capital, which, together with a significant revaluation of the us dollar denominated foreign debt, causes a sharp fall in wealth and a large collapse of private consumption expenditure. the fall in the return to capital, and the large rise in real longterm interest rates, lead to a fall in private investment. early in the debate over the asian crisis, the results from g-cubed were interesting and controversial because they were counter to popular commentary, both in australia and in the us. the model showed that although the international trade effects were negative for countries that export to asia, the capital outflow from crisis economies would push down world interest rates and stimulate non-traded sectors of economies that were not affected by changes in risk assessment. the model suggested that a country like australia would slow only slightly in the short run and the us would experience stronger growth as a result of the capital reallocation. this is now conventional wisdom. furthermore, for australia, in particular, the existence of markets outside asia, and changes in relative competitiveness, meant that substitution was possible for australian exports. models with an aggregate world growth variable or a single exchange rate variable would not capture this international substitution effect. models with exogenous balance of payments could replicate the shock, but it required an exogenous change in the trade balance and other factors that are exogenous to the model. in a number of papers stoeckel (2010a, 2010b) used the approach of mckibbin and martin (1998) together with shock to us housing markets and policy responses of central banks and fiscal authorities around the world to model the global financial crisis of 2008. specifically they modeled the key aspects of the crisis as: (i) the bursting of the housing bubble and loss in asset prices and household wealth with consumers cutting back on spending and lifting savings; (ii) a sharp reappraisal of risk with a spike in bond spreads on corporate loans and interbank lending rates with the cost of credit, including trade credit, rising with a commensurate collapse of stock markets around the world; and (iii) a massive policy response including a monetary policy easing, bailouts of financial institutions and fiscal stimulus. simulating the loss in confidence through higher risk premia on the us alone (the 'epicenter' of the crisis) showed several things. had there not been the contagion across other countries in terms of risk reappraisal, the effects would not have been as dramatic as subsequently occurred. the adverse trade effects from the us downturn would have been offset to some degree by positive effects from a global reallocation of capital. were the us alone affected by the crisis, chinese investment could have actually risen. the world could have escaped recession. when there is a reappraisal of risk everywhere including china, investment falls sharply e in a sense there is nowhere for the capital to go in a global crisis of confidence. the implication is that if markets, forecasters and policy makers misunderstand the effects of the crisis and mechanisms at work, they can inadvertently fuel fears of a 'meltdown' and make matters far worse. the bursting of the housing bubble had a bigger effect on falling consumption and imports in the us than does the reappraisal of risk, but the reappraisal of risk has the biggest effect on investment. rising risk causes several effects. the cost of capital rises that leads to a contraction in the desired capital stock. hence, there is disinvestment by business and this can go on for several years e a deleveraging in the popular business media. the higher perception of risk by households causes them to discount future labor incomes at a higher risk adjusted interest rate that leads to higher savings and less consumption, fuelling the disinvestment process by business. when there is a global reappraisal of risk there is a large contraction in output and trade e the scale of which depends on whether the crisis is believed to be permanent or temporary. the long-run implications for growth and the outlook for the world economy are dramatically different depending on the degree of persistence of the shock. these papers found that, as expected, the effects of the crisis are deeper and last longer when the reappraisal of risk by business and households is expected to be permanent versus where it is expected to be temporary. a third combination was explored in mckibbin and stoeckel (2010b) where agents unexpectedly switch from one scenario of believing the shock to be permanent to one the temporary scenario several years later. the dynamics for 2010 are quite different between the temporary scenario and the expectation revision scenario even though the shocks are identical from 2010 onwards. one of the key results of both these studies was that there was a substantially larger contraction in exports relative to the contraction in gdp in all economies. this was observed in the actual data. this massive shift in the relationship between trade and gdp is not the result of an assumption about the income elasticity of imports. it reflects some key characteristics of the model. first, imports are modeled on a bilateral basis between countries where imports are partly for final demand by households and government and partly for intermediate inputs across the six sectors. in addition, investment is undertaken by a capital sector that uses domestic and imported goods from domestic production and imported sources. as consumption and investment collapse more than gdp, imports will contract more than gdp. one country's imports are another country's exports; thus exports will contract more than gdp unless there is a change in the trade position of a particular country. the assumption that all risk premia rise and the results that all real interest rates fall everywhere implies small changes in trade balances but big changes in the extent of trade in durable goods. as durable goods have a much bigger share in trade than in gdp the compositional shift of demand away from durable goods due to higher risk premia causes a structural change in the relationship between trade and gdp. as part of research for the world health organization (who) g-cubed was adapted to explore two major pandemics: (i) the sars (severe acute respiratory syndrome) outbreak in 2003, which was explored in lee and mckibbin (2004) (ii) the potential of a pandemic resulting from the outbreak of bird flu, which was examined in mckibbin and sidorenko (2006) . in lee and mckibbin (2004) the authors used emerging data on changes in risk premiums observed in financial pricing and changes in spending behavior in the affected countries on hong kong, china to develop shocks to country risk, based on observed exchange rate changes, sector specific shifts in demand away from sectors with high human-to-human contact (mostly services) and an increase in the input costs of the service sector of roughly 5%. this study was the first of a new approach to analyzing the macroeconomic costs of diseases through general equilibrium modeling. the key insight for policy design and investment in public health was that the short-run cost of major disease outbreaks is significant. traditional estimates based on loss of life and income foregone estimates underestimate the costs of large-scale change in economic behavior and the spillovers between economies of disease outbreaks. the authors estimated that the cost in 2003 of sars for the world economy as a whole was close to $40 billion, which is the official who estimate of the sars outbreak. the approach in lee and mckibbin (2004) on sars was significantly extended in mckibbin and sidorenko (2006) to explore the possible implications of more widespread influenza pandemics. based on historical experience of influenza pandemics, mckibbin and sidorenko (2006) considered four mortality scenarios under current economic linkages in the global economy. the scenarios were: (i) a 'mild' pandemic, modeled on 1968e1969 hong kong flu; (ii) a 'moderate' pandemic, modeled on the asian flu of 1957; (iii) a 'severe' pandemic similar to the lower estimates of mortality and morbidity in the spanish flu of 1918e1919; and (v) an 'ultra' pandemic, modeled on high-end estimates of the spanish flu. these scenarios were used to generate a range of shocks to individual countries and sectors due to the pandemic (including mortality and morbidity shocks to labor force, increase in cost of doing business, an exogenous shift in consumer preferences away from exposed sectors, and a re-evaluation of country risk premiums). these shocks generate a complex response of incomes and prices driving global economic outcomes. the results illustrated that even a mild pandemic can have significant consequences for global economic output, with the developing countries experiencing the largest economic loss due to the compounding effect of a weaker public health response, capital reallocation and monetary policy responses within different exchange rate regimes. the use of a general equilibrium model that included changes in behavior of a large scale in response not only to market signals, but also changes in risk perceptions can cause a much larger economic loss that conventional estimates of pandemics imply. in a series of papers, mckibbin and nguyen (2004) , bryant and mckibbin (2004) , mckibbin (2006b) , and nguyen (2011) have incorporated overlapping cohorts of generations in g-cubed, in order to explore demographic change in various countries. the approach followed is based on the work of blanchard (1985) , yaari (1965) , and weil (1989) as extended by faruqee (2003) . this work was also adapted in batini et al. (2005) for the international monetary fund world economic outlook (international monetary fund, 2004) . the basic approach was to introduce individual cohorts of agents into g-cubed. by following the blanchard approach and assuming a constant probability of death across cohorts we are able to aggregate agents outside the model and feed in the change in productivity by agent cohort using estimated age-earnings profiles to generate shocks to effective labor supply in the model. this short cut approach of assuming a constant probability of death across cohorts is a strong assumption. to abandon that simplifying assumption requires an explicit multicohort olg model which is recently undertaken in nguyen (2011) . an analysis of the impact of the global and regional differences in demographic change needs to take into account the effects of changing growth rates as well as the numbers of adults and children. mckibbin (2006b) incorporated these projections into a general equilibrium model that allows for the changing composition of the population, and captures its effect on labor supply, investment, growth potential, saving, asset markets, international trade and financial flows. there are at least two most important policy implications from this research. the first is that the projected demographic transition in the global economy will likely have important macroeconomic impacts on growth, trade flows, asset prices (real interest rate and real exchange rates) and investment rates. the second result is that policy makers should not ignore the global demographic transition when focusing on domestic issues related to demographics. the fact that the demographic transition is at different stages across countries, particularly in industrialized countries relative to developing countries, implies that the global nature of demographic change cannot be ignored. mckibbin (2006b) showed that the developing world has important impacts on the industrial economies. as well as creating a framework for exploring a range of possible policy responses directly related to demographics, the model could be used to explore how other policies, apparently unrelated to demographics, might impact on the macro economy to offset any negative consequences or reinforce any positive consequences of global demographic a global approach to energy and the environment: the g-cubed model change. a first attempt at this is contained in batini et al. (2005) , which explored the impact of productivity improvements induced by economic reform and lowering barriers to international capital flows in developing countries. by using a general equilibrium model other policies in other parts of the economy might have a more substantial positive contribution to dealing with demographic change than the more direct policies that are usually proposed, such as increased migration, subsidies to child birth or changes in retirement ages. in this section we present results illustrating the use of g-cubed for analysis of financial shocks and international trade agreements. the first analysis draws on mckibbin and stoeckel (2010b) and examines the effects of a financial crisis on the global economy. the second analysis draws on mckibbin and wilcoxen (2003) and examines the effects of the proposed ftaa on trade patterns and carbon emissions. to analyze a financial crisis, we used an extended version of the model (aggregation n) which has greater regional detail. there are seven additional regions including five new countries (canada, the uk, germany, india and new zealand) and two new aggregates (other asia and latin america). in addition, the aggregate region representing europe has been replaced with a narrower aggregate representing the euro zone countries other than germany. the full list of regions is shown in table 15 .4. we model financial crises as changes in the risks perceived by investors, which are reflected in the risk premia they demand for holding assets. risk premia enter the model in a number of places. they play an important role in the model's calibration as well as having large impacts on economic outcomes through intertemporal relationships. for example, risk premia m k and m j appear in equation (15.30), the arbitrage equation between returns on domestic and us bonds, which is repeated below: in addition, as shown in equation (4) there are risk premia, m ei , between bonds and equity in each sector within each economy, which represent the sector's equity risk premium. there is also a risk premium, m h , on the rate at which households discount future after tax labor income, as shown in equation (15.16) . in calibrating the model, these risk premia are calculated so that the model's solution values for forward looking variables in the base year (2006) are equal to the historical values of those variables. for example, in the case of country risk (m), a constant is chosen so that the current exchange rate, which is the expected future path of interest differentials plus the period t exchange rate, is equal to the actual exchange rate in the base period 2006. the equity risk premium in each sector in each country is chosen so that the stock market value for sector i in country n is equal to its actual stock market value in 2006. once the risk premia are calculated they held constant for most simulations. however, they can be shocked to explore the impact of changes in perceived risks. to illustrate the importance of these risk premia, two experiments are presented in this section. the first is a rise in country risk in europe (consisting of the country models for germany, the rest of the euro zone and the uk). this shock could represent a sovereign debt crisis in this region or some other change in perceived risk that causes investors to demand a higher rate of return on government bonds from that region (relative to the us government bond rate adjusted by expected exchange rate changes). the second experiment examines a broader risk shock that extends to the us as well. in this case the relative risk between europe and the us is unchanged from the baseline but the risk of both regions relative to all other countries rises. in the reference case the world economy is assume to grow along the model's baseline projections. all risk premia are held constant at their calibrated values discussed above. in the first simulation, country risk in europe (including germany, the rest of the euro zone and the uk) is assumed to rise unexpectedly in 2011 by 300 basis points. this increase is assumed to be permanent. as a result, investors demand that all financial assets within europe pay an additional 300 basis points (relative to competing assets) to compensate for the additional risk. the immediate effect of the shock is a reduction in the financial value of european assets as investors reallocate their portfolios away from those assets. financial capital flows out of europe causing a sharp fall in nominal and real european exchange rates. for example, figure 15 these changes in exchange rates and financial flows are reflected in the trade balances of each region. as shown in figure 15 .3 european regions experiencing exchange rate declines and capital outflows see their trade balances move sharply toward surplus: their exports become more competitive and investors are less willing to finance trade deficits. for similar reasons, the trade balances of the us and china (where exchange rates have strengthened and capital inflows have increased) move toward deficit. in the longer term, the change in the required financial return causes the marginal physical product of capital in europe to rise to re-equilibrate the arbitrage condition between bonds and equity. this comes about via a decline in european capital stocks: the stocks initially in place when the shock occurs are too high to generate the physical return required. the expectation that increased risk is permanent leads to a long period of falling european capital and higher european interest rates relative to the reference case. as shown in figure 15 .4 the shock raises european real interest rates by more than 100 basis points. interest rates in the us and china, on the other hand, fall slightly. real investment, shown in figure 15 .5 also changes as expected: a sharp immediate drop in europe, followed by a gradual recovery as european capital stocks converge to their new, lower, long-term levels; and the reverse in the us and china. the drop in asset values in europe lowers the wealth of european households and causes private consumption to fall, as shown in figure 15 .6 relative to the reference case, consumption increases slightly in the us and somewhat more in china due to china's slightly large fall in interest rates. overall, european regions experience lower consumption and investment, and higher net exports. on balance, the effect on european gdp is negative, as shown in figure 15 .7. the results are consistent with supply-side effects: european capital stocks gradually fall over time and the loss of gdp is exacerbated in the short run by temporary unemployment. the change in risk is sufficient to cause a recession in europe with gdp in the first year down by nearly 5% relative to its reference level. in contrast, consumption, investment and gdp all rise slightly in the us and china under the europe-only shock. interestingly, the transmission of the shock to countries outside europe is positive (i.e. other countries gain) despite the fall in european gdp. the large outflow of financial capital from europe to the rest of the world pushes down long-term real interest rates in other regions, stimulating non-european investment and expanding a global approach to energy and the environment: the g-cubed model the supply side of other economies. the capital reallocation effect is sufficiently large that for most other regions it more than offsets the negative effect of lower import demands from a weaker europe. roughly speaking, the shock tends to reallocate financial capital rather than destroy it. although the value of capital drops sharply in europe (as reflected in the real exchange rate shown in figure 15 .2), it rises in the us and china. in the second simulation, the us also experiences an increase in perceived risk (perhaps through contagion or its own fiscal crisis). as noted above, results for this simulation are shown in the earlier figures along with those for the european financial crisis. broadly speaking, the effects of the broader crisis on the us are much like those of the narrower crisis on europe: the real exchange rate falls, the trade balance moves toward surplus, the real interest rate increases, and investment, consumption and gdp decline. interestingly, however, the spread of the crisis to the us also attenuates the effects on germany and the rest of europe: european losses in consumption, investment and gdp are reduced relative to the case when the shock is confined to europe. this result reflects the role of adjustment costs in capital accumulation in each sector. the us is a large economy that can absorb a lot of the capital that flows out of europe without much being lost to adjustment costs (see equation 15.3). in contrast, when the inflow from europe to the us is reduced by the rise in us risk, adjustment costs cause less capital to flow out of europe. the remaining countries (other than the us and europe) have much less capacity to absorb large inflows of additional capital without incurring rising adjustment costs from expanding their physical capital stocks. thus, more financial capital stays within europe under the second simulation, reducing the loss of european gdp. this result illustrates one of the benefits of intertemporal general equilibrium models that explicitly model the supply side of economies: in more traditional keynesian macroeconomic models, this effect does not exist and demands driven by trade dominate the results for the international transmission of economic shocks. finally, the results for china in the second simulation show the importance of assumptions about monetary policy. in g-cubed, china is assumed to peg its nominal exchange rate to the us dollar. 37 as a result, china effectively loosens its monetary policy at the onset of the us shock in order to have its nominal exchange rate move with the us dollar. thus, there is a substantial monetary expansion in china. short-term interest rates fall, real consumption, investment and gdp rise sharply, and inflation spikes markedly, as shown in figure 15 .8 (panel 4). our second illustration of analysis using g-cubed focuses on the proposed ftaa. we evaluated the ftaa by comparing the evolution of the world economy with and without the agreement. 38 in mckibbin and wilcoxen (2003) we considered a range of competing assumptions about the manner in which the ftaa would be implemented and the effects it would have on individual economies. in particular, we evaluated the ftaa under two different assumptions about its effect on productivity growth and under alternative assumptions about how governments respond to a decline in tariff revenue. in this section we discuss a subset of those results. the direct effect of reducing tariffs is to improve the efficiency of an economy's resource allocation by reducing the wedge between a buyer's willingness to pay for an imported product and the product's marginal cost. traditionally, general equilibrium studies of trade reform have focused on measuring these efficiency gains, and measuring them at a given point in time, usually either the immediate short run after the reform has been implemented, or far in the future at the model's long run equilibrium. by this standard, trade liberalization is usually found to improve welfare 38 other papers in the literature on trade and the environment include strutt and anderson (1999) , who find that trade can improve environmental quality in some circumstances and does little harm otherwise, and tsigas et al. (2002) , who find that the effect of trade on the environment is ambiguous. other general equilibrium studies of the ftaa include diao and somwaru (2000) and adkins and garbaccio (2002) . but the magnitude of the improvement tends to be small. for example, hertel et al. (1999) find that a worldwide cut in tariffs of 40% would raise world gdp by 0.24%. 39 however, liberalization leads to a host of indirect dynamic effects as well. these can cause profound changes in an economy by altering its rate of growth. unfortunately, they are often very difficult to measure, particularly because competing effects can work in opposite directions. for example, reductions in tariffs cause imports to rise, pushing a country's trade balance toward deficit, leading to a depreciation of its exchange rate and a consequent increase in its exports. deterioration of the trade balance is accompanied by inflows of capital from abroad which augment domestic saving and tend to raise the rate of investment. at the same time, the drop in tariff revenues will push the country toward fiscal deficit, raising government borrowing and tending to crowd out private investment. to further complicate matters, capital accumulation is also affected by reductions in the prices of imported durable goods, which tend to reduce the cost of new capital and thereby increase the rate of capital formation and growth. disentangling these effects requires a multisector general intertemporal equilibrium model with considerable financial detail. in addition to changing capital accumulation, the empirical literature suggests that trade improves industry productivity by placing additional competitive pressure on previously protected industries, and by increasing the flow of investment and embodied technical change across borders (frankel and romer, 1999; chand, 1999) . moreover, these studies find that trade liberalization has much larger effects than traditional static analysis suggests: frankel and romer, for example, find that a one percentage point increase in the ratio of trade to gdp raises per capita income by 2e3%. although there is clear evidence of a link between trade and productivity at the aggregate level, the literature is not yet sufficient to permit precise predictions about the magnitude of improvement in productivity of individual industries. as a result, we approach the issue by running two sets of simulations. the first employs the traditional assumption that firms in liberalizing economies do nothing when faced by increased competition from imports (apart from substituting toward cheaper inputs): they do not cut costs or adopt better management practices or newer technology. although this assumption is conventional, it is quite strong. it says, in effect, that a firm's technology choice is not affected by its industry's level of protection. it is hard to find any empirical support for that position and there is much evidence for the reverse: there are countless 39 martin et al. (2003) point out that traditional general equilibrium measures of the gains from liberalization are biased downward very significantly by aggregation across goods. tariff rates differ sharply between individual products and efficiency costs are proportional to the square of the price changes caused by the tariffs. when products are aggregated, however, their individual tariffs are replaced by a weighted average. the efficiency cost of an average tariff can be shown to be smaller than the average of the efficiency costs of the individual tariffs it replaced. a global approach to energy and the environment: the g-cubed model examples of industries clinging to obsolete, high-cost technology because protection allowed them to do so. our second set of simulations introduces a link between trade and productivity by assuming that previously protected industries are able to take modest steps to reduce their costs. 40 it captures, at least to first order, the empirical features seen in the econometric literature on trade and growth. since both sets of simulations depend on assumptions about the link between trade and productivity, neither one can be interpreted as a precise forecast of the ftaa's effects. however, they characterize the set of possible outcomes. other general equilibrium studies that have introduced a link between trade and productivity include stoeckel et al. (1999) , diao and somwaru (2000) , and monteagudo and watanuki (2001) . finally, a third indirect effect of trade agreements is that increased openness lowers the risk premium attached to a country's sovereign debt by rating agencies such as standard and poor's and moody's (stoeckel et al., 1999) . this can lead to pronounced increases in capital inflows, particularly for developing countries. however, that mechanism will not be discussed here. g-cubed's basic design is well-suited to the task because it has a full, integrated treatment of international trade and financial flows: each country's current account position must be offset by its capital account, which in turn leads to accumulation or erosion of its stock of foreign assets and thus to changes in its future flow of interest payments. in addition, it accounts for the relative immobility of physical capital and the high mobility of financial capital. to analyze the ftaa, we developed an extended version of the model with greater regional detail in the western hemisphere. it includes five regions particularly relevant for the ftaa: the us, canada, mexico, brazil and an aggregate region representing the rest of latin america. to keep the size of the model manageable, australia was merged into the rest of the oecd. the full list of regions is shown in table 15 .5. within each region, the disaggregation of production remained the same: the 12 sectors shown in table 15 .2. the structure of the model was also modified to facilitate simulations involving preferential trade agreements. the updated version allowed each region to have two sets of tariffs: one set for imports from countries within a preferred trade area and one for imports from everywhere else. for free trade agreements such as nafta or the ftaa, the tariffs on trade within the preferential area are set to zero. it should be noted that the model does not require participants in a free trade agreement have harmonized external tariffs: each country retains its original tariffs on trade outside the free trade area unless otherwise specified in a simulation. to determine the effects of the ftaa we carried out a suite of simulations: a reference case having no multiregion free trade areas; a pair of simulations examining the effects of nafta and the ftaa under the assumption that tariff reductions and trade flows have no effect on industry productivity; a pair of simulations examining the effect of nafta and the ftaa under an alternative assumption in which tariff reductions and increased trade lead to modest improvements in the productivity of previously protected industries; and a pair of simulations investigating the effect of announcing nafta or the ftaa 5 years before it is actually implemented. in this chapter we focus only on the simulations that include productivity effects; full results including the other simulations can be found in mckibbin and wilcoxen (2003) . the simulations discussed in here are listed in table 15 .6. the first was a reference case having no multiregion free trade agreements, not even nafta. 41 in this simulation, each region's tariff rates do not distinguish between imports from different trading partners. for example, the us imposes a single tariff on imports of durable goods, regardless of whether any particular imported good originates in canada, europe, brazil or somewhere else. as it does not include nafta, the reference case does not represent the current world economy. however, it allows us to a global approach to energy and the environment: the g-cubed model simulate the adoption of nafta itself, which is very useful for putting the ftaa results in context. the reference case tariff rates were derived by aggregating historical data and are listed in table 15 .7. 42 the pattern of trade under the reference case is exemplified by the figures shown in table 15 .8 for year 12 of the simulation; refer to table 15 .5 for a list of region codes. 43 each panel of the table gives the bilateral trade matrix for a particular good; panel nine, for example, shows trade in durable goods. the columns of table 15 .8 indicate the origin of each trade flow and the rows indicate the destination. each entry is the us dollar value of the corresponding flow of goods. 44 for example, in panel 5 the value in the 'u' row and 'p' column is 35.3, which indicates that shipments of crude oil from opec to the us were worth $35.3 billion. where the value of trade was less than $0.1 billion, the entry is left blank. as exports from different regions are imperfect substitutes, most goods flow in both directions between each pair of regions. for example, the us exports $45.5 billion dollars' worth of durables to japan while simultaneously importing $145.3 billion dollars of japanese durables. at g-cubed's level of aggregation, traded goods are generally far from homogeneous due to differences in the product mix of exports from different countries. aircraft, for example, are an important component of durables exported by the us but are not a significant portion of us imports of durables from japan. the row sums in table 15 .8 show the total value of imports of the good by each region; the sum of the 'u' row in panel 5, for example, shows that total us imports of crude oil from all of its trading partners were worth $96.2 billion. the column sums show the total value of exports of the good from each region; the sum of the 'p' column of panel 5 shows that total crude oil exports from opec were worth $156.4 billion. the value in the lower right corner of each panel shows the total us dollar value of trade in the good; in panel 5, the value is $297.4 billion. the model's 12 goods fall into three distinct categories in terms of the total dollar value of trade. six sectors each account for less than $100 billion: electricity ($5 billion), natural gas delivered by utilities ($12 billion), refined petroleum products ($86 billion), coal ($22 billion), non-fuel mining ($48 billion) and forestry ($80 billion). at the opposite extreme, two sectors each account for more than a trillion dollars: durables ($2926 billion) and non-durables ($1365 billion). the remaining four sectors fall in between: crude oil and natural gas ($297 billion), agriculture ($183 billion), transportation ($530 billion) and services ($607 billion). the overwhelming importance of durables is emphasized by the fact that shipments from europe (column 'e') to developing countries (row 'l') e a single entry in the trade matrix for durables e are worth $303 billion, or more than the total value of world trade in the six least-traded goods. in order to evaluate subsequent simulations, it is useful to group the model's regions into three aggregates: (i) the nafta countries: the us, canada, mexico; 45 (ii) the other table 15 .9 shows the dollar value of trade flows within and between each of these aggregates. 46 as in the detailed bilateral trade matrices, the column indicates the source of each trade flow and the row indicates its destination. for example, the entry in the 'row' column and 'nafta' row for crude oil and natural gas (good 5) shows that the us, canada and mexico together import $66 billion worth of crude oil and natural gas from the countries comprising row. the entry in the 'nafta' column and 'nafta' row, in contrast, shows the value of trade in crude oil and gas among the nafta countries. these aggregate regions will be used to assess the overall effects of nafta or the ftaa on the value of trade within the free trade area and between the trade area and the rest of the world. as discussed earlier, there is an empirical literature suggesting that tariff reform and increased international trade stimulate productivity growth. there are many mechanisms by which this could occur. industries previously protected by high tariffs and now faced with increased competition would almost certainly undertake cost-cutting measures and shift toward global best practices in production. lower trade barriers on durables would also allow a freer flow of new technology and embodied technical change. to incorporate this effect, we assume that when tariffs are reduced, previously protected industries are able to make modest improvements in productivity in response. in particular, we assume they are able to reduce their costs by a percentage equal to half of the change in their tariff, or by 5%, whichever is smaller. for example, the canadian tariff on durables is initially 4.14% so under this assumption trade reform would lead to a 2.07% improvement in the productivity of the canadian durables sector. in contrast, the mexican tariff on durables is initially 11.3% so the corresponding industry's productivity improvement would be limited to 5%. the full set of productivity shocks used in this section is shown in table 15 .10. under the nafta-p simulation, tariffs are reduced to zero on trade between the us, canada and mexico, and industries in those three countries receive the productivity improvements listed in table 15 .10. the ftaa-p simulation is similar to nafta-p, but also includes brazil and the rest of latin america. in both cases, it is important to note that the productivity shocks are one-time changes in productivity levels, not changes in the rate of productivity growth. they are very modest effects in the sense that they correspond to at most 2e3 years of ordinary productivity improvements. on the other hand, table 15 .9 value of trade flows between regions in the reference case: column shows source and row they do not include the effect of any adjustment costs or investment that might arise as the protected industries adapt. thus, they allow us to gauge the importance of productivity changes over the medium to long run but are not a precise prediction. table 15 .11 shows the effect of nafta-p on output, exports and capital stocks by sector and region in year 12. the results are percentage changes relative to the reference case. entries with changes greater than or equal to 1% in magnitude are given in italics and those with changes less than 0.1% in magnitude are left blank. as would be expected, the reduction in tariffs leads to an increase in trade among nafta countries. exports from the us, canada and mexico increase significantly. exports of durables (panel 2) rise by 2.4% in the us, 6.9% in canada and 8.6% in mexico. exports of non-durables increase even more because tariffs on non-durables are initially higher and hence fall more dramatically under a free trade agreement (the high tariffs on non-durables largely reflects the high levels of protection on textiles and apparel). exports of non-durables rise by 5.3% in the us, 18.5% in canada and 11.9% in mexico. the increase in trade raises the level of output of all industries in the us (panel 1), albeit by very small percentages in most cases. the corresponding capital stocks rise as well (panel 3). the output of almost all canadian industries increases, as does the output of most mexican industries. a notable exception is services (sector c) for both canada and mexico: output of services falls under nafta-p even though exports of services rise slightly in percentage terms due to the change in exchange rates (as well as increased demand for services in other countries that expand as a result of the policy). the reason is straightforward: the price of services rises, in part because the traded sectors grow and consume more labor, and in part because depreciation of the exchange rate raises the price of imported intermediate goods other than those whose tariffs have been cut. this effect is a recurring theme in the results and can be seen clearly in figure 15 .9, which shows percentage changes from the reference case in selected industry prices and quantities over time for the us, canada and mexico. the total value of the trade flows among nafta regions increases as shown in table 15 .12 (which also includes results for the ftaa, which will be discussed below). the value of trade in durables among nafta regions, for example, increases by $16 billion, while the value of trade in non-durables increases by $14 billion. comparing the magnitudes of the within-nafta flows with those between nafta and the rest of the world shows that nafta clearly increases trade rather than just redirecting it. in fact, the increase in economic activity stimulated within nafta actually causes aggregate nafta imports of both durables and non-durables from the rest of the world to rise. summing across goods and regions, nafta raises the total dollar value of trade flows in year 12 by $50 billion. the effects of nafta-p on trade and selected macroeconomic variables are shown in figure 15 .10. the reduction in tariffs in canada and mexico causes the demand for imports in those regions to increase, leading to depreciation of the two exchange rates relative to the us dollar. 47 the trade balances in the us, canada and mexico initially move toward deficit. the trade balances for brazil and the rest of latin america (as well as most other regions, although they are omitted from the graph) move toward surplus as imports by the us, canada and mexico rise. over time, however, the canadian and mexican trade deficits accumulate into increased stocks of foreign debt. the higher debt levels require larger interest payments, which consume an increasing share of each country's current account and eventually force the trade balance back toward surplus. this mechanism is made even stronger by the effect of exchange rates on each country's initial stocks of foreign debt. in particular, the depreciation of the canadian and mexican currencies relative to the us dollar increases the burden of servicing their us dollar denominated foreign debt. the reduction in tariffs also has an important fiscal effect: by reducing government revenue it increases the fiscal deficit in each region. the effect is very small in the us because tariff revenue is a small part of the government budget but it is significant in canada and mexico. in the short run, the reduction in tariffs functions as a fiscal stimulus. this effect would be significantly different under alternative monetary and fiscal assumptions. for example, other taxes could be raised to compensate for the reduction in tariff revenue, or government spending could be cut. in addition, monetary policy could be altered e in these simulations the money supply has been held constant at its base case value. either policy could reduce or eliminate the macroeconomic effects caused by the increase in the fiscal deficit. 47 in g-cubed, exchange rates are defined as the number of us dollars per unit of foreign currency. a decline in the exchange rate is a reduction in the number of dollars per unit of foreign currency and hence a depreciation of the currency. a global approach to energy and the environment: the g-cubed model table 15 .13 shows the effect of ftaa-p relative to nafta-p on output, exports and capital stocks by industry and region for year 12. the results are percentage changes relative to the nafta-p simulation; as before, entries with changes greater than or equal to 1% in magnitude are given in italics and those below 0.1% are left blank. the general nature of the results is highly analogous to those for nafta-p: the effect of the ftaa on brazil (i) and the rest of latin america (v) is very much like the effect of nafta-p on canada and mexico. the main difference is that the percentage changes tend to be larger in magnitude for brazil and the rest of latin america. for most industries, output, exports and capital stocks all increase substantially. this can be seen graphically in figure 15 .11, which shows the effects of ftaa-p relative to nafta-p on selected industry prices and output for all regions. in general, prices fall significantly in brazil and the rest of latin america, and output rises accordingly. as with nafta-p relative to the reference case, service sector output falls in brazil and the rest of latin america; however, the magnitude is relatively small. the value of trade flows between aggregate regions is shown in table 15 .12 above. the most notable result is a pronounced decline in imports of durables from non the final simulation was an anticipated implementation of the ftaa: the agreement was announced in the first year of the simulation but took effect in the fifth year. to distinguish it from the previous ftaa simulation, this version will be denoted ftaa5-p where the '5' indicates that implementation of the agreement is anticipated 5 years in advance. the effects of the anticipated ftaa will be equal to the differences between the ftaa5-p simulation and a counterfactual nafta simulation, nafta5-p, in which nafta was announced 5 years before its implementation. 48 when the ftaa is announced in advance, figure 15 .13 shows that very large anticipatory changes occur in exchange rates, trade accounts and macroeconomic variables. the key mechanism by which this occurs is the real exchange rate, which can be shown to be the price to foreigners of a given country's domestic assets. when the ftaa is implemented, real exchange rates for brazil and the rest of latin america will drop sharply for the reasons discussed in the previous section. investors anticipating the fall will be less willing to hold brazilian and latin american assets in advance, even at the beginning of the simulation. as a result, exchange rates for brazil and latin america deteriorate immediately. financial capital flows out of those regions and into the us and other large economies, whose trade balances deteriorate as a result. investment, labor demand, gdp and consumption all decline in brazil and the rest of latin america 48 this approach is used for the same reason that other ftaa simulations are compared to analogous nafta runs: the model's internal structure does not currently allow the size of a free trade area to change in the middle of a simulation. in the two simulations discussed in this section, either nafta or the ftaa is adopted immediately but remains dormant for 5 years. during that time, tariffs on imports from trade area partners remain the same as tariffs on other imports. this approximates an anticipated introduction of the ftaa. a global approach to energy and the environment: the g-cubed model during the period of anticipation and then rebound after implementation. by year 12, output levels, exports and capital stocks become similar to those from the unanticipated ftaa, as can be seen in table 15 .14. finally, figure 15 .14 shows the effect of each of the simulations on total carbon dioxide emissions from key regions. in keeping with the modest effects of nafta and the ftaa on industry output and gdp, the effect on carbon emissions is relatively small; in most cases, the change is 1e2% of emissions in the reference case. the only exception is the ftaa5-p experiment, which causes emissions to change by more than 3% in some years. the overall effects of the ftaa are highly analogous to nafta, but smaller in magnitude. countries reducing their tariffs see imports rise, exchange rates fall, trade balances move toward deficit, capital inflows increase and foreign debt levels rise. trade increases significantly between member countries and the largest changes arise in the most heavily traded sectors: durables and non-durables. the effects are most pronounced for non-durables because the initial tariffs are highest. liberalization is good for importers and exporters, as would be expected. non-traded sectors, particularly services, are hurt by the expansion of exporting industries which draw in labor and raise wages (even though, in percentage terms, exports of services rise slightly). for several of the ftaa countries the agreement would have a significant fiscal impact by reducing an importance source of government revenue. unless another tax is increased to compensate for the reduction in tariff revenue, the ftaa raises the country's fiscal deficit. providing a short-term stimulus but crowding out some private investment in the long run. allowing for industries to respond to liberalization by adopting modest productivity improvements sharply increases the overall gain from liberalization and reduces the fiscal drag causes by the drop in tariff revenue (tax revenue from other sources rises). both gdp and consumption rise significantly in liberalizing economies. in addition, productivity effects tend to reduce the changes in trade flows caused by liberalization because the difference in relative prices between foreign and domestic goods is smaller. this effect is particularly noticeable with durables imported by brazil and the rest of latin america. the ftaa and nafta are not analogous in one respect. nafta increases overall trade rather than just redirecting it away from non-nafta countries. the effect of the ftaa, however, is closer to trade redirection than to trade creation. the difference stems from the relative effects of the agreements on the us. nafta does more to stimulate the us economy and thus has a larger effect on the us demand for imports. finally, the effect of both nafta and the ftaa on carbon emissions are very small. neither agreement has much effect on energy consumption. the effect on criteria air pollutants would be small as well. g-cubed bridges three areas of research e econometric general equilibrium modeling, international trade theory and modern macroeconomics e to provide a versatile multicountry, multisector, intertemporal general equilibrium model that can be used for a wide variety of policy analyses. it distinguishes between financial and physical capital, tracking financial capital by currency and physical capital by region and sector where it is installed. investment, saving and international asset markets are driven by agents solving intertemporal optimization problems and having expectations driven by foresight (although not always perfect foresight). all budget constraints are imposed, including those applying to regions as a whole: all trade deficits must eventually be repaid by future trade surpluses. this combination of features allows the model to be used for a wide range of applications. its industry detail allows it to be used to examine environmental and tax policies, which tend to have their largest direct effects on small segments of the economy. intertemporal modeling of investment and saving allows it to trace out the transition of the economy between the short run and the long run. slow wage adjustment and liquidity-constrained agents improves the empirical accuracy with which the model captures the transition. to date, g-cubed has been used in nearly 80 studies covering topics ranging from climate and energy policy to pandemic influenza. its core strengths are: (i) scenario analysis, where scenarios are made up of different shocks that might confront the world economy or an individual country, and (ii) policy evaluation, especially where dynamic adjustment towards a long-run equilibrium is important. it has also occasionally been used as a forecasting model although it was not designed for that purpose. g-cubed continues to evolve and there a number of areas where research is underway to improve it. one project currently underway is an analysis of the effects of alternative fiscal closures on the consequences of imposing a carbon tax in the us. a second project, also underway, is further disaggregation of the energy sectors, which will allow analysis of a wider range of primary energy inputs will include explicit treatment of alternative energy generation technologies. a third project focuses on the role of infrastructure. this is particularly important for better understanding the determinants of economic growth especially in developing countries. it will also be critical when using the model to evaluate large fiscal consolidation programs in heavily indebted industrial economies over future years. a fourth area where more work is underway is improved estimation of g-cubed's dynamic adjustment parameters. although many of the intratemporal parameters of the model are estimated, the key dynamic parameters are largely calibrated. a number of alternative approaches are possible to improve this. perhaps the most attractive, particularly in adapting the core model to be used as a forecasting tool is to further develop the approach in pagan et al. 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collaboration with many coauthors including kym key: cord-303165-ikepr2p2 authors: tulchinsky, theodore h.; varavikova, elena a. title: expanding the concept of public health date: 2014-10-10 journal: the new public health doi: 10.1016/b978-0-12-415766-8.00002-1 sha: doc_id: 303165 cord_uid: ikepr2p2 ancient societies recognized the needs of sanitation, food safety, workers’ health, and medical care to protect against disease and to promote well-being and civic prosperity. new energies and knowledge since the eighteenth century produced landmark discoveries such as prevention of scurvy and vaccination against smallpox. the biological germ theory and competing miasma theory each proved effective in sanitation, and immunization in control of infectious diseases. non-communicable diseases as the leading causes of mortality have responded to innovative preventive care of health risk factors, smoking, hypertension, obesity, physical inactivity, unhealthful diets, and diabetes mellitus. health promotion proved effective to modern public health in tackling disease origins, individual behavior, and social and economic conditions. the global burden of infectious and non-communicable diseases, aging and chronic illness faces rising costs and still inadequate prevention. the evolution of concepts of public health will have to address these new challenges of population health. the development of public health from its ancient and recent roots, especially in the past several centuries, is a continuing process, with evolutionary and sometimes dramatic leaps forward, and important continuing and new challenges for personal and population health and well-being. everything in the new public health is about preventing avoidable disease, injuries, disabilities, and death while promoting and maximizing a healthy environment and optimal conditions for current and future generations. thus, the new public health addresses overall health policy, resource allocation, as well as the organization, management, and provision of medical care and of health systems in general within a framework of overall social policy and in a community, state, national, transnational, and global context. the study of history (see chapter 1) helps us to understand the process of change, to define where we came from and where we are going. it is vital to recognize and understand change in order to deal with radical transformations in direction that occur as a result of changing demography and epidemiology, new science, evolving best practices in public health and clinical medicine, and above all inequalities in health resulting from societal system failures and social and economic factors. health needs will continue to develop in the context of environmental, demographic and societal adjustments, with knowledge gained from social and physical sciences, practice, and economics. for the coming generations, this is about not only the quality of life, but the survival of society itself. over the past century there have been many definitions of public health and health for all. mostly they represent visions and ideals of societal and global aspirations. this chapter examines the very base of the new public health, which encompasses the classic issues of public health with recognition of the advances made in health promotion and the management of health care systems as integral components of societal efforts to improve the health of populations and of individuals. what follows in succeeding chapters will address the major concepts leading to modern and comprehensive elements of public health. inevitably, concepts of public health continue to evolve and to develop both as a philosophy and as a structured discipline. as a professional field, public health requires specialists trained with knowledge and appreciation of its evolution, scientific advances, concepts, and best practices, old and modern. it demands sophisticated professional and managerial skills, the ability to address a problem, reasoning to define the issues, and to advocate, initiate, develop, and implement new and revised programs. it calls for profoundly humanistic values and a sense of responsibility towards protecting and improving the health of communities and every individual. in the twenty-first century, this set of values was well expressed in the human development index agreed to by 160 nations (box 2.1). public health is a multidimensional field and therefore multidisciplinary in its workforce and organizational needs. it is based on scientific advances and application of best practices as they evolve, and includes many concepts, including holistic health, first established in ancient times. the discussion will return to the diversity of public health throughout this chapter and book many times. in previous centuries, public health was seen primarily as a discipline which studies and implements measures for control of communicable diseases, primarily by sanitation and vaccination. the sanitary revolution, which preceded the development of modern bacteriology, made an enormous contribution to improved health, but many other societal factors including improved nutrition, education, and housing were no less important for population health. maternal and child health, occupational health, and many other aspects of a growing public health network of activities played important roles, as have the physical and social environment and personal habits of living in determining health status. in recent decades recognition of the importance of women's health and health inequalities associated with many high-risk groups in the population have seen both successes and failures in addressing their challenges. male health issues have received less attention, apart from issues associated with specific diseases, or those of healthy military personnel. the scope of public health has changed along with growth of the medical, social, and public health sciences, public expectations, and practical experience. taken together, these have all contributed to changes in the concepts and causes of disease. health systems that fail to adjust to changes in fundamental concepts of public health suffer from immense inequity and burdens of preventable disease, disability, and death. this chapter examines expanding concepts of public health, leading to the development of a new public health. public health has evolved as a multidisciplinary field that includes the use of basic and applied science, education, social sciences, economics, management, and communication skills to promote the welfare of the individual and the community. it is greater than the sum of its component elements and includes the art and politics of the funding and coordination of the wide diversity of community and individual health services. the concept of the interdependence of health in body and in mind has ancient origins. they continue to be fundamental to individuals and societies, and part of the fundamental rights of all humans to have knowledge of healthful lifestyles and to have access to those measures of good health that society alone is able to provide, such as immunization programs, food and drug safety and quality standards, environmental and occupational health, and universal access to high-quality primary and specialty medical and other vital health services. this holistic view of balance and equilibrium may be a renaissance of classical greek and biblical traditions, applied with the broad new knowledge and experience of public health and medical care of the nineteenth, twentieth, and the early years of the twenty-first centuries as change continues to challenge our capacity to adapt. the competing nineteenth-century germ and miasma theories of biological and environmental causation of illness each contributed to the development of sanitation, hygiene, immunization, and understanding of the biological and social determinants of disease and health. they come together in the twenty-first century encompassed in a holistic new public health addressing individual and population health needs. medicine and public health professionals both engage in organization and in direct care services. these all necessitate an understanding of the issues that are included in the new public health, how they evolved, interact, are put together in organizations, and are financed and operated in various parts of the world in order to understand changes going on before our eyes. great success has been achieved in reducing the burden of disease with tools and concepts currently at our disposal. the idea that this is an entitlement for everyone was articulated in the health for all concept of alma-ata in 1978. the health promotion movement emerged in the 1970s and showed dramatically effective results in managing the new human immunodeficiency virus (hiv) pandemic and in tackling smoking and other risk factors for non-communicable diseases (ncds). a health in all policy concept emerged in 2006 promoting the concept that health should be a basic component of all public and private policies to achieve the full potential of public health and eliminate inequalities associated with social and economic conditions. profound changes are taking place in the world population, and public health is crucial to respond accordingly: mass migration to the cities, fewer children, extended life expectancy, and the increase in the population of older people who are subject to more chronic diseases and disabilities in a changing physical, social, and economic climate. health systems are challenged with continuing development of new medical technologies and related reforms in clinical practice, while experiencing strong influences of pharmaceuticals and the medicalization of health, with prevention and health promotion less central in priorities and resource allocation. globalization of health has many meanings: international trade, improving global communications, and economic changes with increasing flows of goods, services, and people. ecological and climate change bring droughts, hurricanes, arctic meltdown, and rising sea levels. globalization also has political effects, with water and food shortages, terrorism, and economic distress affecting billions of people. in terms of health, disease can spread from one part of the world to others, as in pandemics or in a quiet spread such as that of west nile fever moving from its original middle eastern natural habitat to the americas and europe, or severe acute respiratory syndrome (sars), which spread with lightning speed from chinese villages to metropolitan cities such as toronto, canada. it can also mean that the ncds characteristic of the industrialized countries are now recognized as the leading causes of death in low-and middle-income countries, associated with diet, activity levels, and smoking, which are themselves pandemic risk factors. the potential for global action in health can also be dramatic. the eradication of smallpox was a stunning victory for public health. the campaign to eradicate poliomyelitis is succeeding even though the end-stage is fraught with setbacks, and measles elimination has turned out to be more of a challenge than was anticipated a decade ago, with resurgence in countries thought to have it under control. global health policies have also made the achievements of public-private partnerships of great importance, particularly in vaccination and acquired immunodeficiency syndrome (aids) control programs. there have been failures as well, with very limited progress in human resources development of the public health workforce in low-income countries. the new public health is necessarily comprehensive in scope and it will continue to evolve as new technologies and scientific discoveries -biological, genetic, and sociological -reveal more methods of disease control and health promotion. it relates to or encompasses all community and individual activities directed towards improving the environment for health, reducing factors that contribute to the burden of disease, and fostering those factors that relate directly to improved health. its programs range broadly from immunization, health promotion, and child care, to food labeling and fortification, as well as to the assurance of well-managed, accessible health care services. a strong public health system should have adequate preparedness for natural and human-made disasters, as seen in the recent tsunamis, hurricanes, biological or other attacks by terrorists, wars, conflicts, and genocidal terrorism (box 2.2) . the concepts of health promotion and disease prevention are essential and fundamental elements of the new public health. parallel scientific advances in molecular biology, genetics and pharmacogenomics, imaging, information technology, computerization, biotechnology, and nanotechnology hold great promise for improving the productivity of the health care system. advances in technology with more effective and less expensive drug and vaccine development, with improved safety and effectiveness, and fewer adverse reactions, will over time greatly increase efficiency in prevention and treatment modalities. the new public health is important as a conceptual base for training and practice of public health. it links classical topics of public health with adaptation in the organization and financing of personal health services. it involves a changed paradigm of public health to incorporate new advances in political, economic, and social sciences. failure at the political level to appreciate the role of public health in disease control holds back many societies in economic and social development. at the same time, organized public health systems need to work to reduce inequities between and inside countries to ensure equal access to care. it also demands special attention through health promotion activities of all kinds at national and local societal levels to provide access for groups with special risks and needs to medical and community health care with the currently available and newly developing knowledge and technologies. the great gap between available capabilities to prevent and treat disease and actually reaching all in need is still the the mission of the nph is to maximize human health and well-being for individuals and communities, nationally and globally. the methods with which the nph works to achieve this are in keeping with recognized international best practices and scientific advances: 1. societal commitment and sustained efforts to maximize quality of life and health, economic growth with equity for all (health for all and health in all). collaboration between international, national, state, and local health authorities working with public and private sectors to promote health awareness and activities essential for population health. 3. health promotion of knowledge, attitudes, and practices, including legislation and regulation to protect, maintain, and advance individual and community health. 4. universal access to services for prevention and treatment of illness and disability, and promotion of maximum rehabilitation. 5. environmental, biological, occupational, social, and economic factors that endanger health and human life, addressing: (a) physical and mental illness, diseases and infirmity, trauma and injuries (b) local and global sanitation and environmental ecology (c) healthful nutrition and food security including availability, quality, safety, access, and affordability of food products (d) disasters, natural and human-made, including war, terrorism, and genocide (e) population groups at special risk and with specific health needs. 6. promoting links between health protection and personal health services through health policies and health systems management, recognizing economic and quality standards of medical, hospital, and other professional care in health of individuals and populations. 7. training of professional public health workforces and education of all health workers in the principles of ethical best practices of public health and health systems. 8. research and promotion of current best practices: wide application of current international best practices and standards. 9. mobilizing the best available evidence from local and international scientific and epidemiological studies and best practices recognized as contributing to the overall goal. 10. maintaining and promoting equity for individual and community rights to health with high professional and ethical standards. source of great international and internal national inequities. these inequities exist not only between developed and developing countries, but also within transition countries, mid-level developing countries, and those newly emerging with rapid economic development. the historical experience of public health will help to develop the applications of existing and new knowledge and societal commitment to social solidarity in implementation of the new discoveries for every member of the society, despite socioeconomic, ethnic, or other differences. political will and leadership in health, adequate financing, and organization systems in the health setting are crucial to furthering health as an objective with defined targets, supported by well-trained staff for planning, management, and monitoring the population health and functioning of health systems. political leadership and professional support are both indispensable in a world of limited resources, with high public expectations and the growing possibilities of effectiveness of public health programs. well-developed information and knowledge management systems are required to provide the feedback and information needed for good management. it includes responsibilities and coordination at all levels of government. non-governmental organizations (ngos) and participation of a well-informed media and strong professional and consumer organizations also have significant roles in furthering population health. no less important are clear designations of responsibilities of the individual for his or her own health, and of the provider of care for humane, high-quality professional care. the complexities and interacting factors are suggested in figure 2 .1, with the classic host-agent-environment triad. many changes have signaled a need for transformation towards the new public health. religion, although still a major political and policy-making force in many countries, is no longer the central organizing power in most societies. organized societies have evolved from large extended families and tribes to rural societies, cities, regions, and national governments. with the growth of industrialized urban communities, rapid transport, and extensive trade and commerce in multinational economic systems, the health of individuals and communities has become more than just a personal, family, and/or local problem. an individual is not only a citizen of the village, city, or country in which he or she lives, but a citizen of a "global village". the agricultural revolutions and international explorations of the fifteenth to seventeenth centuries that increased food supply and diversity were followed only much later by knowledge of nutrition as a public health issue. the scientific revolution of the seventeenth to nineteenth centuries provided the basics to describe and analyze the spread of disease and the poisonous effects of the industrial revolution, including crowded living conditions and pollution of the environment with serious ecological damage. in the latter part of the twentieth century, a new agricultural "green revolution" had a great impact in reducing human deprivation internationally, yet the full benefits of healthier societies are yet to be realized in the large populations living in abject poverty in sub-saharan africa, south-east asia, and other parts of the world. global water shortages can be addressed with new methods of irrigation, water conservation and the application of genetic sciences to food production, and issues of economics and food security are of great importance to a still growing world population with limited supplies. further, food production capacity can and must be enlarged to meet current food insecurity, rising expectations of developing nations, and population growth. the sciences of agriculture-related fields, including genetic sciences and practical technology, will be vital to human progress in the coming decades. these and other societal changes discussed in chapter 1 have enabled public health to expand its potential and horizons, while developing its pragmatic and scientific base. organized public health in the twentieth century proved effective in reducing the burden of infectious diseases and has contributed to improved quality of life and longevity by many years. in the last half-century, chronic diseases have become the primary causes of morbidity and mortality in the developed countries and increasingly in developing countries. growing scientific and epidemiological knowledge increases the capacity to deal with these diseases. many aspects of public health can only be influenced by the behavior of and risks to the health of individuals. these require interventions that are more complex and relate to societal, environmental, and community standards and expectations as much as to personal lifestyle. the dividing line between communicable and non-communicable diseases changes over time. scientific advances have shown the causation of chronic conditions by infectious agents and their prevention by curing the infection, as in helicobacter pylori and peptic ulcers, and in prevention of cancer of the liver and cervix by immunization for hepatitis b and human papillomavirus (hpv), respectively. chronic diseases have come to the center stage in the "epidemiological transition", as infectious diseases came under increasing control. this, in part, has created a need for reform in the funding and management of health systems due to rapidly rising costs, aging of the population, the rise of obesity and diabetes and other chronic conditions, mushrooming therapeutic technology, and expanding capacity to deal with public health emergencies. reform is also needed in international assistance to help less developed nations build the essential infrastructure to sustain public health in the struggle to combat aids, malaria, tuberculosis (tb), and the major causes of preventable infant, childhood, and motherhood-related deaths. the nearly universal recognition of the rights of people to have access to health care of acceptable quality by international standards is a challenge of political will and leadership backed up by adequate staffing with public health-trained staff and organizations. the challenges of the current global economic crisis are impacting social and health systems around the world. the interconnectedness of managing health systems is part of the new public health. setting the priorities and allocating resources to address these challenges requires public health training and orientation of the professionals and institutions participating in the policy, management, and economics of health systems. conversely, those who manage such institutions are recognizing the need for a wide background in public health training in order to fulfill their responsibilities effectively. concepts such as objectives, targets, priorities, cost-effectiveness, and evaluation have become part of the new public health agenda. an understanding of how these concepts evolved will help the future health provider or manager to cope with the complexities of mixing science, humanity, and effective management of resources to achieve higher standards of health, and to cope with new issues as they develop in the broad scope of the new public health for the twenty-first century, in what breslow called the "third public health era" of long and healthy quality of life (box 2.3). health can be defined from many perspectives, ranging from statistics on mortality, life expectancy, and morbidity rates to idealized versions of human and societal perfection, as in the world health organization's (who's) founding charter. the first public health era -the control of communicable diseases. second public health era -the rise and fall of chronic diseases. third public health era -the development of long and high-quality life. preamble to the constitution of the who, as adopted by the international health conference in new york in 1946 and signed by the representatives of 61 states, entered into force on 7 april 1948, with the widely cited definition: "health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity". this definition is still important conceptually as an ideal accepted as fundamental to public policy over the years. a more operational definition of health is a state of equilibrium of the person with the biological, physical, and social environment, with the object of maximum functional capability. health is thus seen as a state characterized by anatomical, physiological, and psychological integrity, and an optimal functional capability in the family, work, and societal roles (including coping with associated stresses), a feeling of well-being, and freedom from risk of disease and premature death. deviances in health are referred to as unhealthy and constitute a disease nomenclature. there are many interrelated factors in disease and in their management through what is now called risk reduction. in 1878, claude bernard described the phenomenon of adaptation and adjustment of the internal milieu of the living organism to physiological processes. this concept is fundamental to medicine. it is also central to public health because understanding the spectrum of events and factors between health and disease is basic to the identification of contributory factors affecting the balance towards health, and to seeking the points of potential intervention to reverse the imbalance. as described in chapter 1, from the time of hippocrates and galen, diseases were thought to be due to humors and miasma or emanations from the environment. this was termed the miasma theory, and while without a direct scientific explanation, it was acted upon in the early to mid-nineteenth century and promoted by leading public health theorists including florence nightingale, with practical and successful measures to improve sanitation, housing, and social conditions, and having important results in improving health conditions. the competing germ theory developed by pioneering nineteenthcentury epidemiologists (panum, snow, and budd), scientists (pasteur, cohn, and koch), and practitioners (lister and semmelweiss) led to the science of bacteriology and a revolution in practical public health measures. the combined application of the germ (agent-host-environment) and miasma theories (social and sanitary environment) has been the basis of classic public health, with enormous benefits in the control of infectious and other diseases or harmful conditions. the revolutionary changes occurring since the 1960s have brought about a decline in cardiovascular and cancer mortality, and conceptual changes such as health for all and health in all to bring health issues to all policies at both governmental and individual levels. the concepts of public health advanced with the 1974 marc lalonde health field concept (new perspectives on the health of canadians, 1974) , stating that health was the result of the physical and social environment, lifestyle and personal habits, genetics, as well as organization and provision of medical care. the lalonde report was a key concept leading to ideas advanced at the alma-ata conference on primary care held in 1978 and more explicitly in the development of the basis for health promotion as articulated in the ottawa charter of 1986 on health promotion. this marked the beginning of a whole new aspect of public health, which proved itself in addressing with considerable success the epidemic of hiv and cardiovascular diseases. in the usa, the surgeon general's reports of 1964 on smoking and health, and of 1979 defining health targets as national policy promoted the incorporation of "management by objectives" from the business world applied to the health sector (see chapter 12). this led to healthy people usa 2000 and later versions, and the united nations (un) millennium development goals (mdgs), aimed primarily at the middle-and low-income countries (box 2.4). the identification of infectious causes of cancers of the liver and cervix established a new paradigm in epidemiology, and genetic epidemiology has important potential for public health and clinical medicine. in the basic host-agent-environment paradigm, a harmful agent comes through a sympathetic environment into contact with a susceptible host, causing a specific disease. this idea dominated public health thinking until the midtwentieth century. the host is the person who has or is at risk for a specific disease. the agent is the organism or direct cause of the disease. the environment includes the external factors which influence the host, his or her susceptibility to the agent, and the vector which transmits or carries the agent to the host from the environment. this explains the causation and transmission of many diseases. this paradigm (figure 2. 2), in effect, joins together the contagion and miasma theories of disease causation. a specific agent, a method of transmission, and a susceptible host are involved in an interaction, which are central to the infectivity or severity of the disease. the environment can provide the carrier or vector of an infective (or toxic) agent, and it also contributes factors to host susceptibility; for example, unemployment, poverty, or low education level. the expanded host-agent-environment paradigm widens the definition of each of the three components ( figure 2 .3), in relation to both acute infectious and chronic noninfectious disease epidemiology. in the latter half of the twentieth century, this expanded host-agent-environment paradigm took on added importance in dealing with the complex of factors related to chronic diseases, now the leading causes of disease and premature mortality in the developed world, and increasingly in developing countries. interventions to change host, environmental, or agent factors are the essence of public health. in infectious disease control, the biological agent may be removed by pasteurization of food products or filtration and disinfection (chlorination) of water supplies to prevent transmission of waterborne disease. the host may be altered by immunization to provide immunity to a specific infective organism. the environment may be changed to prevent transmission by destroying the vector or its reservoir of the disease. a combination of these interventions can be used against a specific risk factor, toxic or nutritional deficiency, infectious organism, or disease process. vaccine-preventable diseases may require both routine and special activities to boost herd immunity to protect the individual and the community. for other infectious diseases for which there is no vaccine (e.g., malaria), control involves a broad range of activities including case finding and treatment to improve the individual's health and to reduce the reservoir of the disease in the population, and other measures such as bed nets to reduce exposure of the host to vector mosquitoes, as well as vector control to reduce the mosquito population. tb control requires not only case finding and treatment, but understanding the contributory factors of social conditions, diseases with tb as a secondary condition (substance abuse and aids), agent resistance to treatment, and the inability of patients or carriers to complete treatment without supervision. sexually transmitted infections (stis) which are not controllable by vaccines require a combination of personal behavior change, health education, medical care, and skilled epidemiology. with non-infectious diseases, intervention is even more complex, involving human behavior factors and a wide range of legal, administrative, and educational issues. there may be multiple risk factors, which have a compounding effect in disease causation, and they may be harder to alter than infectious diseases factors. for example, smoking in and of itself is a risk factor for lung cancer, but exposure to asbestos fibers has a compounding effect. preventing exposure to the compounding variables may be easier than smoking cessation. reducing trauma morbidity and mortality is equally problematic. the identification of a single specific cause of a disease is of great scientific and practical value in modern public health, enabling such direct interventions as the use of vaccines or antibiotics to protect or treat individuals from infection by a causative organism, toxin, deficiency condition, or social factor. the cumulative effects of several contributing or risk factors in disease causation are also of great significance in many disease processes, in relation to infectious diseases such as nutritional status as for chronic diseases such as the cardiovascular group. the health of an individual is affected by risk factors intrinsic to that person as well as by external factors. intrinsic factors include the biological ones that the individual inherits and those life habits he or she acquires, such as smoking, overeating, or engaging in other high-risk behaviors. external factors affecting individual health include the environment, the socioeconomic and psychological state of the person, the family, and the society in which he or she lives. education, culture, and religion are also contributory factors to individual and community health. there are factors that relate to health of the individual in which the society or the community can play a direct role. one of these is provision of medical care. another is to ensure that the environment and community services include safety factors that reduce the chance of injury and disease, or include protective measures; for example, fluoridation of a community water supply to improve dental health, and seat-belt or helmet laws to reduce motor vehicle injury and death. these modifying factors may affect the response of the individual or the spread of an epidemic (see chapter 3). an epidemic may also include chronic disease, because common risk factors may cause an excess of cases in a susceptible population group, in comparison to the situation before the risk factor appeared, or in comparison to a group not exposed to the risk factor. these include rapid changes or "epidemics" in such conditions as type 2 diabetes, asthma, cardiovascular diseases, trauma, and other non-infectious disorders. disease is a dynamic process, not only of causation, but also of incubation or gradual development, severity, and the effects of interventions intended to modify outcome. knowledge of the natural history of disease is fundamental to understanding where and with what means intervention can have the greatest chance for successful interruption or change in the disease process for the patient, family, or community. the natural history of a disease is the course of that disease from beginning to end. this includes the factors that relate to its initiation; its clinical course leading up to resolution, cure, continuation, or long-term sequelae (further stages or complications of a disease); and environmental or intrinsic (genetic or lifestyle) factors and their effects at all stages of the disease. the effects of intervention at any stage of the disease are part of the disease process (figure 2 .4). as discussed above, disease occurs in an individual when agent, host, and environment interact to create adverse conditions of health. the agent may be an infectious organism, a chemical exposure, a genetic defect, or a deficiency condition. a form of individual or social behavior, such as reckless driving or risky sexual behavior, may lead to injury or disease. the host may be immune or susceptible as a result of many contributing social and environmental factors. the environment includes the vector, which may be a malaria-bearing mosquito, a contaminated needle shared by drug users, lead-contaminated paint, or an abusive family situation. assuming a natural state of "wellness" -i.e., optimal health or a sense of well-being, function, and absence of disease -a disease process may begin with the onset of a disease, infectious or non-infectious, following a somewhat characteristic pattern of "incubation" described by clinicians and epidemiologists. preclinical or predisposing events may be detected by a clinical history, with determination of risk including possible exposure or presence of other risk factors. interventions, before and during the process, are intended to affect the later course of the disease. the clinical course of a disease, or its laboratory or radiological findings, may be altered by medical or public health intervention, leading to the resolution or continuation of the disease with fewer or less severe secondary sequelae. thus, the intervention becomes part of the natural history of the disease. the natural history of an infectious disease in a population will be affected by the extent of prior vaccination or previous exposure in the community. diseases particular to children are often so because the adult population is immune from previous exposure or vaccinations. measles and diphtheria, primarily childhood diseases, now affect adults to a large extent because they are less protected by naturally acquired immunity or are vulnerable when their immunity wanes naturally or as a result of inadequate vaccination in childhood. in chronic disease management, high costs to the patient and the health system accrue where preventive services or management are inadequate, not yet available, or inaccessible or where there is a failure to apply the necessary interventions. the progress of diabetes to severe complications such as cardiovascular, renal, and ocular disease is delayed or reduced by good management of the condition, with a combination of smoking cessation, diet, exercise, and medications with good medical supervision. the patient with advanced chronic obstructive pulmonary disease or congestive heart failure may be managed well and remain stable with smoking avoidance, careful management of medications, immunizations against influenza and pneumonia, and other prevention-oriented care needs. where these are not applied or if they fail, the patient may require long and expensive medical and hospital care. failure to provide adequate supportive care will show up in ways that are more costly to the health system and will prove more life-threatening to the patient. the goal is to avoid where possible the necessity for tertiary care, substituting tertiary prevention, i.e., supportive rehabilitation to maximum personal function and maintaining a stable functional status. as in an individual, the phenomenon of a disease in a population may follow a course in which many factors interplay, and where interventions affect the natural course of the disease. the epidemiological patterns of an infectious disease can be assessed in their occurrence in the population or their mortality rates, just as they can for individual cases. the classic mid-nineteenth-century description of measles in the faroe islands by panum showed the transmission and the epidemic nature of the disease as well as the protective effect of acquired immunity (see chapter 1). similar, more recent breakthroughs in medical, epidemiological, biological, and social sciences have produced enormous benefit for humankind as discussed throughout this text, with some examples. these include the eradication of smallpox and in the coming years, poliomyelitis, measles, leprosy, and other dreaded diseases known for millennia; the near-elimination of rheumatic heart disease and peptic ulcers in the industrialized countries; vast reduction in mortality from stroke and coronary heart disease (chd); and vaccines (against hepatitis b and hpv) for the prevention of cancers. these and other great achievements of the twentieth and early part of the twenty-first centuries hold great promise for humankind in the coming decades, but great challenges lie ahead as well. the biggest challenge is to bring the benefits of known public health capacity to the poorest population of each country and the poorest populations globally. in developed countries a major challenge is to renew efforts of public health capacity to bear on prevention of chronic conditions such as diabetes and obesity, considered to be at pandemic proportions; and the individual and societal effects of mental diseases. in public health today, fears of a pandemic of avian influenza are based on transmission of avian or other animal-borne (zoonotic) prions or viruses to humans and then their adaptation permitting human-to-human spread. with large numbers of people living in close contact with many animals (wild and domestic fowl), such as in china and south-east asia, and rapid transportation around the world, the potential for global spread of disease is almost without historical precedent. indeed, many human infectious diseases are zoonotic in origin and transferred from natural wildlife reservoirs to humans either directly or via domestic or other wild animals, such as from birds to chickens to humans in avian influenza. monitoring or immunization of domestic animals requires a combination of multidisciplinary zoonotic disease management strategies, public education and awareness, and veterinary public health monitoring and control. rift valley fever, equine encephalitis, and more recently sars and avian influenza associated with bird-borne viral disease which can affect humans, each show the terrible dangers of pandemic diseases. ebola virus is probably sustained between outbreaks among fruit bats, or as recently suggested wild or domestic pigs, and may become a major threat to public health as human case fatality rates decline, meaning that patients and carriers, or genetic drift of the virus with possible airborne transmission, may spread this deadly disease more widely than in the past (see chapter 4). the health of populations, like the health of individuals, depends on societal factors no less than on genetics, personal risk factors, and medical services. social inequalities in health have been understood and documented in public health over the centuries. the chadwick and shattuck reports of 1840-1850 documented the relationship of poverty and bad sanitation, housing, and working conditions with high mortality, and ushered in the idea of social epidemiology. political and social ideologies thought that the welfare state, including universal health care systems of one type or another, would eliminate social and geographic differences in health status and this is in large part true. from the introduction of compulsory health insurance in germany in the 1880s to the failed attempt in the usa at national health insurance in 1995 (see chapters 1, 10 and 13) and the more recent achievements of us president obama in 2010-2011, social reforms to deal with inequalities in health have focused on improving access to medical and hospital care. almost all industrialized countries have developed such systems, and the contribution of these programs to improve health status has been an important part of social progress, especially since world war ii. but even in societies with universal access to health care, people of lower socioeconomic status (ses) suffer higher rates of morbidity and mortality from a wide variety of diseases. the black report (douglas black) in the uk in the early 1980s pointed out that the class v population (unskilled laborers) had twice the total and specific mortality rates of the class i population (professional and business) for virtually all disease categories, ranging from infant mortality to death from cancer. the report was shocking because all britons have had access to the comprehensive national health service (nhs) since its inception in 1948, with access to a complete range of services at no cost at time of service, close relations to their general practitioners, and good access to specialty services. these findings initiated reappraisals of the social factors that had previously been regarded as the academic interests of medical sociologists and anthropologists and marginal to medical care. more recent studies and reviews of regional, ethnic, and socioeconomic differentials in patterns of health care access, morbidity, and mortality indicate that health inequities are present in all societies including the uk, the usa, and others, even with universal health insurance or services. the ottawa charter on health promotion in 1986 placed a new paradigm before the world health community that recognized social and political factors as no less important ion health that traditional medical and sanitary public health measures. these concepts helped the world health community to cope with new problems such as hiv/aidsfor which there was neither a medical cure nor a vaccine to prevent the disease. its control came to depend in the initial decades almost entirely on education and change in lifestyles, until the advent of the antiretroviral drugs in the 1990s. there is still no viable vaccine. although the epidemiology of cardiovascular disease shows the direct relationship of the now classic risk factors of stress, smoking, poor diet, and physical inactivity, differences in mortality from cardiovascular disease between different classes among british civil servants are not entirely explainable by these factors. the differences are also affected by social and economic issues that may relate to the psychological needs of the individual, such as the degree of control people have over their own lives. blue-collar workers have less control over their lives, their working life in particular, than their white-collar counterparts, and have higher rates of chd mortality than higher social classes. other work shows the effects of migration, unemployment, drastic social and political change, and binge drinking, along with protective effects of healthy lifestyle, religiosity, and family support systems in cardiovascular diseases. social conditions affect disease distribution in all societies. in the usa and western europe, tb has re-emerged as a significant public health problem in urban areas partly because of high-risk population groups, owing to poverty and alienation from society, as in the cases of homelessness, drug abuse, and hiv infection. in countries of eastern europe and the former soviet union, the recent rise in tb incidence has resulted from various social and economic factors in the early 1990s, including the large-scale release of prisoners. in both cases, diagnosis and prescription of medication are inadequate, and the community at large becomes at risk because of the development of antibioticresistant strains of tubercle bacillus readily spread by inadequately treated carriers, acting as human vectors. studies of ses and health are applicable and valuable in many settings. in alameda county, california, differences in mortality between black and white population groups in terms of survival from cancer became insignificant when controlled for social class. a 30-year follow-up study of the county population reported that low-income families in california are more likely than those on a higher income to have physical and mental problems that interfere with daily life, contributing to further impoverishment. studies of the association between indicators of ses and recent screening in the usa, australia, finland, and elsewhere showed that lower ses women use less preventive care such as papanicolaou (pap) smears for cervical cancer than women of higher ses, despite having greater risk for cervical cancer. many factors in ses inequalities are involved, including transportation and access to primary care, differences in health insurance coverage, educational levels, poverty, high-risk behaviors, social and emotional distress, feeling a lack of control over one's own life, employment, occupation, and inadequate family or community social support systems. many barriers exist owing to difficulties in access and the lack of availability of free or low-cost medical care, and the absence or limitations of health insurance is a further factor in the socioeconomic gradient. the recognition that health and disease are influenced by many factors, including social inequalities, plays a fundamental role in the new public health paradigm. health care systems need to take into account economic, social, physical, and psychological factors that otherwise will limit the effectiveness of even the best medical care. the health system includes access to competent and responsible primary care as well as by the wider health system, including health promotion, specific prevention and population-based health protection. the paradigm of the host-agent-environment triad (figures 2.2 and 2. 3) is profoundly affected by the wider context. the sociopolitical environment and organized efforts at intervention affect the epidemiological and clinical course of disease of the individual. medical care is essential, as is public health, but the persistent health inequities seen in most regions and countries require societal attention. success or failure in improving the conditions of life for the poor, and other vulnerable "risk groups", affect national or regional health status and health system performance. the health system is meant to reduce the occurrence or bad outcome of disease, either directly by primary prevention or treatment as secondary prevention or by maximum rehabilitation as tertiary prevention, or equally important indirectly by reducing community or individual risk factors. the the effects of social conditions on health can be partly offset by interventions intended to promote healthful conditions; for example, improved sanitation, or through good-quality primary and secondary health services, used efficiently and effectively made available to all. the approaches to preventing disease or its complications may require physical changes in the environment, such as removal of the broad street pump handle to stop the cholera epidemic in london, or altering diets as in goldberger's work on pellagra. some of the great successes of public health have been and continue to be low technology. examples, among many others, include insecticide-impregnated bednets and other vector control measures, oral rehydration solutions, treatment and cure of peptic ulcers, exercise and diet to reduce obesity, hand washing in hospitals (and other health facilities), community health workers, and condoms and circumcision for the prevention of stis, including hiv and cancer of the cervix. the societal context in terms of employment, social security, female education, recreation, family income, cost of living, housing, and homelessness is relevant to the health status of a population. income distribution in a wealthy country may leave a wide gap between the upper and lower socioeconomic groups, which affects health status. the media have great power to sway public perception of health issues by choosing what to publish and the context in which to present information to society. modern media may influence an individual's tendency to overestimate the risk of some health issues while underestimating the risk of others, ultimately influencing health choices, such as occurred with public concern regarding false claims of an association between the measles-mumps-rubella (mmr) vaccine and autism in the uk (see the wakefield effect, chapter 4). the new public health has an intrinsic responsibility for advocacy of improved societal conditions in its mission to promote optimal community health. an ultimate goal of public health is to improve health and to prevent widespread disease occurrence in the population and in an individual. the methods of achieving this are wide and varied. when an objective has been defined in "social justice is a matter of life and death. it affects the way people live, their consequent chance of illness, and their risk of premature death. we watch in wonder as life expectancy and good health continue to increase in parts of the world and in alarm as they fail to improve in others. a girl born today can expect to live for more than 80 years if she is born in some countries -but less than 45 years if she is born in others. within countries there are dramatic differences in health that are closely linked with degrees of social disadvantage. differences of this magnitude, within and between countries, simply should never happen. these inequities in health, avoidable health inequalities arise because of the circumstances in which people grow, live, work, and age, and the systems put in place to deal with illness. the conditions in which people live and die are, in turn, shaped by political, social, and economic forces. social and economic policies have a determining impact on whether a child can grow and develop to its full potential and live a flourishing life, or whether its life will be blighted. increasingly the nature of the health problems rich and poor countries have to solve are converging. the development of a society, rich or poor, can be judged by the quality of its population's health, how fairly health is distributed across the social spectrum, and the degree of protection provided from disadvantage as a result of ill-health." preventing disease, the next step is to identify suitable and feasible methods of achieving it, or a strategy with tactical objectives. this determines the method of operation, course of action, and resources needed to carry it out. the methods of public health are categorized as health promotion, and primary, secondary, and tertiary prevention (box 2.6). health promotion is the process of enabling people and communities to increase control over factors that influence their health, and thereby to improve their health (adapted from the ottawa charter of health promotion, 1986; box 2.7). health promotion is a guiding concept involving activities intended to enhance individual and community health and well-being (box 2.8). it seeks to increase involvement and control by the individual and the community in their own health. it acts to improve health and social welfare, and to reduce specific determinants of diseases and risk factors that adversely affect the health, well-being, and productive capacities of an individual or society, setting targets based on the size of the problem but also the feasibility of successful intervention, in a cost-effective way. this can be through direct contact with the patient or risk group, or act indirectly through changes in the environment, legislation, or public policy. control of aids relies on an array of interventions that promote change in sexual behavior and other contributory risks such as sharing of needles among drug users, screening of blood supply, safe hygienic practices in health care settings, and education of groups at risk such as teenagers, sex workers, migrant workers, and many others. control of aids is also a clinical problem in that patients need antiretroviral therapy (art), but this becomes a management and policy issue for making these drugs available and at an affordable price for the poor countries most affected. this is an example of the challenge and effectiveness of health promotion and the new public health. health promotion is a key element of the new public health and is applicable in the community, the clinic or hospital, and in all other service settings. some health promotion activities are government legislative and box 2.6 modes of prevention l health promotion -fostering national, community, and individual knowledge, attitudes, practices, policies, and standards conducive to good health; promoting legislative, social, or environmental conditions; promoting knowledge and practices for self-care that reduce individual and community risk; and creating a healthful environment. it is directed toward action on the determinants of health. l health protection -activities of official health departments or other agencies empowered to supervise and regulate food hygiene, community and recreational water safety, environmental sanitation, occupational health, drug safety, road safety, emergency preparedness, and many other activities to eliminate or reduce as much as possible risks of adverse consequences to health. l primary prevention -preventing a disease from occurring, e.g., vaccination to prevent infectious diseases, advice to stop smoking to prevent lung cancer. l secondary prevention -making an early diagnosis and giving prompt and effective treatment to stop progress or shorten the duration and prevent complications from an already existing disease process, e.g., screening for hypertension or cancer of cervix and colorectal cancer for early case finding, early care and better outcomes. l tertiary prevention -stopping progress of an already occurring disease, and preventing complications, e.g., in managing diabetes and hypertension to prevent complications; restoring and maintaining optimal function once the disease process has stabilized, e.g., promoting functional rehabilitation after stroke and myocardial infarction with long-term follow-up care. health promotion (hp) is the process of enabling people to increase control over, and to improve their health. hp represents a comprehensive social and political process, and not only embraces actions directed at strengthening the skills and capabilities of individuals. hp also undertakes action directed towards changing social, environmental, and economic conditions so as to alleviate their impact on public and individual health. health promotion is the process of enabling people to increase control over the determinants of health and thereby improve their health. participation is essential to sustain health promotion action. the ottawa charter identifies three basic strategies for health promotion. these are advocacy for health to create the essential conditions for health indicated above; enabling all people to achieve their full health potential; and mediating between the different interests in society in the pursuit of health. these strategies are supported by five priority action areas as outlined in the ottawa charter for health promotion: regulatory interventions such as mandating the use of seat belts in cars, requiring that children be immunized to attend school, declaring that certain basic foods must have essential minerals and vitamins added to prevent nutritional deficiency disorders in vulnerable population groups, and mandating that all newborns should be given prophylactic vitamin k to prevent hemorrhagic disease of the newborn. setting food and drug standards and raising taxes on cigarettes and alcohol to reduce their consumption are also part of health promotion. promoting a healthy lifestyle is a major known obesity-preventive activity. health promotion is provided by organizations and people with varied professional backgrounds working towards common goals of improvement in the health and quality of individual and community life. initiatives may come from government with dedicated allocation of funds to address specific health issues, from donors, or from advocacy or community groups or individuals to promote a specific or general cause in health. raising awareness to inform and motivate people about their own health and lifestyle factors that might put them at risk requires teaching young people about the dangers of sexually transmitted diseases, smoking, and alcohol abuse to reduce risks associated with their social behavior. it might include disseminating information on healthy nutrition; for example, the need for folic acid supplements for women of childbearing age and multiple vitamins for elderly, as well as the elements of a healthy diet, compliance with immunization recommendations, compliance with screening programs, and many others. community and peer group attitudes and standards affect individual behavior. health promotion endeavors to create a climate of knowledge, attitudes, beliefs, and practices that are associated with better health outcomes. international conferences following on from the ottawa charter were held in adelaide in 1988 , sundsvall in 1991 , jakarta in 1999 , mexico in 2000 , bangkok in 2005 , and nairobi in 2009 . the principles of health promotion have been reiterated and have influenced public policy regarding public health as well as the private sector. health promotion has a track record of proven success in numerous public health issues where a biomedical solution was not available. the hiv/aids pandemic from the 1980s until the late 1990s had no medical treatment and control measures relied on screening, education, lifestyle changes, and supportive care. health promotion brought forward multiple interventions, from condom use and distribution, to needle exchanges for intravenous drug users, to male circumcision in high-prevalence african countries. medical treatment was severely limited until art was developed. the success of art also depends on a strong element of health promotion in widening the access to treatment and the success of medications to reduce transmission, most remarkably in reducing maternal-fetal transmission (see chapter 4). similarly, in the battle against cardiovascular diseases, health promotion was an instrumental factor in raising public awareness of the importance of management of hypertension and smoking reduction, dietary restraint, and physical exercise. the success of massive reductions in stroke and chd mortality is as much the result of health promotion as of improved medical care (see chapter 5). the character of public health carries with it a "good cop, bad cop" dichotomy. the "good cop" is persuasive and educational trying to convince people to do the right thing in looking after their own health: diet, exercise, smoking cessation, and others. on the other side, the "bad cop" role is regulatory and punitive. public health has a serious responsibility and role in the enforcement of laws and regulation to protect the public health. some of these are restrictive box 2.8 elements of health promotion 1. address the population as a whole in health-related issues, in everyday life as well as people at risk for specific diseases. 2. direct action to risk factors or causes of illness or death. 3. undertake activist approach to seek out and remedy risk factors in the community that adversely affect health. 4. promote factors that contribute to a better condition of health of the population. 5. initiate actions against health hazards, including communication, education, legislation, fiscal measures, organizational change, community development, and spontaneous local activities. 6. involve public participation in defining problems and deciding on action. 7. advocate relevant environmental, health, and social policy. 8. encourage health professional participation in health education and health advocacy. 9. advocate for health based on human rights and solidarity. 10. invest in sustainable policies, actions, and infrastructure to address the determinants of health. 11. build capacity for policy development, leadership, health promotion practice, knowledge transfer and research, and health literacy. 12. regulate and legislate to ensure a high level of protection from harm and enable equal opportunity for health and well-being for all people. 13. partner and build alliances with public, private, nongovernmental, and international organizations and civil society to create sustainable actions. 14. make the promotion of health central to the global development agenda. of individual rights that may damage other people or are requirements based on strong evidence of benefits to population health. readily accepted are food and drug standards, such as pasteurization of milk, and iodization of salt; requirements to drive on the right-hand side of the road (except in some countries such as the uk), to wear seat belts and for motorcyclists to wear safety helmets; and not smoking in public places. enforcement of these and similar statutory or regulatory requirements is vital in a civil society to protect the public from health hazards and to protect people from harm and exploitation by unscrupulous manufacturers and marketing. cigarette advertising and sponsorship of sports events by tobacco companies are banned in most upper income countries. the use of transfats in food manufacturing and baking is now banned and salt reduction is being promoted and even mandated in many us local authorities to reduce cardiovascular disease. advertising of unhealthy snack foods on children's television programs and during child-watching hours is commonly restricted. banning high-sugar soda drink distribution in schools is a successful intervention to reduce the current child obesity epidemic. melamine use in milk powders and baby formulas, which caused widespread illness and death of infants in china, is now banned and a punishable offence for manufacture or distribution in china and worldwide. examples of this aspect of public health are mentioned throughout this text, especially in chapters 8 and 9 on nutrition, and environmental and occupational health, respectively. the regulatory enforcement function of public health is sometimes controversial and portrayed as interference with individual liberty. fluoridation of community water supplies is an example where aggressive lobby groups opposing this safe and effective public health measure are still common. this is discussed in chapter 7. equally important is the public health policy issue of resource allocation and taxation for health purposes. taxation is an unpopular measure that governments must employ and enforce in order to do the public's business. the debate over the patient protection and affordable care act 2010 (ppaca or "obamacare"), discussed elsewhere in this and other chapters, shows how bitter the arguments can become, yet the goal of equality of access to health care cannot be denied as a public good, demonstrably contributing to the health of the nation. primary prevention refers to those activities that are undertaken to prevent disease or injury from occurring at all. primary prevention works with both the individual and the community. it may be directed at the host to increase resistance to the agent (such as in immunization or cessation of smoking), or at environmental activities to reduce conditions favorable to the vector for a biological agent, such as mosquito vectors of malaria or dengue fever. landmark examples include the treatment and prevention of scurvy among sailors based on james lind's findings in a classic clinical epidemiological study in 1747, and john snow's removal of the handle from the broad street pump to stop a cholera epidemic in london in 1854 (see chapter 1). primary prevention includes elements of health protection such as ensuring water, food and drug, and workplace safety; chlorination of drinking water to prevent transmission of waterborne enteric diseases; pasteurization of milk to prevent gastrointestinal diseases; mandating wearing seat belts in motor vehicles to prevent serious injury and death in road crashes; and reducing the availability of firearms to reduce injury and death from intentional, accidental, or random violence. it also includes direct measures to prevent diseases, such as immunization to prevent polio, tetanus, pertussis, and diphtheria. health promotion and health protection blend together as a group of activities that reduce risk factors and diseases through many forms of intervention such as changing smoking legislation or preventing birth defects by fortification of flour with folic acid. prevention of hiv transmission by needle exchange for intravenous drug users, promoting condom usage, and promoting male circumcision in africa, and the distribution of condoms and clean needles for hivpositive drug users are recent examples of primary prevention associated with health promotion programs. primary prevention also includes activities within the health system that can lead to better health. this may mean, for example, setting standards and to reduce hospital infections, and ensuring that doctors not only are informed of appropriate immunization practices and modern prenatal care or screening programs for cancer of the cervix, colon, and breast, but also are aware of their vital role in preventing cardiovascular and other non-communicable diseases. in this role, the health care provider serves as a teacher and guide, as well as a diagnostician and therapist. like health promotion, primary prevention does not depend on health care providers alone; health promotion works to increase individual and community consciousness of self-care, mainly by raising awareness and information levels and empowering the individual and the community to improve self-care, to reduce risk factors, and to live healthier lifestyles. secondary prevention is early diagnosis and management to prevent complications from a disease. public health interventions to prevent the spread of disease include the identification of sources of the disease and the implementation of steps to stop it, as shown in snow's closure of the broad street pump. secondary prevention includes steps to isolate cases and treat or immunize contacts so as to prevent further cases of meningitis or measles, for example, in outbreaks. for current epidemics such as hiv/aids, primary prevention is largely based on education, abstinence from any and certainly risky sexual behavior, circumcision, and treatment of patients in order to improve their health and to reduce the risk of spread of hiv. for high-risk groups such as intravenous drug users, needleexchange programs reduce the risk of spread of hiv, and hepatitis b and c. distribution of condoms to teenagers, military personnel, truck drivers, and commercial sex workers helps to prevent the spread of stis and aids in schools and colleges, as well as among the military. the promotion of circumcision is shown to be effective in reducing the transmission of hiv and of hpv (the causative organism for cancer of the cervix). all health care providers have a role in secondary prevention; for example, in preventing strokes by early identification and adequate care of hypertension. the child who has an untreated streptococcal infection of the throat may develop complications which are serious and potentially life-threatening, including rheumatic fever, rheumatic valvular heart disease, and glomerulonephritis. a patient found to have elevated blood pressure should be advised about continuing management by appropriate diet and weight loss if obese, regular physical exercise, and long-term medication with regular follow-up by a health provider in order to reduce the risk of stroke and other complications. in the case of injury, competent emergency care, safe transportation, and good trauma care may reduce the chance of death and/or permanent handicap. screening and high-quality care in the community prevent complications of diabetes, including heart, kidney, eye, and peripheral vascular disease. they can also prevent hospitalizations, amputations, and strokes, thus lengthening and improving the quality of life. health care systems need to be actively engaged in secondary prevention, not only as individual doctors' services, but also as organized systems of care. public health also has a strong interest in promoting highquality care in secondary and tertiary care hospital centers in such areas of treatment as acute myocardial infarction, stroke, and injury in order to prevent irreversible damage. measures include quality of care reviews to promote adequate longterm postmyocardial infarction care with aspirin and betablockers or other medication to prevent or delay recurrence and second or third myocardial infarctions. the role of highquality transportation and care in emergency facilities of hospitals in public health is vital to prevent long-term damage and disability; thus, cardiac care systems including publicly available defibrillators, catheterization, the use of stents, and bypass procedures are important elements of health care policy and resource allocation, which should be accessible not only in capital cities but also to regional populations. tertiary prevention involves activities directed at the host or patient, but also at the social and physical environment in order to promote rehabilitation, restoration, and maintenance of maximum function after the disease and its complications have stabilized. the person who has undergone a cerebrovascular accident or trauma will reach a stage where active rehabilitation can help to restore lost functions and prevent recurrence or further complications. the public health system has a direct role in the promotion of disability-friendly legislation and standards of building, housing, and support services for chronically ill, handicapped, and elderly people. this role also involves working with many governmental social and educational departments, but also with advocacy groups, ngos, and families. it may also include the promotion of disability-friendly workplaces and social service centers. treatment for conditions such as myocardial infarction or a fractured hip now includes early rehabilitation in order to promote early and maximum recovery with restoration to optimal function. the provision of a wheelchair, walkers, modifications to the home such as special toilet facilities, doors, and ramps, along with transportation services for paraplegics are often the most vital factors in rehabilitation. public health agencies work with groups in the community concerned with promoting help for specific categories of risk group, disease, or disability to reduce discrimination. community action is often needed to eliminate financial, physical, or social barriers, promote community awareness, and finance special equipment or other needs of these groups. close follow-up and management of chronic disease, physical and mental, require home care and ensuring an appropriate medical regimen including drugs, diet, exercise, and support services. the follow-up of chronically ill people to supervise the taking of medications, monitor changes, and support them in maximizing their independent capacity in activities of daily living is an essential element of the new public health. public health uses a population approach to achieve many of its objectives. this requires defining the population, including trends of change in the age and gender distribution of the population, fertility and birth rates, spread of disease and disability, mortality, marriage and migration, and socioeconomic factors. the reduction of infectious disease as the major cause of mortality, increased longevity coupled with declining fertility rates, resulted in changes in the age composition, or a demographic transition. demographic changes, such as fertility and mortality patterns, are important factors in changing the age distribution of the population, resulting in a greater proportion of people surviving to older ages. declining infant mortality, increasing educational levels of women, the availability of birth control, and other social and economic factors lead to changes in fertility patterns and the demographic transition -an aging of the population -with important effects on health service needs. the age and gender distribution of a population affects and is affected by patterns of disease. change in epidemiological patterns, or an epidemiological shift, is a change in predominant patterns of morbidity and mortality. the transition of infectious diseases becoming less prominent as causes of morbidity and mortality and being replaced by chronic and non-infectious diseases has occurred in both developed and developing countries. the decline in mortality from chronic diseases, such as cardiovascular disease, represents a new stage of epidemiological transition, creating an aging population with higher standards of health but also long-term community support and care needs. monitoring and responding to these changes are fundamental responsibilities of public health, and a readiness to react to new, local, or generalized changes in epidemiological patterns is vital to the new public health. societies are not totally homogeneous in ethnic composition, levels of affluence, or other social markers. on one hand, a society classified as developing may have substantial numbers of people with incomes that promote overnutrition and obesity, so that disease patterns may include increasing prevalence of diseases of excesses, such as diabetes. on the other hand, affluent societies include population groups with disease patterns of poverty, including poor nutrition and low birth-weight babies. a further stage of epidemiological transition has been occurring in the industrialized countries since the 1960s, with dramatic reductions in mortality from chd, stroke and, to a lesser extent, trauma. the interpretation of this epidemiological transition is still not perfectly clear. how it occurred in the industrialized western countries but not in those of the former soviet union is a question whose answer is vital to the future of health in russia and some countries of eastern europe. developing countries must also prepare to cope with increasing epidemics of non-infectious diseases, and all countries face renewed challenges from infectious diseases with antibiotic resistance or newly appearing infectious agents posing major public health threats. demographic change in a country may reflect social and political decisions and health system priorities from decades before. russia's rapid population decline since the 1990s, china's gender imbalance with a shortage of millions of young women, egypt's rapid population growth outstripping economic capacity, and many other examples indicate the severity and societal importance of capacity to analyze and formulate public health and social policies to address such fundamental sociopolitical issues. aging of the population is now the norm in most developed countries as a result of low birth and declining mortality rates. this change in the age distribution of a population has many associated social and economic issues as to the future of social welfare with a declining age cohort to provide the workforce. the aging population requires pension and health care support which make demands of social security systems that will depend on economic growth with a declining workforce. in times of economic stress, as in europe, this situation is made more difficult by longstanding short working weeks, early pension ages, and high social benefits. however, this results in unemployment among young people in particular and social conflict. the interaction of increasing life expectancy and a declining workforce is a fundamental problem in the high-income countries. this imbalance may be resolved in part through productivity gains and switching of primary production to countries with large still underutilized workforces, while employment in the developed countries will depend on service industries including health and the economic growth generated by higher technology and intellectual property and service industries. the challenge of keeping populations and individuals healthy is reflected in modern health services. each component of a health service may have developed with different historical emphases, operating independently as a separate service under different administrative auspices and funding systems, competing for limited health care resources. in this situation, preventive community care receives less attention and resources than more costly treatment services. figure 2 .5 suggests a set of health services in an interactive relationship to serve a community or defined population, but the emphasis should be on the interdependence of these services with one other and with the comprehensive network in order to achieve effective use of resources and a balanced set of services for the patient, the client or patient population, and the community. clinical medicine and public health each play major roles in primary, secondary, and tertiary prevention. each may function separately in their roles in the community, but optimal success lies in their integrated efforts. allocation of resources should promote management and planning practices to assist this integration. there is a functional interdependence of all elements of health care serving a definable population. the patient should be the central figure in the continuum or complex of services available. effectiveness in use of resources means that providing the service most appropriate for meeting the individual's or group's needs at a point in time are those that should be applied. this is the central concept in currently developing innovations in health care delivery in the usa with organizations using terms such as patient centered medical home, accountable care organizations (acos), and population health management systems, which are being promoted in the obamacare health reforms now in process (see chapter 10) (shortell et al., 2010) . separate organization and financing of services place barriers to appropriate provision of services for both the community and the individual patient. the interdependence of services is a challenge in health care organizations for the future. where there is competition for limited resources, pressures for tertiary services often receive priority over programs to prevent children from dying of preventable diseases. public health must be seen in the context of all health care and must play an influential role in promoting prevention at all levels. clinical services need public health in order to provide prevention and community health services that reduce the burden of disease, disability, and dependence on the institutional setting. health was traditionally thought of as a state of absence of disease, pain, or disability, but has gradually been expanded to include physical, mental, and societal well-being. in 1920, c. e. a. winslow, professor of public health at yale university, defined public health as follows: "public health is the science and art of (1) preventing disease, (2) prolonging life, and (3) winslow's far-reaching definition remains a valid framework but is unfulfilled when clinical medicine and public health have financing and management barriers between them. in many countries, isolation from the financing and provision of medical and nursing care services left public health with the task of meeting the health needs of the indigent and underserved population groups with inadequate resources and recognition. health insurance organizations for medical and hospital care have in recent years been more open to incorporating evidence-based preventive care, but the organization of public health has lacked the same level of attention. in some countries, the limitations have been conceptual in that public health was defined primarily in terms of control of infectious, environmental, and occupational diseases. a more recent and widely used definition is: "public health is the science and art of preventing disease, prolonging life, and promoting health through the organized efforts of society." this definition, coined in 1988 in the public health in england report by sir donald acheson, reflects the broad focus of modern public health. terms such as social hygiene, preventive medicine, community medicine, and social medicine have been used to denote public health practice over the past century. preventive medicine is the application of preventive measures by clinical practitioners combining some elements of public health with clinical practice relating to individual patients. preventive medicine defines medical or clinical personal preventive care, with stress on risk groups in the community and national efforts for health promotion. the focus is on the health of defined populations to promote health and well-being using evidence-based guidelines for cost-effective preventive measures. measures emphasized include screening and follow-up of chronic illnesses, and immunization programs; for example, influenza and pneumococcal pneumonia vaccines are used by people who are vulnerable because of their age, chronic diseases, or risk of exposure, such as medical and nursing personnel and those providing other personal clinical services. clinical medicine also deals in the area of prevention in the management of patients with hypertension or diabetes, and in doing so prevents the serious complications of these diseases. social medicine is also primarily a medical specialty which looks at illness in an individual in the family and social context, but lacks the environmental and regulatory and organized health promotion functions of public health. community health implies a local form of health intervention, whereas public health more clearly implies a global approach, which includes action at the international, national, state, and local levels. some issues in health can be dealt with at the individual, family, or community level; others require global strategies and intervention programs with regional, national, or international collaboration and leadership. the social medicine movement originated to address the harsh conditions of the working population during the industrial revolution in mid-nineteenth-century europe. an eminent pioneer in cellular pathology, rudolph virchow provided leadership in social medicine powered by the revolutionary movements of 1848, and subsequent social democrat political movements. their concern focused on harsh living and health conditions among the urban poor working class and neglectful political norms of the time. social medicine also developed as an academic discipline and advocacy orientation by providing statistical evidence showing, as in various governmental reports in the mid-nineteenth century, that poverty among the working class was associated with short life expectancy and that social conditions were key factors in the health of populations and individuals. this movement provided the basis for departments in medical faculties and public health education throughout the world stressing the close relationship between political priorities and health status. this continued in the twentieth century and in the usa found expression in pioneering work since the 1940s at montefiore hospital in new york and with victor sidel, founding leader of the community health center movement the usa from the 1960s. in the twenty-first century this movement continues to emphasize relationships between politics, society, disease, and medicine, and forms of medical practice derived from it, as enunciated by prominent advocates such as harvardbased paul farmer in haiti, russia and rwanda, and in the uk by martin mckee and others (nolte and mckee, 2008) . similar concepts are current in the usa under headings such as family medicine, preventive medicine, and social medicine. this movement has also influenced sir michael marmot and others in the world health commission of health inequalities of 2008, with a strong influence on the un initiative to promote mdgs, whose first objective is poverty reduction (commission on inequalities report 2010). application of the idea of poverty reduction as a method of reducing health inequalities has been successful recently in a large field trial in brazil showing greater reduction in child mortality where cash bonuses were awarded by municipalities for the poor families than that observed in other similar communities (rasella, 2013). in the usa, this movement is supported by increased health insurance coverage for the working poor, with funding for preventive care and incentives for community health centers in the obamacare plan of 2010 for implementation in the coming years to provide care for uninsured and underserved populations, particularly in urban and rural poverty areas. the political aspect of social medicine is the formulation of and support for national initiatives to widen health care coverage to the 16 percent of the us population who are still uninsured, and to protect those who are arbitrarily excluded owing to previous illnesses, caps on coverage allowed, and other exploitative measures taken by private insurance that frequently deny americans access to the high levels of health care available in the country. the ethical base of public health in europe evolved in the context of its successes in the nineteenth and early twentieth centuries along with ideas of social progress. but the twentieth century was also replete with extremism and wide-scale abuse of human rights, with mass executions, deportations, and starvation as official policy in fascist and stalinist regimes. eugenics, a pseudoscience popularized in the early decades of the twentieth century, promoted social policies meant to improve the hereditary qualities of a race by methods such as sterilization of mentally handicapped people. the "social and racial hygiene" of the eugenics movements led to the medicalization of sterilization in the usa and other countries. this was adopted and extended in nazi germany to a policy of murder, first of the mentally and physically handicapped and then of "racial inferiors". these eugenics theories were widely accepted in the medical community in germany, then used by the nazi regime to justify medically supervised killing of hundreds of thousands of helpless, incapacitated individuals. this practice was linked to wider genocide and the holocaust, with the brutalization and industrialized murder of over 6 million jews and 6 million other people, and corrupt medical experimentation on prisoners. following world war ii, the ethics of medical experimentation (and public health) were codified in the nuremberg code and universal declaration of human rights based on lessons learned from these and other atrocities inflicted on civilian populations (see chapter 15). threats of genocide, ethnic cleansing, and terrorism are still present on the world stage, often justified by current warped versions of racial hygienic theories. genocidal incitement and actual genocide and terrorism have recurred in the last decades of the twentieth century and into the twenty-first century in the former yugoslav republics, africa (rwanda and darfur), south asia, and elsewhere. terrorism against civilians has become a worldwide phenomenon with threats of biological and chemical agents, and potentially with nuclear capacity. asymmetrical warfare of insurgencies which use innocent civilians for cover, as with other forms of warfare, carries with it grave dangers to public health, human rights, and international stability, as seen in the twenty-first century in south sudan, darfur, dr congo, chechnya, iraq, afghanistan, and pakistan. in 1961, kerr white and colleagues defined medical ecology as population-based research providing the foundation for management of health care quality. this concept stresses a population approach, including those not attending and those using health services. this concept was based on previous work on quality of care, randomized clinical trials, medical audit, and structure-process-outcome research. it also addressed health care quality and management. these themes influenced medical research by stressing the population from which clinical cases emerge as well as public health research with clinical outcome measures, themes that recur in the development of health services research and, later, evidence-based medicine. this led to the development of the agency for health care policy and research and development in the us department of health and human services and evidence-based practice centers to synthesize fundamental knowledge for the development of information for decision-making tools such as clinical guidelines, algorithms, or pathways. clinical guidelines and recommended best practices have become part of the new public health to promote quality of patient care and public health programming. these can include recommended standards; for example, follow-up care of the postmyocardial infarction patient, an internationally recommended immunization schedule, recommended dietary intake or food fortification standards, and mandatory vitamin k and eye care for all newborns and many others (see chapter 15). community-oriented primary care (copc) is an approach to primary health care that links community epidemiology and appropriate primary care, using proactive responses to the priority needs identified. copc, originally pioneered in south africa and israel by sidney and emily kark and colleagues in the 1950s and 1960s, stresses medical services in the community which need to be adapted to the needs of the population as defined by epidemiological analysis. copc involves community outreach and education, as well as clinical preventive and treatment services. copc focuses on community epidemiology and an active problem-solving approach. this differs from national or larger scale planning that sometimes loses sight of the local nature of health problems or risk factors. copc combines clinical and epidemiological skills, defines needed interventions, and promotes community involvement and access to health care. it is based on linkages between the different elements of a comprehensive basket of services along with attention to the social and physical environment. a multidisciplinary team and outreach services are important for the program, and community development is part of the process. in the usa, the copc concept has influenced health care planning for poor areas, especially provision of federally funded community health centers in attempts to provide health care for the underserved since the 1960s. in more recent years, copc has gained wider acceptance in the usa, where it is associated with family physician training and community health planning based on the risk approach and "managed care" systems. indeed, the three approaches are mutually complementary (box 2.9). as the emphasis on health care reform in the late 1990s moved towards managed care, the principles of copc were and will continue to be important in promoting health and primary prevention in all its modalities, as well as tertiary prevention with followup and maintenance of the health of the chronically ill. copc stresses that all aspects of health care have moved towards prevention based on measurable health issues in the community. through either formal or informal linkages between health services, the elements of copc are part of the daily work of health care providers and community services systems. the us institute of medicine issued the report on primary care in 1995, defining primary care as "the provision of integrated, accessible health care services by clinicians who are accountable for addressing the majority of personal health care needs, developing a sustained partnership with patients and practicing in the context of the family and the community". this formulation was criticized by the american public health association (apha) as lacking a public health perspective and failing to take into account both the individual and the community health approaches. copc tries to bridge this gap between the perspectives of primary care and public health. the community, whether local, regional, or national, is the site of action for many public health interventions. moreover, understanding the characteristics of the community is vital to a successful community-oriented approach. by the 1980s, new patterns of public health began to emerge, including all measures used to improve the health of the community, and at the same time working to protect and promote the health of the individual. the range of activities to achieve these general goals is very wide, including individual patient care systems and the community-wide activities that affect the health and well-being of the individual. these include the financing and management of health systems, evaluation of the health status of the population, and measures to improve the quality of health care. they place reliance on health promotion activities to change environmental risk factors for disease and death. they promote integrative and multisectoral approaches and the international health teamwork required for global progress in health. the definition of health in the charter of the who as a complete state of physical, mental, and social well-being had a ring of utopianism and irrelevance to states struggling to provide even minimal care in severely adverse political, economic, social, and environmental conditions (box 2.10). in 1977, a more modest goal was set for attainment of a level of health compatible with maximum feasible social and economic productivity. one needs to recognize that health and disease are on a dynamic continuum that affects everyone. the mission for public health is to use a wide range of methods to prevent disease and premature death, and improve quality of life for the benefit of individuals and the community. the world health organization defines health as "a state of complete physical, mental and social well-being, not merely the absence of disease or infirmity" (who constitution, 1948) . in 1978 at the alma-ata conference on primary health care, the who related health to "social and economic productivity in setting as a target the attainment by all the people of the world of a level of health that will permit them to lead a socially and economically productive life". three general programs of work for the periods 1984-1989, 1990-1995, and 1996-2001 were formulated as the basis of national and international activity to promote health. in 1995, the who, recognizing changing world conditions of demography, epidemiology, environment, and political and economic status, addressed the unmet needs of developing countries and health management needs in the industrialized countries, calling for international commitment to "attain targets that will make significant progress towards improving equity and ensuring sustainable health development". the 1999 object of the who is restated as "the attainment by all peoples of the highest possible level of health" as defined in the who constitution, by a wide range of functions in promoting technical cooperation, assisting governments, and providing technical assistance, international cooperation, and standards. in the 1960s, most industrialized countries were concentrating energies and financing in health care on providing access to medical and hospital services through national insurance schemes. developing countries were often spending scarce resources trying to emulate this trend. the who was concentrating on categorical programs, such as eradication of smallpox and malaria, as well as the expanded program of immunization and similar specific efforts. at the same time, there was a growing concern that developing countries were placing too much emphasis and expenditure on curative services and not enough on prevention and primary care. the world health assembly (wha) in 1977 endorsed the primary care approach under the banner of "health for all by the year 2000" (hfa 2000) . this was a landmark decision and has had important practical results. the who and the united nations children's fund (unicef) sponsored a seminal conference held in alma-ata, in the ussr ( kazakhstan), in 1978, which was convened to refocus health policy on primary care. the alma-ata declaration stated that health is a basic human right, and that governments are responsible to assure that right for their citizens and to develop appropriate strategies to fulfill this promise. this proposition has come to be increasingly accepted in the international community. the conference stressed the right and duty of people to participate in the planning and implementation of their health care. it advocated the use of scientifically, socially, and economically sound technology. joint action through intersectoral cooperation was also emphasized. the alma-ata declaration focused on primary health care as the appropriate method of assuming adequate access to health care for all (box 2.11). many countries have gradually come to accept the notion of placing priority on primary care, resisting the temptation to spend high percentages of health care resources on high-tech and costly medicine. spreading these same resources into highly costeffective primary care, such as immunization and nutrition programs, provides greater benefit to individuals and to society as a whole. alma-ata provided a new sense of direction for health policy, applicable to developing countries and in a different way than the approaches of the developed countries. during the 1980s, the health for all concept influenced national health policies in the developing countries with signs of progress in immunization coverage, for example, but the initiative was diluted as an unintended consequence by more categorical programs such as eradication of poliomyelitis. for example, developing countries have accepted immunization and diarrheal disease control as high-priority issues and achieved remarkable success in raising immunization coverage from some 10 percent to over 75 percent in just a decade. developed countries addressed these principles in different ways. in these countries, the concept of primary health care led directly to important conceptual developments in health. national health targets and guidelines are now common in many countries and are integral parts of box 2.11 declaration of alma-ata, 1978: a summary of primary health care (phc) 1. reaffirms that health is a state of complete physical, mental, and social well-being, and not merely the absence of disease or infirmity, and is a fundamental human right. existing gross inequalities in the health status of the people, particularly between developed and developing countries as well as within countries, are of common concern to all countries. 3. governments have a responsibility for the health of their people. the people have the right and duty to participate in planning and implementation of their health care. 4. a main social target is the attainment, by all peoples of the world by the year 2000, of a level of health that will permit them to lead a socially and economically productive life. 5. phc is essential health care based on practical, scientifically sound, and socially acceptable methods and technology. 6. it is the first level of contact of individuals, the family, and the national health system bringing health care as close as possible to where people live and work, as the first element of a continuing health care process. 7. phc evolves from the conditions and characteristics of the country and its communities, based on the application of social, biomedical, and health services research and public health experience. 8. phc addresses the main health problems in the community, providing promotive, preventive, curative, and rehabilitative services accordingly. 9. phc includes the following: (a) education concerning prevailing health problems and methods of preventing and controlling them (b) promotion of food supply and proper nutrition (c) adequate supply of safe water and basic sanitation (d) maternal and child health care, including family planning (e) immunization against the major infectious diseases (f) prevention of locally endemic diseases (g) appropriate treatment of common diseases and injuries (h) the provision of essential drugs (i) relies on all health workers … to work as a health team. 10. all governments should formulate national health policies, strategies and plans, mobilize political will and resources, used rationally, to ensure phc for all people. national health planning. reforms of the nhs -for example, as discussed in chapter 13, remuneration increases for family physicians and encouraging group practice with public health nursing support -have become widespread in the uk. leading health maintenance organizations, such as kaiser permanente in the usa and district health systems in canada, have emphasized integrated approaches to health care for registered or geographically defined populations (see chapters 11-13). this approach is becoming common in the usa in acos, which will be fostered by the 2010 obamacare legislation (ppaca). this systematic approach to individual and community health is an integral part of the new public health. the interactions among community public health, personal health services, and health-related behavior, including their management, are the essence of the new public health. how the health system is organized and managed affects the health of the individual and the population, as does the quality of providers. health information systems with epidemiological, economic, and sociodemographic analysis are vital to monitor health status and allow for changing priorities and management. well-qualified personnel are essential to provide services, manage the system, and carry out relevant research and health policy analysis. diffusion of data, health information, and responsibility helps to provide a responsive and comprehensive approach to meet the health needs of the individual and community. the physical, social, economic, and political environments are all important determinants of the health status of the population and the individual. joint action (intersectoral cooperation) between public and non-governmental or community-based organizations is needed to achieve the well-being of the individual in a healthy society. in the 1980s and 1990s, these ideas contributed to an evolving new public health, spurred on by epidemiological changes, health economics, the development of managed care linking health systems, and prepayment. knowledge and self-care skills, as well as community action to reduce health risks, are no less important in this than the roles of medical practitioners and institutional care. all are parts of a coherent holistic approach to health. the concept of selective primary care, articulated in 1979 by walsh and warren, addresses the needs of developing countries to select those interventions on a broad scale that would have the greatest positive impact on health, taking into account limited resources such as money, facilities, and human resources. the term selective primary care is meant to define national priorities that are based not on the greatest causes of morbidity or mortality, but on common conditions of epidemiological importance for which there are effective and simple preventive measures. throughout health planning, there is an implicit or explicit selection of priorities for allocation of resources. even in primary care, selection of targets is a part of the process of resource allocation. in modern public health, this process is more explicit. a country with limited resources and a high birth rate will emphasize maternal and child health before investing in geriatric care. this concept has become part of the microeconomics of health care and technology assessment, discussed in chapters 11 and 15, respectively, and is used widely in setting priorities and resource allocation. in developing countries, cost-effective primary care interventions have been articulated by many international organizations, including iodization of salt, use of oral rehydration therapy (ort) for diarrheal diseases, vitamin a supplementation for all children, expanded programs of immunization, and others that have the potential for saving hundreds of thousands of lives yearly at low cost. in developed countries, health promotions targeted to reduce accidents and risk factors such as smoking, high-fat diets, and lack of exercise for cardiovascular diseases are low-cost public health interventions that save lives and reduce the use of hospital care. targeting specific diseases is essential for efforts to control tb or eradicate polio, but at the same time, development of a comprehensive primary care infrastructure is equally or even more important than the single-disease approach. some disease entities such as hiv/aids attract donor funding more readily than basic infrastructure services such as immunization, and this can sometimes be detrimental to addressing the overall health needs of the population and other neglected but also important diseases. the risk approach selects population groups on the basis of risk and helps to determine interventional priorities to reduce morbidity and mortality. the measure of health risk is taken as a proxy for need, so that the risk approach provides something for all, but more for those in need, in proportion to that need. in epidemiological terms, these are people with higher relative risk or attributed risk. some groups in the general population are at higher risk than others for specific conditions. the expanded programme on immunization (epi), control of diarrhoeal diseases (cdd), and acute respiratory disease (ard) programs of the who are risk approaches to tackling fundamental public health problems of children in developing countries. public health places considerable emphasis on maternal and child health because these are vulnerable periods in life for specific health problems. pregnancy care is based on a basic level of care for all, with continuous assessment of risk factors that require a higher intensity of follow-up. prenatal care helps to identify factors that increase the risk for the pregnant woman or her fetus/newborn. efforts directed towards these special risk groups have the potential to reduce morbidity and mortality. high-risk case identification, assessment, and management are vital to a successful maternal care program. similarly, routine infant care is designed not only to promote the health of infants, but also to find the earliest possible indications of deviation and the need for further assessment and intervention to prevent a worsening of the condition. low birth-weight babies are at greater risk for many short-and long-term hazards and should be given special treatment. all babies are routinely screened for birth defects or congenital conditions such as hypothyroidism, phenylketonuria, and other metabolic and hematological diseases. screening must be followed by investigating and treating those found to have a clinical deficiency. this is an important element of infant care because infancy itself is a risk factor. as will be discussed in chapters 6 and 7 and others, epidemiology has come to focus on the risk approach with screening based on known genetic, social, nutritional, environmental, occupational, behavioral, or other factors contributing to the risk for disease. the risk approach has the advantage of specificity and is often used to initiate new programs directed at special categories of need. this approach can lead to narrow and somewhat rigid programs that may be difficult to integrate into a more general or comprehensive approach, but until universal programs can be achieved, selective targeted approaches are justifiable. indeed, even with universal health coverage, it is still important to address the health needs or issues of groups at special risk. working to achieve defined targets means making difficult choices. the supply and utilization of some services will limit availability for other services. there is an interaction, sometimes positive, sometimes negative, between competing needs and the health status of a population. public health identifies needs by measuring and comparing the incidence or prevalence of the condition in a defined population with that in other comparable population groups and defines targets to reduce or eliminate the risk of disease. it determines ways of intervening in the natural epidemiology of the disease, and develops a program to reduce or even eliminate the disease. it also assesses the outcomes in terms of reduced morbidity and mortality, as well as the economic justification in cost-effectiveness analysis to establish its value in health priorities. because of the interdependence of health services, as well as the total financial burden of health care, it is essential to look at the costs of providing health care, and how resources should be allocated to achieve the best results possible. health economics has become a fundamental methodology in policy determination. the costs of health care, the supply of services, the needs for health care or other health-promoting interventions, and effective means of using resources to meet goals are fundamental in the new public health. it is possible to err widely in health planning if one set of factors is overemphasized or underemphasized. excessive supply of one service diminishes the availability of resources for other needed investments in health. if diseases are not prevented or their sequelae not well managed, patients must use costly health care services and are unable to perform their normal social functions such as learning at school or performing at work. lack of investment in health promotion and primary prevention creates a larger reliance on institutional care, driving health costs upwards, and restricting flexibility in meeting patients' needs. the interaction of supply and demand for health services is an important determinant of the political economy of health care. health and its place in national priorities are determined by the social-political philosophy and resource allocation of a government. the case for action, or the justification for a public health intervention, is a complex of epidemiological, economic, and public policy factors (table 2 .1). each disease or group of diseases requires its own case for action. the justification for public health intervention requires sufficient evidence of the incidence and prevalence of the disease (see chapter 3). evidence-based public health takes into account the effectiveness and safety of an intervention; risk factors; safe means at hand to intervene; the human, social, and economic cost of the disease; political factors; and a policy decision as to the priority of the problem. this often depends on subjective factors, such as the guiding philosophy of the health system and the way it allocates resources. some interventions are so well established that no new justification is required to make the case, and the only question is how to do it most effectively. for example, infant vaccination is a cost-effective and cost-beneficial program for the protection of the individual child and the population as a whole. whether provided as a public service or as a clinical preventive measure by a private medical practitioner, it is in the interest of public health that all children be immunized. an outbreak of diarrheal disease in a kindergarten presents an obvious case for action, and a public health system must respond on an emergency basis, with selection of the most suitable mode of intervention. the considerations in developing a case for action are outlined above. need is based on clinical and epidemiological evidence, but also on the importance of an intervention in the eyes of the public. the technology available, its effectiveness and safety, and accumulated experience are important in the equation, as are the acceptability and affordability of appropriate interventions. the precedents for use of an intervention are also important. on epidemiological evidence, if the preventive practice has been seen to provide reduction in risk for the individual and for the population, then there is good reason to implement it. the costs, risks and benefits must be examined as part of the justification to help in the selection of health priorities. health systems research examines the efficiency of health care and promotes improved efficiency and effective use of resources. this is a vital function in determining how best to use resources and meet current health needs. past emphasis on hospital care at the expense of less development of primary care and prevention is still a common issue, particularly in former soviet and developing countries, where a high percentage of total health expenditure goes to acute hospital care with long length of stay, with smaller allocation to preventive and community health care. the result of this imbalance is high mortality from preventable diseases. new drugs, vaccines, and medical equipment are continually becoming available, and each new addition needs to be examined among the national health priorities. sometimes, owing to cost, a country cannot afford to add a new vaccine to the routine. however, when there is good evidence for efficacy and safety of new vaccines, drugs, diagnostic methods or other innovations, it could be applied for those at greatest risk. although there are ethical issues involved, it may be necessary to advise parents or family members to purchase the vaccine independently. clearly, recommending individual purchase of a vaccine is counter to the principle of equity and solidarity, benefiting middleclass families, and providing a poor basis of data for evaluation of the vaccine and its target disease. on the other hand, failure to advise parents of potential benefits to their children creates other ethical problems, but may increase public pressure and insurance system acceptance of new methods, e.g., varicella and hpv vaccines. mass screening programs involving complete physical examinations have not been found to be cost-effective or to significantly reduce disease. in the 1950s and 1960s, routine general health examinations were promoted as an effective method of finding disease early. since the late 1970s, a selective and specific approach to screening has become widely accepted. this involves defining risk categories for specific diseases and bearing in mind the potential for remedial action. early case finding of colon cancer by routine fecal blood testing and colonoscopy has been found to be effective, and pap smear testing to discover cancer of the cervix is timed according to risk category. screening for colorectal cancer is essential for modern health programs and has been adopted by most industrialized countries. outreach programs by visits, telephones, emails or other modern methods of communication are important to contact non-attenders to promote utilization, and have been shown to increase compliance with proven effective measures. these programs are important for screening, follow-up, and maintenance of treatment for hypertension, diabetes, and other conditions requiring long-term management. screening technology is changing and often the subject of intense debate as such programs are costly and their cost-effectiveness is an important matter for policy making: screening for lung cancer is becoming a feasible and effective matter for high-risk groups, whereas breast cancer screening frequency is now in dispute; while nanotechnology and bioengineering promises new methods for cancer screening. the factor of contribution to quality of life should be considered. a vaccine for varicella is justified partly for the prevention of deaths or illness from chickenpox. a stronger the right to health public expectation and social norms argument is often based on the fact that this is a disease that causes moderate illness in children for up to 2 weeks and may require parents to stay home with the child, resulting in economic loss to the parent and society. the fact that this vaccination prevents the occurrence of herpes zoster or shingles later in life may also be a justification. widespread adoption of hepatitis b vaccine is justified on the grounds that it prevents cancer of the liver, liver cirrhosis, and hepatic failure in a high percentage of the population affected. how many cases of a disease are enough to justify an intervention? one or several cases of some diseases, such as poliomyelitis, may be considered an epidemic in that each case constitutes or is an indicator of a wider threat. a single case of polio suggests that another 1000 persons are infected but have not developed a recognized clinical condition. such a case constitutes a public health emergency, and forceful organization to meet a crisis is needed. current standards are such that even one case of measles imported into a population free of the disease may cause a large outbreak, as occurred in the uk, france, and israel during 2007 through 2013, by contacts on an aircraft, at family gatherings, or even in medical settings. a measles epidemic indicates a failure of public health policy and practice. screening for some cancers, such as cervix and colon, is cost effective. screening of all newborns for congenital disorders is important because each case discovered early and treated effectively saves a lifetime of care for serious disability. assessing a public health intervention to prevent the disease or reduce its impact requires measurement of the disease in the population and its economic impact. there is no simple formula to justify a particular intervention, but the cost-benefit approach is now commonly required to make such a case for action. sometimes public opinion and political leadership may oppose the views of the professional community, or may impose limitations of policy or funds that prevent its implementation. conversely, professional groups may press for additional resources that compete for limited resources available to provide other needed health activities. both the professionals of the health system and the general public need full access to health-related information to take part in such debates in a constructive way. to maintain progress, a system must examine new technologies and justify their adoption or rejection (see chapter 15). the association between health and political issues was emphasized by european innovators such as rudolf virchow (and in great britain by edwin chadwick; see chapter 1) in the mid-nineteenth century, when the conditions of the working population were such that epidemic diseases were rife and mortality was high, especially in the crowded slums of the industrial revolution. the same observations led bismarck in germany to introduce early forms of social insurance for the health of workers and their families in the 1880s, and to britain's 1911 national health insurance, also for workers and families. the role of government in providing universal access to health care was a struggle in individual countries during the twentieth century and lasting into the second decade of the twenty-first century (e.g. president obama's affordable health care act of 2010). as the concept of public health has evolved, and the cost effectiveness of medical care has improved through scientific and technological advances, societies have identified health as a legitimate area of activity for collective bargaining and government. with this process, the need to manage health care resources has become more clearly defined as a public responsibility. in industrialized countries, each with very different political make-up, national responsibility for universal access to health has become part of the social ethos. with that, the financing and managing of health services have developed into part of a broad concept of public health, and economics, planning, and management have come to be part of the new public health (discussed in chapters 10-13). social, ethical, and political philosophies have profound effects on policy decisions including allocation of public monies and resources. investment in public health is now recognized as an integral part of socioeconomic development. governments are major suppliers of funds and leadership in health infrastructure development, provision of health services, and health payment systems. they also play a central role in the development of health promotion and regulation of the environment, food, and drugs essential for community health. in liberal social democracies, the individual is deemed to have a right to health care. the state accepts responsibility to ensure availability, accessibility, and quality of care. in many developed countries, government has also taken responsibility to arrange funding and services that are equitably accessible and of high quality. health care financing may involve taxation, allocation, or special mandatory requirements on employers to pay for health insurance. services may be provided by a state-financed and -regulated service or through ngos and/or private service mechanisms. these systems allocate between 6 percent and 14 percent of gross national product (gnp) to health services, with some governments funding over 80 percent of health expenditure; for example, canada and the uk. in communist states, the state organizes all aspects of health care with the philosophy that every citizen is entitled to equity in access to health services. the state health system manages research, staff training, and service delivery, even if operational aspects are decentralized to local health authorities. this model applied primarily to the soviet model of health services. these systems, except for cuba, placed financing of health low on the national priority, with funding less than 4 percent of gnp. in the shift to market economies in the 1990s, some former socialist countries, such as russia, are struggling with poor health status and a difficult shift from a strongly centralized health system to a decentralized system with diffusion of powers and responsibilities. promotion of market concepts in former soviet countries has reduced access to care and created a serious dilemma for their governments. former colonial countries, independent since the 1950s and 1960s, largely carried on the governmental health structures established in the colonial times. most developing countries have given health a relatively low place in budgetary allotment, with expenditures under 3 percent of gnp. since the 1980s, there has been a trend in developing countries towards decentralization of health services and greater roles for ngos, and the development of health insurance. some countries, influenced by medical concepts of their former colonial master countries, fostered the development of specialty medicine in the major centers with little emphasis on the rural majority population. soviet influence in many ex-colonial countries promoted state-operated systems. the who promoted primary care, but the allocations favored city-based specialty care. israel, as an ex-colony, adapted british ideas of public health together with central european sick funds and maternal and child health as major streams of development until the mid-1990s. a growing new conservatism in the 1980s and 1990s in the industrialized countries is a restatement of old values in which market economics and individualistic social values are placed above concepts of the "common good" of liberalism and socialism in its various forms. in the more extreme forms of this concept, the individual is responsible for his or her own health, including payment, and has a choice of health care providers that will respond with high-quality personalized care. market forces, meaning competition in financing and provision of health services with rationing of services, based on fees or private insurance and willingness and ability to pay, have become part of the ideology of the new conservatism. it is assumed that the patient (i.e., the consumer) will select the best service for his or her need, while the provider best able to meet consumer expectations will thrive. in its purest form, the state has no role in providing or financing of health services except those directly related to community protection and promotion of a healthful environment without interfering with individual choices. the state ensures that there are sufficient health care providers and allows market forces to determine the prices and distribution of services with minimal regulation. the usa retains this orientation in a highly modified form, with 86 percent of the population covered by some form of private or public insurance systems (see chapters 10 and 13). modified market forces in health care are part of health reforms in many countries as they seek not only to ensure quality health care for all but also to constrain costs. a free market in health care is costly and ultimately inefficient because it encourages inflation of provider incomes or budgets and increasing utilization of highly technical services. further, even in the most free market societies, the economy of health care is highly influenced by many factors outside the control of the consumer and provider. the total national health expenditure in the usa rose rapidly until reaching over 17.7 percent of gross domestic product (gdp) in 2011, the highest of any country, despite serious deficiencies for those without any or with very inadequate health insurance (in total more than 30 percent of the population). this figure compares to some 11.2 percent of gdp in canada, which has universal health insurance under public administration. following the 1994 defeat of president clinton's national health program, the conservative congress and the business community took steps to expand managed care in order to control costs, resulting in a revolution in health care in the usa (see chapters 11 and 13). in the 2011-2019 decade health expenditure in the usa is expected to rise to 19.6 percent of gdp, partly owing to increased population coverage with implementation of the ppaca (obamacare). reforms are being implemented in many "socialized" health systems. these may be through incentives to promote achievement of performance indicators, such as full immunization coverage. others are using control of supply, such as hospital beds or licensed physicians, as methods of reducing overutilization of services that generates increasing costs. market mechanisms in health are aimed not only at the individual but also at the provider. incentive payment systems must work to protect the patient's legitimate needs, and conversely incentives that might reduce quality of care should be avoided. fee-for-service promotes high rates of services such as surgery. increasing private practice and user fees can adversely affect middle-and low-income groups, as well as employers, by raising the costs of health insurance. managed care systems, with restraints on fee-for-service medical practice, have emerged as a positive response to the market approach. incentive systems in payments for services may be altered by government or insurance agencies in order to promote rational use of services, such as reduction of hospital stays. the free market approach is affecting planning of health insurance systems in previously highly centralized health systems in developing countries as well as the redevelopment of health systems in former soviet countries. despite political differences, reform of health systems has become a common factor in virtually all health systems since the 1990s, as each government searches for costeffectiveness, quality of care, and universality of coverage. the new paradigm of health care reform sees the convergence of different systems to common principles. national responsibility for health goals and health promotion leads to national financing of health care with regional and managed care systems. most developed countries have long since adopted national health insurance or service systems. some governments may, as in the usa, insure only the highest risk groups such as the elderly and the poor, leaving the working and middle classes to seek private insurers. the nature and direction of health care reform affecting coverage of the population are of central importance in the new public health because of its effects on allocation of resources and on the health of the population. the effects of the economic crisis in the usa are being felt worldwide. while the downturn has largely occurred in wealthier nations, the poor in low-income countries will be among those affected. past economic downturns have been followed by substantial drops in foreign aid to developing countries. as public health gained from sanitary and other control measures for infectious diseases, along with mother and child care, nutrition, and environmental and occupational health, it also gained strength and applicability from advances in the social and behavioral sciences. social darwinism, a political philosophy that assumed "survival of the fittest" and no intervention of the sate to alleviate this assumption, was popular in the early nineteenth century but became unacceptable in industrialized countries, which adopted social policies to alleviate the worst conditions of poverty, unemployment, poor education, and other societal ills. the political approach to focusing on health and poverty is associated with jeremy bentham in britain in the late eighteenth century, who promoted social and political reform and "the greatest good for the greatest number", or utilitarianism. rudolf virchow, an eminent pathologist and a leader in recognizing ill-health and poverty as cause and effect, called for political action to create better conditions for the poor and working-class population. the struggle for a social contract was promoted by pioneer reformists such as edwin chadwick (general report on the sanitary condition of the labouring population of great britain, 1842), who later became the first head of the board of health in britain, and lemuel shattuck (report of a general plan for the promotion of public and personal health, 1850) . shattuck was the organizer and first president of the american statistical association. the social sciences have become fundamental to public health, with a range of disciplines including vital statistics and demography (seventeenth century), economics and politics (nineteenth century), sociology (twentieth century), history, anthropology, and others, which provide collectively important elements of epidemiology of crucial significance for survey methods and qualitative research (see chapter 3). these advances contributed greatly to the development of methods of studying diseases and risk factors in a population and are still highly relevant to addressing inequalities in health. individuals in good health are better able to study and learn, and be more productive in their work. improvements in the standard of living have long been known to contribute to improved public health; however, the converse has not always been recognized. investment in health care was not considered a high priority in many countries where economic considerations directed investment to the "productive" sectors such as manufacturing and large-scale infrastructure projects, such as hydroelectric dams. whether health is a contributor to economic development or a drain on societies' resources has been a fundamental debate between socially and market-oriented advocates. classic economic theory, both free enterprise and communist, has tended to regard health as a drain on economies, distracting investment needed for economic growth. as a result, in many countries health has been given low priority in budgetary allocation, even when the major source of financing is governmental. this belief among economists and banking institutions prevented loans for health development on the grounds that such funds should focus on creating jobs and better incomes, before investing in health infrastructure. consequently, the development of health care has been hampered. a socially oriented approach sees investment in health as necessary for the protection and development of "human capital", just as investment in education is needed for the long-term benefit of the economy of a country. in 1993, the world bank's world development report: investing in health articulated a new approach to economics in which health, along with education and social development, is seen as an essential precondition for and contributor to economic development. while many in the health field have long recognized the importance of health for social and economic improvement, its adoption by leading international development banking may mark a turning point for investment in developing nations, so that health may be a contender for increased development loans. the concept of an essential package of services discussed in that report establishes priorities in low-and middle-income countries for efficient use of resources based on the burden of disease and cost-effectiveness analysis of services. it includes both preventive and curative services targeted to specific health problems. it also recommends support for comprehensive primary care, such as for children, and infrastructure development including maternity and hospital care, medical and nursing outreach services, and community action to improve sanitation and safe water supplies. reorientation of government spending on health is increasingly being adopted, as in the uk, to improve equity in access for the poor and other neglected sectors or regions of society with added funding for relatively deprived areas to improve primary care services. differential capitation funding as a form of affirmative action to provide for highneeds populations is a useful concept in public health terms to address the inequities still prevalent in many countries. as medical care has gradually become more involved in prevention, and as it has moved into the era of managed care, the gap between public health and clinical medicine has narrowed. as noted above, many countries are engaged in reforms in their health care systems. the motivation is largely derived from the need for cost containment, but also to extend health care coverage to underserved parts of the population. countries without universal health care still have serious inequities in distribution of or access to services, and may seek reform to reduce those inequities, perhaps under political pressures to improve the provision of services. incentives for reform are needed to address regional inequities, and preserving or developing universal access and quality of care, but also on inequities in health between the rich and the poor countries and within even the wealthy countries. in some settings, a health system may fail to keep pace with developments in prevention and in clinical medicine. some countries have overdeveloped medical and hospital care, neglecting important initiatives to reduce the risk of disease. the process of reform requires setting standards to measure health status and the balance of services to optimize health. a health service can set a target of immunizing 95 percent of infants with a national immunization schedule, but requires a system to monitor performance and incentives for changes. a health system may also have failed to adapt to changing needs of the population through lack, or misuse, of health information and monitoring systems. as a result, the system may err seriously in its allocation of resources, with excessive emphasis on hospital care and insufficient attention to primary and preventive care. all health services should have mechanisms for correctly gathering and analyzing needed data for monitoring the incidence of disease and other health indicators, such as hospital utilization, ambulatory care, and preventive care patterns. for example, the uk's nhs periodically undertakes a restructuring process of parts of the system to improve the efficiency of service. this involves organizational changes and decentralization with regional allocation of resources (see chapter 13). health systems are under pressures of changing demographic and epidemiological patterns as well as public expectations, rising costs of new technology, financing, and organizational change. new problems must be continually addressed with selection of priority issues and the most effective methods chosen. reforms may create unanticipated problems, such as professional or public dissatisfaction, which must be evaluated, monitored, and addressed as part of the evolution of public health. literacy, freedom of the press, and increasing public concern for social and health issues have contributed to the development of public health. the british medical community lobbied for restrictions on the sale of gin in the 1780s in order to reduce the damage that it caused to the working class. in the late eighteenth and the nineteenth centuries, reforms in society and sanitation were largely the result of strongly organized advocacy groups influencing public opinion through the press. such pressure stimulated governments to act in regulating the working conditions of mines and factories. abolition of the slave trade and its suppression by the british navy in the early nineteenth century resulted from successful advocacy groups and their effects on public opinion through the press. vaccination against smallpox was promoted by privately organized citizen groups, until later taken up by local and national government authorities. advocacy consists of activities of individuals or groups publicly pleading for, supporting, espousing, or recommending a cause or course of action. the advocacy role of reform movements in the nineteenth century was the basis of the development of modern organized public health. campaigns ranged from the reform of mental hospitals, nutrition for sailors to prevent scurvy and beriberi, and labor laws to improve working conditions for women and children in particular, to the promotion of universal education and improved living conditions for the working population. reforms on these and other issues resulted from the stirring of the public consciousness by advocacy groups and the public media, all of which generated political decisions in parliaments (box 2.12). such reforms were in large part motivated by fear of revolution throughout europe in the mid-nineteenth century and the early part of the twentieth century. trade unions, and before them medieval guilds, fought to improve hours, safety, and conditions of work, as well as social and health benefits for their members. in the usa, collective bargaining through trade unions achieved wage increases and widespread coverage of the working population under voluntary health insurance. unions and some industries pioneered prepaid group practice, the predecessor of health maintenance organizations and managed care or the more recent acos (see chapters 10 and 13). through raising public consciousness on many issues, advocacy groups pressure governments to enact legislation to restrict smoking in public places, prohibit tobacco advertising, and mandate the use of bicycle helmets. advocacy groups play an important role in advancing health based on disease groups, such as cancer, multiple sclerosis, and thalassemia, or advancing health issues, such as the organizations promoting breastfeeding, environmental improvement, or smoking reduction. some organizations finance services or facilities not usually provided within insured health programs. such organizations, which can number in the hundreds in a country, advocate the importance of their special concern and play an important role in innovation and meeting community health needs. advocacy groups, including trade unions, professional groups, women's groups, self-help groups, and many others, focus on specific issues and have made major contributions to advancing the new public health. the history of public health is replete with pioneers whose discoveries led to strong opposition and sometimes violent rejection by conservative elements and vested interests in medical, public, or political circles. opposition to jennerian vaccination, the rejection of semmelweiss by colleagues in vienna, and the contemporary opposition to the work of great pioneers in public health such as pasteur, florence nightingale, and many others may deter or delay implementation of other innovators and new breakthroughs in preventing disease. although opposition to jenner's vaccination lasted well into the late nineteenth century in some areas, its supporters gradually gained ascendancy, ultimately leading to the global eradication of smallpox. these and other pioneers led the way to improved health, often after bitter controversy on topics later accepted and which, in retrospect, seem to be obvious. advocacy has sometimes had the support of the medical profession but elicited a slow response from public authorities. david marine of the cleveland clinic and david cowie, professor of pediatrics at the university of michigan, proposed the prevention of goiter by iodization of salt. marine carried out a series of studies in fish, and then in a controlled clinical trial among schoolgirls in 1917-1919, with startlingly positive results in reducing the prevalence of goiter. cowie campaigned for the iodization of salt, with support from the medical profession. in 1924, he convinced a private manufacturer to produce morton's iodized salt, which rapidly became popular throughout north america. similarly, iodized salt came to be used in many parts of europe, mostly without governmental support or legislation. iodine-deficiency disorders (idds) remain a widespread condition, estimated to have affected 2 billion people worldwide in 2013. the target of international eradication of idds by 2000 was set at the world summit for children in 1990, and the who called for universal iodization of salt in 1994. by 2008, nearly 70 percent of households in developing countries consumed adequately iodized salt. china and nigeria, have had great success in recent years with mandatory salt fortification in increasing iodization rates, in china from 39 percent to 95 percent in 10 years. but the problem is not yet gone and even in europe there is inadequate standardization of iodine levels and population follow-up despite decades of work on the problem. professional organizations have contributed to promoting causes such as children's and women's health, and environmental and occupational health. the american academy of pediatrics has contributed to establishing and promoting high standards of care for infants and children in the usa, and to child health internationally. hospital accreditation has been used for decades in the usa, canada, and more recently in australia and the uk. it has helped to raise standards of health facilities and care by carrying out systematic peer review of hospitals, nursing homes, primary care facilities, and mental hospitals, as well as ambulatory care centers and public health agencies (see chapter 15). public health needs to be aware of negative advocacy, sometimes based on professional conservatism or economic self-interest. professional organizations can also serve as advocates of the status quo in the face of change. opposition by the american medical association (ama) and the health insurance industry to national health insurance in the usa has been strong and successful for many decades. the passage of the ppaca has been achieved despite widespread political and public opposition, yet was sustained in the us supreme court and is gaining widening popular support as the added value to millions of formerly uninsured americans becomes clear. in some cases, the vested interest of one profession may block the legitimate development of others, such as when ophthalmologists lobbied successfully against the development of optometry, now widely accepted as a legitimate profession. political activism for reform in nineteenth-century britain led to banning and suppressing the slave trade, improvements in working conditions for miners and factory workers, and other major political reforms. in keeping with this tradition, samuel plimsoll (1824-1898), british member of parliament elected for derby in 1868, conducted a solo campaign for the safety of seamen. his book, our seamen, described ships sent to sea so heavily laden with coal and iron that their decks were awash. seriously overloaded ships, deliberately sent to sea by unscrupulous owners, frequently capsized, drowning many crew members, with the owners collecting inflated insurance fees. overloading was the major cause of wrecks and thousands of deaths in the british shipping industry. plimsoll pleaded for mandatory load-line certificate markers to be issued to each ship to prevent any ships putting to sea when the marker was not clearly visible. powerful shipping interests fought him every inch of the way, but he succeeded in having a royal commission established, leading to an act of parliament mandating the "plimsoll line", the safe carrying capacity of cargo ships. this regulation was adopted by the us bureau of shipping as the load line act in 1929 and is now standard practice worldwide. jenner's discovery of vaccination with cowpox to prevent smallpox was adopted rapidly and widely. however, intense opposition by organized groups of antivaccinationists, often led by those opposed to government intervention in health issues and supported by doctors with lucrative variolation practices, delayed the implementation of smallpox vaccination for many decades. ultimately, smallpox was eradicated in 1972, owing to a global campaign initiated by the who. opposition to legislated restrictions on private ownership of assault weapons and handguns is intense in the usa, led by well-organized, well-funded, and politically powerful lobby groups, despite the amount of morbidity and mortality due to gun-associated violent acts (see chapter 5). fluoridation of drinking water is the most effective public health measure for preventing dental caries, but it is still widely opposed, and in some places the legislation has been rescinded even after implementation, by wellorganized antifluoridation campaigns. opposition to fluoridation of community water supplies is widespread, and effective lobbying internationally has slowed but has not stopped progress (see chapter 6). despite the life-saving value of immunization, opposition still exists in 2013 and harms public health protection. opposition has slowed progress in poliomyelitis eradication; for example, radical islamists killed polio workers in northern nigeria in 2012, one of the last three countries with endemic poliomyelitis. resistance to immunization in the 1980s has resulted in the recurrence of pertussis and diphtheria and a very large epidemic of measles across western europe, including the uk, with further spread to the western hemisphere in 2010-2013 (see chapter 4). progress may be blocked where all decisions are made in closed discussions, not subject to open scrutiny and debate. public health personnel working in the civil service of organized systems of government may not be at liberty to promote public health causes. however, professional organizations may then serve as forums for the essential professional and public debate needed for progress in the field. professional organizations such as the apha provide effective lobbying for the interests of public health programs and can have an important impact on public policy. in mid-1996, efforts by the secretary of health and human services in the usa brought together leaders of public health with representatives of the ama and academic medical centers to try to find areas of common interest and willingness to promote the health of the population. in europe too, increasing cooperation between public health organizations is stimulating debate on issues of transnational importance across the region, which, for example, has a wide diversity of standards on immunization practices and food policies. public advocacy has played an especially important role in focusing attention on ecological issues (box 2.13). in 1995, greenpeace, an international environmental activist group, fought to prevent the dumping of an oil rig in the north sea and forced a major oil company to find another solution that would be less damaging to the environment. an explosion on an oil rig in the gulf of mexico in 2010 led to enormous ecological and economic damage as well as loss of life. damages levied on the responsible company (british petroleum) amount to some $4.5 billion dollars and several criminal negligence charges are pending. greenpeace also continued its efforts to stop the renewal of testing of atomic bombs by france in the south pacific. international protests led to the cessation of almost all testing of nuclear weapons. international concern over global warming has led to growing efforts to stem the tide of air pollution from fossil fuels, coal-burning electrical production, and other manifestations of carbon dioxide and toxic contamination of the environment. progress is far from certain as newly enriched countries such as china and india follow the rising consumption patterns of western countries. public advocacy and rejection of wanton destruction of the global ecology may be the only way to prod consumers, governments, and corporate entities such as the energy and transportation industries to change direction. the pace of change from fossil fuels is slow but has captured public attention, and private companies are seeking more fuel efficiency in vehicles and electrical power production, mainly though the use of natural gas instead of fuel oil and coal for electricity production or better still by wind and solar energy. the search for "green solutions" to the global warming crisis has become increasingly dynamic, with governments, the private sector, and the general public keenly aware of the importance of the effort and the dangers of failure. in the latter part of the twentieth century and the early twenty-first century, prominent international personalities and entertainers have taken up causes such as the removal of land mines in war-torn countries, illiteracy in disadvantaged advocacy is a function in public health that has been important in promoting advances in the field, and one that sometimes places the advocate in conflict with established patterns and organizations. one of the classic descriptions of this function is in henrik ibsen's play an enemy of the people, in which the hero, a young doctor, thomas stockmann, discovers that the water in his community is contaminated. this knowledge is suppressed by the town's leadership, led by his brother the mayor, because it would adversely affect plans to develop a tourist industry of baths in their small norwegian town in the late nineteenth century. the young doctor is taunted and abused by the townspeople and driven from the town, having been declared an "enemy of the people" and a potential risk. the allegory is a tribute to the man of principle who stands against the hysteria of the crowd. the term also took on a far more sinister and dangerous meaning in george orwell's novel 1984 and in totalitarian regimes of the 1930s to the present time. populations, and funding for antiretroviral drugs for african countries to reduce maternal-fetal transmission of hiv and to provide care for the large numbers of cases of aids devastating many countries of sub-saharan africa. rotary international has played a key role in polio eradication efforts globally. the public-private consortium global alliance for vaccines and immunization (gavi) has been instrumental in promoting immunization in recent years, with participation by the who, unicef, the world bank, the gates foundation, vaccine manufacturers, and others. this has had an important impact on extending immunization to protect and save the lives of millions of children in deprived countries not yet able to provide fundamental prevention programs such as immunization at adequate levels. gavi has brought vaccines to low-income countries around the world, such as rotavirus vaccine, pentavalent vaccine in myanmar, and pneumococcal vaccine for children in 15 countries in sub-saharan africa, including dr congo. the bill & melinda gates foundation pledged us $750 million in 1999 to establish gavi, with us $75 million per year and us $1 billion in 2010 to promote the decade of vaccines. international conferences help to create a worldwide climate of advocacy for health issues. international sanitary conferences in the nineteenth century were convened in response to the cholera epidemics. international conferences continue in the twenty-first century to serve as venues for advocacy on a global scale, bringing forward issues in public health that are beyond the scope of individual nations. the who, unicef, and other international organizations perform this role on a continuing basis (see chapter 16). criticisms of this approach have focused on the lack of similar effort or donors to address ncds, weak public health infrastructure, and that this frees national governments from responsibility to care for their own children. no one can question, however, that this kind of endeavor has saved countless lives and needs the backing of other aid donors and national government participation. consumerism is a movement that promotes the interests of the purchaser of goods or services. in the 1960s, a new form of consumer advocacy emerged from the civil rights and antiwar movement in the usa. concern was focused on the environment, occupational health, and the rights of the consumer. rachel carson stimulated concern by dramatizing the effects of ddt on wildlife and the environment but inadvertently jeopardized anti-malarial efforts in many countries. this period gave rise to environmental advocacy efforts worldwide, and a political movement, the greens, in western europe. ralph nader showed the power of the advocate or "whistle-blower" who publicizes health hazards to stimulate active public debate on a host of issues related to the public well-being. nader, a consumer advocate lawyer, developed a strategy for fighting against business and government activities and products which endangered public health and safety. his 1965 book unsafe at any speed took issue with the us automobile industry for emphasizing profit and style over safety, and led to the enactment of the national traffic and motor safety act of 1966, establishing safety standards for new cars. this was followed by a series of enactments including design and emission standards and seat-belt regulations. nader's work continues to promote consumer interests in a wide variety of fields, including the meat and poultry industries, and coal mining, and promotes greater government regulatory powers regarding pesticide usage, food additives, consumer protection laws, rights to knowledge of contents, and safety standards. consumerism has become an integral part of free market economies, and the educated consumer does influence the quality, content, and price of products. greater awareness of nutrition in health has influenced food manufacturers to improve packaging, content labeling, enrichment with vitamins and minerals, and advertisement to promote those values. low-fat dietary products are available because of an increasingly sophisticated public concerned over dietary factors in cardiovascular diseases. the same process occurred in safe toys and clothing for children, automobile safety features such as mandatory use of car seats for infants, and other innovations that quickly became industry standards in the industrialized world. dangerous practices such as the use of lead paint in toys and melamine contamination of milk products from china capture the public attention quickly and remind public health authorities of the importance of continuous alertness to potential hazards. consumerism can also be exploited by pharmaceutical companies with negative impacts on the health system, especially in the advertising of health products which leads to unnecessary visits to health providers and pressure for approval to obtain the product. the internet has provided people with access to a vast array of information and opinion, and to current literature otherwise unavailable because of the often inadequate library resources of medical and other health professionals. the very freedom of information the internet allows, however, also provides a vehicle for extremist and fringe groups to promote disinformation such as "vaccination causes autism, fluoridation causes cancer", which can cause considerable difficulties for basic public health programs or lead to self-diagnosis of conditions, with often disastrous consequences. advocacy and voluntarism go hand in hand. voluntarism takes many forms, including raising funds for the development of services or operating services needed in the community. it may take the form of fund-raising to build clinics or hospitals in the community, or to provide medical equipment for elderly or handicapped people; or retirees and teenagers working as hospital volunteers to provide services that are not available through paid staff, and to provide a sense of community caring for the sick in the best traditions of religious or municipal concerns. this can also be extended to prevention, as in support for immunization programs, assistance for the handicapped and elderly in transportation, meals-on-wheels, and many other services that may not be included in the "basket of services" provided by the state, health insurance, or public health services. community involvement can take many forms, and so can voluntarism. the pioneering role of women's organizations in promoting literacy, health services, and nutrition in north america during the latter part of the nineteenth and the early twentieth centuries profoundly affected the health of the population. the advocacy function is enhanced when an organization mobilizes voluntary activity and funds to promote changes or needed services, sometimes forcing official health agencies or insurance systems to revise their attitudes and programs to meet these needs. by the early 1970s, canada's system of federally supported provincial health insurance plans covered all of the country. the federal minister of health, marc lalonde, initiated a review of the national health situation, in view of concern over the rapidly increasing costs of health care. this led to articulation of the "health field concept" in 1974, which defined health as a result of four major factors: human biology, environment, behavior, and health care organization (box 2.14). lifestyle and environmental factors were seen as important contributors to the morbidity and mortality in modern societies. this concept gained wide acceptance, promoting new initiatives that emphasized health promotion in response to environmental and lifestyle factors. conversely, reliance primarily on medical care to solve all health problems could be counterproductive. this concept was a fundamental contributor to the idea of health promotion later articulated in the ottawa declaration, discussed below. the health field concept came at a time when many epidemiological studies were identifying risk factors for cardiovascular diseases and cancers that related to personal habits, such as diet, exercise, and smoking. the concept advocated that public policy needed to address individual lifestyle as part of the overall effort to improve health status. as a result, the canadian federal government established health promotion as a new activity. this quickly spread to many other jurisdictions and gained wide acceptance in many industrialized countries. concern was expressed that this concept could become a justification for a "blame the victim" approach, in which those ill with a disease related to personal lifestyles, such as smokers or aids patients, are seen as having chosen to contract the disease. such a patient might then be considered not to be entitled to all benefits of insurance or care that others may receive. the result may be a restrictive approach to care and treatment that would be unethical in the public health tradition and probably illegal in western jurisprudence. this concept was also used to justify withdrawal from federal commitments in cost sharing and escape from facing controversial health reform in the national health insurance program. during the 1960s and 1970s, outspoken critics of health care systems, such as ivan illytch, questioned the value of medical care for the health of the public. this became a widely discussed, somewhat nihilistic, view towards medical care, and was influential in promoting skepticism regarding the value of the biomedical mode of health care, and antagonism towards the medical profession. in 1976, thomas mckeown presented a historicalepidemiological analysis showing that up to the 1950s, medical care had only a limited impact on mortality rates, although improvements in surgery and obstetrics were notable. he showed that crude death rates in england averaged about 30 per 1000 population from 1541 to 1750, declining steeply to 22 per 1000 in 1851, 15 per 1000 in 1901, and 12 per 1000 in 1951, when medical care became truly effective. mckeown concluded that much of the improvement in health status over the past several centuries was due to reduced mortality from infectious diseases. this he related to limitation of family size, increased food supplies, improved nutrition and sanitation, specific preventive and therapeutic measures, and overall gains in quality of life for growing elements of the population. he cautioned against placing excessive reliance for health on medical care, much of which was of unproved effectiveness. this skepticism of the biomedical model of health care was part of wider antiestablishment feelings of the 1960s and 1970s in north america. in 1984, milton roemer pointed out that the advent of vaccines, antibiotics, antihypertensives, and other medications contributed to great improvements in infant and child care, and in the management of infectious diseases, hypertension, diabetes, and other conditions. therapeutic gains continue to arrive from teaching centers around the world. vaccine, pharmaceutical, and diagnostic equipment manufacturers continue to provide important innovations that have major benefits, but also raise the cost of health care. the latter issue is one which has stimulated the search for reforms, and search for lower cost technologies such as in treatment of hepatitis c patients, a huge international public health issue. the value of medical care to public health and vice versa has not always been clear, either to public health personnel or to clinicians. the achievements of modern public health in controlling infectious diseases, and even more so in reducing the mortality and morbidity associated with chronic diseases such as stroke and chd, were in reality a shared achievement between clinical medicine and public health (see chapter 5). preventive medicine has become part of all medical practice, with disease prevention through early diagnosis and health promotion through individual and community-focused activities. risk factor evaluation determines appropriate screening and individual and community-based interventions. medical care is crucial in controlling hypertension and in reducing the complications and mortality from chd. new modalities of treatment are reducing death rates from first time acute myocardial infarctions. better management of diabetes prevents the early onset of complications. at the same time, the contribution of public health to improving outcomes of medical care is equally important. control of the vaccine-preventable diseases, improved nutrition, and preparation for motherhood contribute to improved maternal and infant outcomes. promotions of reduced exposure to risk factors for chronic disease are a task shared by public health and clinical medical services. both clinical medicine and public health contribute to improved health status. they are interdependent and rely on funding systems for recognition as part of the new public health. during the 1950s, many new management concepts emerged in the business community, such as "management by objective", a concept developed by peter drucker at general motors, with variants such as "zero-based budgeting" developed in the us department of defense (see chapter 12). they focused the activities of an organization and its budget on targets, rather than on previous allocation of resources. these concepts were applied in other spheres, but they influenced thinking in health, whose professionals were seeking new ways to approach health planning. the logical application was to define health targets and to promote the efficient use of resources to achieve those targets. this occurred in the usa and soon afterwards in the who european region. in both cases, a wide-scale process of discussion and consensus building was used before reaching definitive targets. this process contributed to the adoption of the targets by many countries in europe as well as by states and many professional and consumer organizations. the usa developed national health objectives in 1979 for the year 1990 and subsequently for the year 2000, with monitoring of progress in their achievement and development of further targets for 2010 and now for 2020. beginning in 1987, state health profiles are prepared by the epidemiology program office of the centers for disease control and prevention based on 18 health indicators recommended by a consensus panel representing public health associations and organizations. the eight mdgs adopted by the un in 2000 include halving extreme poverty, reducing child mortality by twothirds, improving maternal health, halting the spread of hiv/aids, malaria, and other diseases, and providing universal primary education, all by the target date of 2015. the mdgs form a common blueprint agreed to by all countries and the world's leading development institutions. the process has galvanized unprecedented efforts to meet the needs of the world's poorest, yet 2008 reviews of progress indicate that most developing nations will not meet the targets at current rates of progress. the united nations development programme (undp) global partnership for development 2012 report on the mdgs states that if the national development strategies and initiatives are supported by international development partners, the goals can be achieved by 2015. the mdgs were adopted by over 120 nations and provided guidance for national policies and for international aid agencies. the focus was on middle-and low-income countries and their achievements have been considerable but variable (see box 2.15 and chapter 16) . as of july 2012, extreme poverty was falling in every region, the poverty reduction target had been met, the world had met the target of halving the proportion of people without access to improved sources of water, and the world had achieved parity in primary education between girls and boys. further progress will require sustained political commitment to develop the primary care infrastructure: improved reporting and epidemiological monitoring, consultative mechanisms, and consensus by international agencies, national governments, and non-governmental agencies. the achievement of the targets will also require sustained international support and national commitment with all the difficulties of a time of economic recession. nevertheless, defining a target is crucial to the process. there are encouraging signs that national governments are influenced by the general movement to place greater emphasis on resource allocation and planning on primary care to achieve internationally recognized goals and targets. the successful elimination of smallpox, rising immunization coverage in the developing countries, and increasing implementation of salt iodization have shown that such goals are achievable. while the usa has not succeeded in developing universal health care access, it has a strong tradition of public health and health advocacy. federal, state, and local health authorities have worked out cooperative arrangements for financing and supervising public health and other services. with growing recognition in the 1970s that medical services alone would not achieve better health results, health policy leadership in the federal government formulated a new approach, in the form of developing specific health targets for the nation. in 1979, the surgeon general of the usa published the report on health promotion and disease prevention (healthy people). this document set five overall health goals for each of the major age groups for the year 1990, accompanied by 226 specific health objectives. new targets for the year 2000 were developed in three broad areas: to increase healthy lifespans, to reduce health disparities, and to achieve access to preventive health care for all americans. these broad goals are supported by 297 specific targets in 22 health priority areas, each one divided into four major categories: health promotion, health protection, preventive services, and surveillance systems. this set the public health agenda on the basis of measurable indicators that can be assessed year by year. reduce child mortality -progress on child mortality is gaining momentum. the target is to reduce by two-thirds, between 1990 and 2015, the under-5-year-old mortality rate, from 93 children of every 1000 dying to 31 of every 1000. child deaths are falling, but much more needs to be done in order to reach the development goal. revitalizing efforts against pneumonia and diarrhea, while bolstering nutrition, could save millions of children. l mdg5. improve maternal health -maternal mortality has nearly halved since 1990, but levels are far removed from the 2015 target. the targets for improving maternal health include reducing by three-quarters the maternal mortality ratio and achieve universal access to reproductive health. poverty and lack of education perpetuate high adolescent birth rates. inadequate funding for family planning is a major failure in fulfilling commitments to improving women's reproductive health. l mdg6. combat hiv/aids, malaria, tuberculosis, and other diseases -more people than ever are living with hiv owing to fewer aids-related deaths and the continued large number of new infections. in 2011, an estimated 34.2 million were living with hiv, up 17 percent from 2001. this persistent increase reflects the continued large number of new infections along with a significant expansion of access to lifesaving antiretroviral therapy, especially in more recent years. l mdg7. ensure environmental sustainability -the unparalleled success of the montreal protocol shows that action on climate change is within grasp. the 25th anniversary of the montreal protocol on substances that deplete the ozone layer, in 2012, had many achievements to celebrate. most notably, there has been a reduction of over 98 percent in the consumption of ozone-depleting substances. further, because most of these substances are also potent greenhouse gases, the montreal protocol has contributed significantly to the protection of the global climate system. the reductions achieved to date leave hydrochlorofluorocarbons (hcfcs) as the largest group of substances remaining to be phased out. l mdg8. a global partnership for development -core development aid fell in real terms for the first time in more than a decade, as donor countries faced fiscal constraints. in 2011, net aid disbursements amounted to $133.5 billion, representing 0.31 percent of developed countries' combined national income. while constituting an increase in absolute dollars, this was a 2.7 percent drop in real terms over 2010. if debt relief and humanitarian aid are excluded, bilateral aid for development programmes and projects fell by 4.5 percent in real terms. equitable and sustainable funding of health services. 18. developing human resources (educational programs for providers and managers based on the principles of the health for all policy). 19. research and knowledge: health programs based on scientific evidence. 20. mobilizing partners for health (engaging the media/ television/internet). 21. policies and strategies for health for all -national, targeted policies based on health for all. a 2010-2012 review has been commissioned by the european office of the who to assess inequalities in the social determinants of health. while health has improved there are still significant inequalities. factors include variance in local, regional, national, and global economic forces. the european union and the european region of who are both working on health targets for the year 2020. there are competing demands in society for expenditure by the government, and therefore making the best use of resources -money and people -is an important objective. the uk has devolved many of the responsibilities to the constituent countries (england, wales, scotland, and northern ireland) within an overall national framework (box 2.17). of the health consequences of their decisions and to accept responsibility for health. health promotion policy combines diverse but complementary approaches, including legislation, fiscal measures, taxation, and organizational change. it is a coordinated action that leads to health, income, and social policies that foster greater equity. joint action contributes to ensuring safer and healthier goods and services, healthier public services, and cleaner, more enjoyable environments. health promotion policies require the identification of obstacles to the adoption of healthy public policies in non-health sectors, and ways of removing them. built on progress made from the declaration on primary health care at alma-ata, the aim was to make the healthier choice the easier choice for policy makers as well. the logo of the ottawa charter has been maintained by the who as the symbol and logo of health promotion. health promotion represents activities to enhance and embed the concept of building healthy public policy through: l building healthy public policy in all sectors and levels of government and society l enhancing both self help and social support l developing personal skills through information and education for health l enabling, mediating, and advocating healthy public policy in all spheres l creating supportive environments of mutual help and conservation of the natural environment l reorienting health services beyond providing clinical curative services with linkage to broader social, political, economic, and physical environmental components. (adapted from ottawa charter; health and welfare canada and world health organization, 1986) an effective approach to health promotion was developed in australia where, in the state of victoria, revenue from a cigarette tax has been set aside for health promotion purposes. this has the effect of discouraging smoking, and at the same time finances health promotion activities and provides a focus for health advocacy in terms of promoting cessation of cigarette advertising at sports events or on television. it also allows for assistance to community groups and local authorities to develop health promotion activities at the workplace, in schools, and at places of recreation. health activity in the workplace involves reduction of work hazards as well as promotion of a healthy diet and physical fitness, and avoidance of risk factors such as smoking and alcohol abuse. in the australian model, health promotion is not only the persuasion of people to change their life habits; it also involves legislation and enforcement towards environmental changes that promote health. for example, this involves mandatory filtration, chlorination, and fluoridation for community water supplies, vitamin and mineral enrichment of basic foods. primary care alliances of service providers are organized including hospitals, community health services serving a sub-district population for more efficient and comprehensive care. these are at the level of national or state policy, and are vital to a health promotion program and local community action. community-based programs to reduce chronic disease using the concept of community-wide health promotion have developed in a wide variety of settings. such a program to reduce risk factors for cardiovascular disease was pioneered in the north karelia project in finland. this project was initiated as a result of pressures from the affected population of the province, which was aware of the high incidence of mortality from heart disease. finland had the highest rates of chd in the world and in the rural area of north karelia the rate was even higher than the national average. the project was a regional effort involving all levels of society, including official and voluntary organizations, to try to reduce risk factors for chd. after 15 years of follow-up, there was a substantial decline in mortality with a similar decline in a neighboring province taken for comparison, although the decline began earlier in north karelia. in many areas where health promotion has been attempted as a strategy, community-wide activity has developed with participation of ngos or any valid community group as initiators or participants. healthy heart programs have developed widely with health fairs, sponsored by charitable or fraternal societies, schools, or church groups, to provide a focus for leadership in program development. a wider approach to addressing health problems in the community has developed into an international movement of "healthy cities". following deliberations of the health of towns commission chaired by edwin chadwick, the health of towns association was founded in 1844 by southwood smith, a prominent reform leader of the sanitary movement, to advocate change to reduce the terrible living conditions of much of the population of cities in the uk. the association established branches in many cities and promoted sanitary legislation and public awareness of the "sanitary idea" that overcrowding, inadequate sanitation, and absence of safe water and food created the conditions under which epidemic disease could thrive. in the 1980s, iona kickbush, trevor hancock, and others promoted renewal of the idea that local authorities have a responsibility to build health issues into their planning and development processes. this "healthy cities" approach promotes urban community action on a broad front of health promotion issues (table 2. 2). activities include environmental projects (such as recycling of waste products), improved recreational facilities for young people to reduce violence and drug abuse, health fairs to promote health awareness, and screening programs for hypertension, breast cancer, and other diseases. it combines health promotion with consumerism and returns to the tradition of local public health action and advocacy. the municipality, in conjunction with many ngos, develops a consultative process and program development approach to improving the physical and social life of the urban environment and the health of the population. in 1995, the healthy cities movement involved 18 countries with 375 cities in europe, canada, the usa, the uk, south america, israel, and australia, an increase from 18 cities in 1986. the model now extends to small municipalities, often with populations of fewer than 10,000. networks of healthy cities are the backbone of the movement, with more than 1400 member towns and cities across europe. the choice of core themes offers the opportunity to work on priority urban health issues that are relevant to all european cities. topics that are of particular concern to individual cities and/or are challenging and cutting edge for innovative public health action are especially emphasized. healthy cities encourages and supports experimentation with new ideas by developing concepts and implementing them in diverse organizational contexts. a healthy city is a city for all its citizens: inclusive, supportive, sensitive and responsive to their diverse needs and expectations. a healthy city provides conditions and opportunities that encourage, enable and support healthy lifestyles for people of all social groups and ages. a healthy city offers a physical and built environment that encourages, enables and supports health, recreation and well-being, safety, social interaction, accessibility and mobility, a sense of pride and cultural identity and is responsive to the needs of all its citizens. the apha's formulation of the public health role in 1995, entitled the future of public health in america, was presented at the annual meeting in 1996. the apha periodically revises standards and guidelines for organized public health services provided by federal, state, and local governments ( table 2 .4). these reflect the profession of public health as envisioned in the usa where access to medical care is limited for large numbers of the population because of a lack of universal health insurance. public health in the usa has been very innovative in determining risk groups in need of special care and finding direct and indirect methods of meeting those needs. european countries such as finland have called for setting public health into all public policy, which reflects the vital role that local and county governments can play in developing health-oriented policies. these include policies in housing, recreation, regulation of industrial pollution, road safety, promotion of smoke-free environments, bicycle paths, health impact assessment, and many other applications of health principles in public policy. public health involves both direct and indirect approaches. direct measures in public health include immunization of children, modern birth control, and chronic disease case finding -hypertension, diabetes, and cancer. indirect methods used in public health protect the individual by community-wide means, such as raising standards of environmental safety, ensuring a safe water supply, sewage disposal, and improved nutrition (box 2.18). in public health practice, the direct and indirect pproaches are both relevant. to reduce morbidity and mortality from diarrheal diseases requires an adequate supply of safe water and waste disposal, and also education of the individual in hygiene and the mother in use of ort, and rotavirus vaccination of all children. the targets of public health action therefore include the individual, family, community, region, or nation, as well as a functioning and health system adopting current best practices for health care and health protection. the targets for protection in infectious disease control are both the individual and the total group at risk. for vaccine-preventable diseases, immunization protects the individual but also has an indirect effect by reducing the risk even for non-immunized persons. in control of some diseases, individual case finding and management reduce risk of the disease in others and the community. for example, tb requires case finding and adequate care among high-risk groups as a key to community control. in malaria control, case finding and treatment are essential together with environmental action to reduce the vector population, to prevent transmission of the organism by the mosquito to a new host. control of ncds, where there is no vaccine for mass application, depends on the knowledge, attitudes, beliefs, and practices of individuals at risk. in this case, the social context is of importance, as is the quality of care to which the individual has access. control and prevention of noninfectious diseases involve strategies using individual and population-based methods. individual or clinical measures include professional advice on how best to reduce the risk of the disease by early diagnosis and implementation of appropriate therapy. population-based measures involve indirect measures with government action banning cigarette advertising, or direct taxation on cigarettes. mandating food quality standards, such as limiting the fat content of meat, and requiring food labeling laws are part of the control of cardiovascular diseases. the way individuals act is central to the objective of reducing disease, because many non-infectious diseases are dependent on behavioral risk factors of the individual's choosing. changing the behavior of the individual means addressing the way a person sees his or her own needs. this can be influenced by the provision of information, but how someone sees his or her own needs is more complex than that. an individual may define needs differently from the society or the health system. reducing smoking among women may be difficult to achieve if smoking is thought to reduce appetite and food intake, given the social message that "slim is beautiful". reducing smoking among young people is similarly difficult if smoking is seen as fashionable and diseases such as lung cancer seem very remote. recognizing how individuals define needs helps the health system to design programs that influence behavior that is associated with disease. public health has become linked to wider issues as health care systems are reformed to take on both individual and population-based approaches. public health and mainstream medicine have found increasingly common ground in addressing the issues of chronic disease, growing attention to health promotion, and economics-driven health care reform. at the same time, the social ecology approaches have shown success in slowing major causes of disease, including heart disease and aids, and the biomedical sciences have provided major new technology for preventing major health problems, including cancer, heart disease, genetic disorders, and infectious diseases. technological innovations unheard of just a few years ago are now commonplace, in some cases driving up costs of care and in others replacing older and less effective care. at the same time, resistance of important pathogenic microorganisms to antibiotics and pesticides is producing new challenges from diseases once thought to be under control, and newly emerging infectious diseases challenge the entire health community. new generations of antibiotics, antidepressants, antihypertensive medications, and other treatment methods are changing the way many conditions are treated. research and development in the biomedical to improve the quality of public health practice and performance of public health systems sciences are providing means of prevention and treatment that profoundly affect disease patterns where they are effectively applied. the technological and organizational revolutions in health care are accompanied by many ethical, economic, and legal dilemmas. the choices in health care include heart transplantation, an expensive life-saving procedure, which may compete with provision of funds and labor resources for immunizations for poor children or for health promotion to reduce smoking and other risk factors for chronic disease. new means of detecting and treating acute conditions such as myocardial infarction and peptic ulcers are reducing hospital stays, and improving long-term survival and quality of life. imaging technology has been an important development in medicine since the advent of x-rays in the early twentieth century. technology has forged ahead with high-technology instruments and procedures, new medication, genetic engineering, and important low-technology gains such as impregnated bed nets, simplified tests for hiv and tb, and many other "game changers". new technologies that can enable lower cost diagnostic devices, electronic transmission, and distant reading of transmitted imaging all open up possibilities for advanced diagnostic capacities in rural and less developed countries and communities. molecular biology has provided methods of identifying and tracking movement of viruses such as polio and measles from place to place, greatly expanding the potential for appropriate intervention. the choices in resource allocation can be difficult. in part, these add political commitment to improve health, competent professionally trained public health personnel, the public's level of health information, and legal protection, whether through individuals, advocacy, or regulatory approaches for patients' rights. these are factors in a widening methodology of public health. the centers for disease control and prevention (morbidity and mortality weekly report) in 1999 summarized 10 great achievements of public health in the usa, with an extension of the lifespan by over 30 years and improvements in many measures of quality of life. they were updated in a similar summary report in 2011, showing continuous progress, and a global version which was also encouraging in its scope of progress (table 2 .5). these achievements were also seen in all developed countries over the past century and are beginning to be seen in developing countries as well. they reflect a successful application of a broad approach to prevention and health promotion along with improved medical care and growing access to its benefits. in the past several decades alone, major new innovations are leading to greater control of cardiovascular disease, cancer prevention, and many other improvements to health affecting hundreds of millions of people. a similar 2011 report by the cdc shows global progress in the first decade of the twenty-first century, while mdg reports show progress on all eight target topics, although not at uniformly satisfactory rates. these achievements are discussed throughout this text. this successful track record is very much at the center of a new public health involving a wide range of programs and activities, shown to be feasible and benefiting from continuing advances in science and understanding of social and management issues affecting health care systems worldwide. public health issues have received new recognition in recent years because of a number of factors, including a growing understanding among the populace at different levels in different countries that health behavior is a factor in health status and that public health is vital for protection against natural or human-made disasters. the challenges are also increasingly understood: preparation for bioterrorism, avian influenza, rising rates of diabetes and obesity, high mortality rates from cancer, and a wish for prevention to be effective. health systems offer general population benefits that go beyond preventing and treating illness. appropriately designed and managed, they: l provide a vehicle to improve people's lives, protecting them from the vulnerability of sickness, generating a sense of life security, and building common purpose within society l ensure that all population groups are included in the processes and benefits of socioeconomic development l generate the political support needed to sustain them over time. health systems promote health equity when their design and management specifically consider the circumstances and needs of socially disadvantaged and marginalized populations, including women, the poor, and groups who experience stigma and discrimination, enabling social action by these groups and the civil society organizations supporting them. health systems can, when appropriately designed and managed, contribute to achieving the millennium development goals. the mdgs selected by the un in 2000 have eight global targets for the year 2015, including four directly related to public health (discussed above, box 2.15). these are a recognition and a challenge to the international community and public health as a profession and as organized systems. formal education in newly developing schools of public health is increasing in europe, including many countries of eastern europe, and beginning to develop in india and sub-saharan africa. but there is delay in establishing centers of postgraduate education and research in many developing countries which are concentrating their educational resources on training physicians. many physicians from developing nations are moving to the developed countries, which have become dependent on these countries for a significant part of their supply of medical doctors. progress in implementation of the mdgs is mixed in sub-saharan africa, making some progress in immunization, but falling back on other goals. proposals to renew global health targets following the 2015 end-stage of the mdg health goals will need to add a focus on ncds, which account for 60 percent of global deaths, including 8.1 million premature deaths below the age of 60 (undp). economic growth has been hampered by the global recession since 2008, which will affect continued progress with many other factors of changing population dynamics, the economics of prevention versus expensive treatment costs, and the high costs of health care. environmental degradation with high levels of carbon dioxide contamination is a growing concern, with disastrous global warming and consequent effects of drought, flooding, hurricane, and elevated particulate matter-induced asthma and effects on cardiovascular disease. the potential for the development of basic and medical sciences in genetics, nanotechnology, and molecular biology shows enormous promise for health benefits as yet unimagined. at the same time, the effectiveness of health promotion has shown dramatic successes in reducing the toll of aids, reducing smoking, and increasing consciousness of nutrition and physical fitness in the population, and of the tragic effects of poverty and poor education on health status. the ethics of public health issues are complex and changing with awareness that failure to act on strong evidence-based policies is itself ethically problematic. the future of public health is not as a solo professional sector; it is at the heart of health systems, without which societies are open to chronic and infectious diseases that are preventable, affecting the society as a whole in economic and development matters. there is an expanding role of private donors in global health efforts, such as the rotary club and the polio eradication program, gavi with immunization and bed-nets in sub-saharan africa, and bilateral donor countries' help in reducing the toll of aids in sub-saharan africa. the new public health has emerged as a concept to meet a whole new set of conditions, associated with increasing longevity and aging of the population, with the post-world war ii baby-boom generation reaching the over-65 age group facing the growing importance of chronic diseases. inequalities in health exist in and between affluent and developing societies, as well as within countries, even those having advanced health care systems. regional inequalities are seen across the european region in an east-west gradient and globally a north-south divide of extremes of inequality. the global environmental and ecological degradation and pollution of air and water present grave challenges for developed and developing countries worldwide. yet optimism can be derived from proven track records of success in public health measures that have already been implemented. many of the underlying factors are amenable to prevention through social, environmental, or behavioral change and effective use of medical care. the new public health idea has evolved since alma-ata, which articulated the concept of health for all, followed by a trend in the late 1970s to health in all policies and establishing health targets as a basis for health planning. during the late 1980s and early 1990s, the debate on the future of public health in the americas intensified as health professionals looked for new models and approaches to public health research, training, and practice. this debate helped to redefine traditional approaches of social, community, and preventive medicine. the search for the "new" in public health continued with a return to the health for all concept of alma-ata (renewed in 2008) and a growing realization that the health of both the individual and the society involves the management of personal care services and community prevention, with a comprehensive approach taking advantage of advancing technology and experience of best practices globally. the new public health is an extension of the traditional public health. it describes organized efforts of society to develop healthy public policies: to promote health, to prevent disease, and to foster social equity within a framework of sustainable development. a new, revitalized public health must continue to fulfill the traditional functions of sanitation, protection, and related regulatory activities, but in addition to its expanded functions. it is a widened philosophy and practical application of many different methods of addressing health, and preventing disease and avoidable death. it necessarily addresses inequities so that programs need to meet special needs of different groups in the population according to best standards, limited resources, and population needs. it is proactive and advocates interventions within legal and ethical limits to promote health as a value in and of itself and as an economic gain for society as well for its individual members. the new public health is a comprehensive approach to protecting and promoting the health status of the individual and the society, based on a balance of sanitary, environmental, health promotion, personal, and community-oriented preventive services, coordinated with a wide range of curative, rehabilitative, and long-term care services. it evolves with new science, technology, and knowledge of human and systems behavior to maximize health gains for the individual and the population. the new public health requires an organized context of national, regional, and local governmental and non-governmental programs with the object of creating healthful social, nutritional, and physical environmental conditions. the content, quality, organization, and management of component services and programs are all vital to its successful implementation. whether managed in a diffused or centralized structure, the new public health requires a systems approach acting towards achievement of defined objectives and specified targets. the new public health works through many channels to promote better health. these include all levels of government and parallel ministries; groups promoting advocacy, academic, professional, and consumer interests; private and public enterprises; insurance, pharmaceutical, and medical products industries; the farming and food industries; media, entertainment, and sports industries; legislative and law enforcement agencies; and others. the new public health is based on responsibility and accountability for defined populations in which financial systems promote achievement of these targets through effective and efficient management, and cost-effective use of financial, human, and other resources. it requires continuous monitoring of epidemiological, economic, and social aspects of health status as an integral part of the process of management, evaluation, and planning for improved health. the new public health provides a framework for industrialized and developing countries, as well as countries in political-economic transition such as those of the former soviet system. they are at different stages of economic, epidemiological, and sociopolitical development, each attempting to ensure adequate health for its population with limited resources. the challenges are many, and affect all countries with differing balances, but there is a common need to seek better survival and quality of life for their citizens (table 2 .6). the object of public health, like that of clinical medicine, is better health for the individual and for society. public health works to achieve this through indirect methods, such as by improving the environment, or through direct means such as preventive care for mothers and infants or other atrisk groups. clinical care focuses directly on the individual patient, mostly at the time of illness. but the health of the individual depends on the health promotion and social programs of the society, just as the well-being of a society depends on the health of its citizens. the new public health consists of a wide range of programs and activities that link individual and societal health. the "old" public health was concerned largely with the consequences of unhealthy settlements and with safety of food, air, and water. it also targeted the infectious, toxic, and traumatic causes of death, which predominated among young people and were associated with poverty. a summary of the great achievements of public health in the twentieth and in the early twenty-first century in the industrialized world is included in chapter 1 and throughout this text. these achievements are reflective of public health gains throughout the industrialized world and are encourage and leverage national, state, and local partnerships to build a stronger foundation for public health preparedness and investigate health problems and health hazards in the community 3. inform, educate, and empower people about health issues 4. mobilize community partnerships to identify and solve health problems 5. develop policies and plans that support individual and community health efforts 6. enforce laws and regulations that protect health and ensure safety 7 evaluate effectiveness, accessibility, and quality of personal and population-based health services vision, mission and goals guidelines on food fortification with micronutrients. who, geneva. alliance for health policy and systems research 10 essential public health services healthy communities, 2000. model standards for community attainment of the year 2000 national health objectives determinants of adult mortality in russia: estimates from sibling data commission on social determinants and health. closing the gap in a generation: health equity through action on the social determinants of health compression of morbidity in the elderly institute of medicine. who will keep the public healthy? educating public health professionals for the 21st century global alliance for vaccine and immunization (gavi) chronic disease prevention and the new public health the evolution, impact and significance of healthy cities/healthy communities world health organization. ottawa charter for health promotion: an international conference on health promotion behavioral and social sciences and public health at cdc. mmwr health in all policies: seizing opportunities, implementing policies. ministry of social affairs and health new perspectives on the health of canadians: a working document new perspective on the health of canadians: 28 years later the us healthy people initiative: its genesis and its sustainability mortality from cardiovascular and cerebrovascular diseases in europe and other areas of the world: an update strategic review of health inequalities in england post. department of health primary care (extended version): ten key actions could globally ensure a basic human right at almost unnoticeable cost public health in europe: power, politics, and where next health: a vital investment for economic development in eastern europe and central asia. european observatory on health systems and policies. who, european regional office it is not just the broad street pump addressing the epidemiologic transition in the former soviet union: strategies for health systems and public health reform in russia what is the "new public health"? millenium development goals: 2013 progress chart united nations development programme, millennium development goals. eight goals for healthy people 2020 healthy people. the surgeon general's report on health promotion and disease prevention the millennium development goals: a cross-sectoral analysis and principles for goal-setting after selective primary health care: an interim strategy for disease control in developing countries declaration of alma-ata. international conference on primary health care healthy cities networks across the who, european region preamble to the constitution of the world health organization as adopted by the international health conference regional office for europe. health 21 -health for all in the 21st century. who regional office for europe, copenhagen. world health organization, 2012. regional office for europe. who european healthy cities network. available at:. who regional office for europe leading health indicators selected for 2010 incorporate the original 467 objectives in healthy people 2010, which served as a basis for planning public health activities for many state and community health initiatives. for each of the leading health indicators, specific objectives and subobjectives derived from healthy people 2010 are used to monitor progress. the specific objectives set for healthy people 2020 are listed in box 2.16. thirteen new topic areas are listed for 2020, such as older adults, genomics, dementias, and social determinants of health. these provide guidelines for national, state, and local public health agencies as well as insurance providers, primary care services, and health promotion advocates. a key issue will be in reducing regional, ethnic, and socioeconomic health disparities.the process of working towards health targets in the usa has moved down from the federal level of government to the state and local levels. professional organizations, ngos, as well as community and fraternal organizations are also involved. the states are encouraged to prepare their own targets and implementation plans as a condition for federal grants, and many states require county health departments to prepare local profiles and targets.diffusion of this approach encourages state and local initiatives to meet measurable program targets. it also sets a different agenda for local prestige in competitive terms, with less emphasis on the size of the local hospital or other agencies than on having the lowest infant mortality or the least infectious disease among neighboring local authorities. the who european region document "health 21 -health for all in the 21st century" addresses health in the twentyfirst century, with 21 principles and objectives for improving the health of europeans, within and between countries of europe. the health 21 targets include:1. closing the health gap between countries. 2. closing the health gap within countries. 3. a healthy start in life (supportive family policies). 4. health of young people (policies to reduce child abuse, accidents, drug use, and unwanted pregnancies). 5. healthy aging (policies to improve health, self-esteem, and independence before dependence emerges). 6. improving mental health. 7. reducing communicable diseases. 8. reducing non-communicable diseases. 9. reducing injury from violence and accidents. 10. a healthy and safe physical environment. 11. healthier living (fiscal, agricultural, and retail policies that increase the availability of and access to and consumption of vegetables and fruits). 12. reducing harm from alcohol, drugs, and tobacco. 13. a settings approach to health action (homes should be designed and built in a manner conducive to sustainable health and the environment).14. multisectoral responsibility for health.15. an integrated health sector and much stronger emphasis on primary care. 16. managing for quality of care using the european health for all indicators to focus on outcomes and compare the effectiveness of different inputs. the uk national health service (nhs) has semi-autonomous units in england, scotland, wales, and northern ireland. they are funded from the central uk nhs but with autonomy within national guidelines. the nhs has defined national health outcomes for improvements grouped around five domains, each comprised of key indicators aimed at improving health with reducing inequalities. l preventing people from dying prematurely from causes amenable to health care for all ages: l the target diseases include cardiovascular, respiratory, and liver diseases, and cancer (with focus on cancer of breast, lung, and colorectal cancer) l reducing premature death in people with serious mental illnesses l reducing infant mortality, neonatal mortality, still births, and deaths in young children l increasing 5-year survival for children with cancer. health improvement; help people to live healthy lifestyles, healthy choices, reduce health inequalities, protection from major incidents and other threats, while reducing health inequalities. l health care, public health and preventing premature mortality; reduce the numbers of people living with preventable ill-health and people dying prematurely, while reducing the gap between communities.source: uk department of health. available at: https://www.gov.uk/government/organisations/department-of-health/about#our-priorities, https:// www.gov.uk/government/uploads/system/uploads/attachment_data/ file/193619/improving-outcomes-and -supporting-transparency-part-1a.pdf. pdf, and https://www.gov.uk/government/uploads/system/uploads/attach-ment_data/file/127106/121109-nhs-outcomes-framework-2013-14.pdf. pdf [accessed 24 june 2013] . national policy in health ultimately relates to health of the individual. the various concepts outlined in the health field concept, community-oriented primary health care, health targets, and effective management of health systems, can only be effective if the individual and his or her community are knowledgeable participants in seeking solutions. involving the individual in his or her own health status requires raising levels of awareness, knowledge, and action. the methods used to achieve these goals include health counseling, health education, and health promotion (figure 2 .6).health counseling has always been a part of health care between the doctor or nurse and the patient. it raises levels of awareness of health issues of the individual patient. health education has long been part of public health, dealing with promoting consciousness of health issues in selected target population groups. health promotion incorporates the work of health education but takes health issues to the policy level of government and involves all levels of government and ngos in a more comprehensive approach to a healthier environment and personal lifestyles.health counseling, health education, and health promotion are among the most cost-effective interventions for improving the health of the public. while costs of health care are rising rapidly, demands to control cost increases should lead to greater emphasis on prevention, and adoption of health education and promotion as an integral part of modern life. this should be carried out in schools, the workplace, the community, commercial locations (e.g., shopping centers), and recreation centers, and in the political agenda.psychologist abraham maslow described a hierarchy of needs of human beings. every human has basic requirements including physiological needs of safety, water, food, warmth, and shelter. higher levels of needs include recognition, community, and self-fulfillment. these insights supported observations of efficiency studies such as those of elton mayo in the famous hawthorne effect in the 1920s, showing that workers increased productivity when acknowledged by management in the objectives of the organization (see chapter 12). in health terms, these translate into factors that motivate people to positive health activities when all barriers to health care are reduced.modern public health faces the problem of motivating people to change behavior; sometimes this requires legislation, enforcement, and penalties for failure to comply, such as in mandating car seat-belt use. in other circumstances it requires sustained performance by the individual, such as the use of condoms to reduce the risk of sti and/or hiv transmission. over time, this has been developed into a concept known as knowledge, attitudes, beliefs, and practices (kabp), a measurable complex that cumulatively affects health behavior (see chapter 3). there is often a divergence between knowledge and practice; for example, the knowledge of the importance of safe driving, yet not putting this into practice. this concept is sometimes referred to as the "kabp gap". the health belief model has been a basis for health education programs, whereby a person's readiness to take action for health stems from a perceived threat of disease, a recognition of susceptibility to disease and its potential severity, and the value of health. action by an individual may be triggered by concern and by knowledge. barriers to appropriate action may be psychological, financial, or physical, including fear, time loss, and inconvenience. spurring action to avoid risk to health is one of the fundamental goals in modern health care. the health belief model is important in defining any health intervention in that it addresses the emotional, intellectual, and other barriers to taking steps to prevent or treat disease.health awareness at the community and individual levels depends on basic education levels. mothers in developing countries with primary or secondary school education are more successful in infant and child care than less educated women. agricultural and health extension services reaching out to poor and uneducated farm families in north america in the 1920s were able to raise consciousness of safe self-health practices and good nutrition, and when this was supplemented by basic health education in schools, generational differences could be seen in levels of awareness of the importance of balanced nutrition. secondary prevention with diabetics and patients with chd hinges on education and awareness of nutritional and physical activity patterns needed to prevent or delay a subsequent myocardial infarction. the who sponsored the first international conference on health promotion held in ottawa, canada, in 1986 ( figure 2.7) . the resulting ottawa charter defined health promotion and set out five key areas of action: building healthy public policy, creating supportive environments, strengthening community action, developing personal skills, and reorienting health services. the ottawa charter called on all countries to put health on the agenda of policy makers in all sectors and at all levels, directing them to be aware a typical healthy city has a population in the multiple thousands, often multilingual, with an average middleclass income. a healthy cities project builds a coalition of municipal and voluntary groups working together in a continuing effort to improve quality of service, facilities, and living environment. the city is divided into neighborhoods, engaged in a wide range of activities fostered by the project. municipalities have traditionally had a leading role in sanitation, safe water supply, building and zoning laws and regulation, and many other responsibilities in public health (see chapter 10). the healthy cities or communities movement has elevated this to a higher level with policies to promote health in all actions. some examples are listed of municipal, advocacy group, and higher governmental activities for healthier city environments: working with senior levels of government, other departments in the municipalities, religious organizations, private donors, and the ngo sector to innovate and especially to improve conditions in poverty-afflicted areas of cities is a vital role for health-oriented local political leadership. human ecology, a term introduced in the 1920s and revived in the 1970s, attempted to apply theory from plant and animal life to human communities. it evolved as a branch of demography, sociology, and anthropology, addressing the social and cultural contexts of disease, health risks, and human behavior. human ecology addresses the interaction of humans with and adaptation to their social and physical environment.parallel subdisciplines of social, community, and environmental psychology, medical sociology, anthropology, and other social sciences contributed to the development of this academic field with wide applications in health-related issues. this led to the incorporation of qualitative research methods alongside the quantitative research methods traditionally emphasized in public health, providing crucial insights into many public health issues where human behavior is a key risk factor.health education developed as a discipline and function within public health systems in school health, rural nutrition, military medicine, occupational health, and many other aspects of preventive-oriented health care, and is discussed in later chapters of this text. directed at behavior modification through information and raising awareness of consequences of risk behavior, this has become a longstanding and major element of public health practice in recent times, being almost the only effective tool to fight the epidemic of hiv and the rising epidemic of obesity and diabetes.health promotion as an idea evolved, in part, from marc lalonde's health field concepts and from growing realization in the 1970s that access to medical care was necessary but not sufficient to improve the health of a population. the integration of the health behavior model, social ecological approach, environmental enhancement, or social engineering formed the basis of the social ecology approach to defining and addressing health issues (table 2 .3).individual behavior depends on many surrounding factors, while community health also relies on the individual; the two cannot be isolated from one another. the ecological perspective in health promotion works towards changing people's behavior to enhance health. it takes into account factors not related to individual behavior, which are determined by the political, social, and economic environment. it applies broad community, regional, or national approaches that are needed to address severe public health problems, such as controlling hiv infection, tb, malnutrition, stis, cardiovascular disorders, violence and trauma, and cancer. beginning to affect the health situation in countries in transition from the socialist period. countries emerging from developing status are also showing signs of mixed progress in the dual burden of infectious and maternal/child health issues, along with growing exposure to the chronic diseases of developed nations such as cardiovascular diseases, obesity, and diabetes. the new public health synthesizes traditional pub lic health with management of personal services and community action for a holistic approach. evaluation of costeffective public health and medical interventions to reduce the burden of disease also contributes to the need to seek and apply new approaches to health. the new public health will continue to evolve as a framework drawing on new ideas, science, technology, and experiences in public health throughout the world. it must address the growing recognition of social inequality in health, even in developed countries with universal health programs with improved education and social support systems. for a complete bibliography and guidance for student reviews and expected competencies please see companion web site at http://booksite.elsevier.com/9780124157668 bibliography key: cord-331714-2qj2rrgd authors: lvov, dimitry konstantinovich; shchelkanov, mikhail yurievich; alkhovsky, sergey vladimirovich; deryabin, petr grigorievich title: single-stranded rna viruses date: 2015-05-29 journal: zoonotic viruses in northern eurasia doi: 10.1016/b978-0-12-801742-5.00008-8 sha: doc_id: 331714 cord_uid: 2qj2rrgd in this chapter, we describe 73 zoonotic viruses that were isolated in northern eurasia and that belong to the different families of viruses with a single-stranded rna (ssrna) genome. the family includes viruses with a segmented negative-sense ssrna genome (families bunyaviridae and orthomyxoviridae) and viruses with a positive-sense ssrna genome (families togaviridae and flaviviridae). among them are viruses associated with sporadic cases or outbreaks of human disease, such as hemorrhagic fever with renal syndrome (viruses of the genus hantavirus), crimean–congo hemorrhagic fever (cchfv, nairovirus), california encephalitis (inkv, tahv, and khatv; orthobunyavirus), sandfly fever (sfcv and sfnv, phlebovirus), tick-borne encephalitis (tbev, flavivirus), omsk hemorrhagic fever (ohfv, flavivirus), west nile fever (wnv, flavivirus), sindbis fever (sinv, alphavirus) chikungunya fever (chikv, alphavirus) and others. other viruses described in the chapter can cause epizootics in wild or domestic animals: geta virus (getv, alphavirus), influenza a virus (influenzavirus a), bhanja virus (bhav, phlebovirus) and more. the chapter also discusses both ecological peculiarities that promote the circulation of these viruses in natural foci and factors influencing the occurrence of epidemic and epizootic outbreaks single-stranded rna viruses the bunyaviridae family was named after the prototypical bunyamwera virus (bunv) isolated in 1943 from mosquitoes (aedes spp.) in bunyamwera, uganda. 1 currently, the bunyaviridae family includes four genera of animal viruses (orthobunyavirus, phlebovirus, nairovirus, and hantavirus) and one genus (tospovirus) of plant viruses. 2 bunyavirus virions are spherical in shape (size, about 80à120 nm) and have an outer lipid bilayer with the viral envelope glycoproteins gn and gc exposed on the surface. the genome consists of three segments of single-stranded, negative-sense rna with a total length from 11,000 to 19,000 nt. depending on the size, the segments are designated l (large), m (medium), and s (small). the viral proteins are synthesized on the mrna that is produced during replication and that is complementary to the genomic rna. the length of segments varies for different genera, but in general, they have a common structure. the l-segment, whose length is from 6,400 nt (phlebovirus) to 12, 200 nt (nairovirus) , has a single open reading frame (orf) encoding rna-dependent rna polymerase (rdrp). the m-segment of all of the genera also has a single orf, which encodes a polyprotein precursor of envelope glycoproteins gn and gc. the length of the m-segment ranges from 3,288 nt for some of the phleboviruses to 4,900à5,366 nt for the nairoviruses. the mature glycoproteins gn and gc of the bunyaviruses are derived during complex endoproteolytic events leading to cleavage of the polyprotein precursor by cellular proteases. the s-segment of the bunyaviruses encodes a nucleocapsid protein. additional nonstructural (nss) protein is encoded by the s-segment of viruses of the phlebovirus, tospovirus, and orthobunyavirus genera. 2, 3 the bunyaviruses are widely distributed in the world and are one of the most numerous known zoonotic viruses. most of the zoonotic bunyaviruses are transmitted to animal or humans by bloodsucking arthropod vectors, usually mosquitoes or ticks. viruses of the hantavirus genus are the exception, being transmitted mainly by aerosol formed from virus-laden urine, feces, or saliva of infected rodents or insectivores that are their natural hosts. 4à6 the genus hantavirus consists of those bunyaviruses of vertebrates which do not have the ability to replicate in an arthropod's cell and which are transmitted by respiratory route through the formation of aerosols from urine or feces containing the virus. 1 the morphology of the virion and the genome structure of the hantaviruses are common to all bunyaviruses. the size of the negative-sense ssrna genome of the prototypical hantaan virus (htnv) is 6,533 nt for the l-segment, 3,616 nt for the m-segment, and 1,696 nt for the s-segment (figure 8 .1). 1 in nature, hantaviruses persist asymptomatically in rodents and insectivores, with each type of hantavirus associated predominantly with one host species. the phylogenetic relationships of hantaviruses enable virologists to divide them into three lineages, which correspond in general to their main hosts. in the s-segment of some hantaviruses carried by arvicolinae and sigmodontinae rodents, there is an additional orf-encoded nonstructural protein nss. but nss is absent in the hantaviruses of the murinae rodents. 2à4 history. hemorrhagic fever with renal syndrome (hfrs) was originally described as a separate nosological category (called "endemic (epidemic) hemorrhagic nephroso-nephritis" at that time) by anatoly smorodintsev (figure 2 .11) during 1935à1940 in the far east. later, japanese scientists described hfrs in northeastern china as "songo fever" and swedish scientists as "epidemic nephropathy"; a similar disease was described in 1960 in china. 1 the abbreviation "hfrs" was suggested by mikhail chumakov (figure 2 korea. 2 hantaviruses. the hantaviruses are members of the hantavirus genus of the bunyaviridae family. the first serotype, -htnv, included strains isolated from mouselike rodents (muridae) in south korea, china, and the southern part of the russian far east (primorsky krai). 2à4 the second serotype, puumala virus (puuv), was isolated from hamsterlike rodents (cricetidae), mainly the bank vole (myodes glareolus) in finland and then in other european countries and the western part of russia, as well we from maximowicz's vole (microtus maximoviczii) in the far east). 5à8 the third serotype, seoul virus (seov), was isolated from brown rats (rattus norvegicus), black rats (rattus rattus), and laboratory albino rats (rattus norvegicus f. domestica) in south korea and elsewhere, including the united states. 3, 4 the fourth serotype, dobravaàbelgrade virus (dobv), was isolated from the striped field mouse (apodemus agrarius) in slovenia 9 and yugoslavia. 10 the fifth serotype, sin nombre virus (snv), literally "nameless virus" in spanish, was isolated from the meadow vole (microtus pennsylvanicus). 8 in addition to the 5 main serotypes, 15 other serotypes are known today, including 6 in eurasia: amur virus (amrv), isolated from asiatic forest mice (apodemus peninsulae) in the far east of russia 11 and in china 12 ; tula virus (tulv), from common voles (microtus arvalis) in central russia 13, 14 ; khabarovsk virus (khav), from from reed voles (microtus fortis) and siberian brown lemmings (lemmus sibiricus) in the far east 15 ; thottapalayam virus (tpmv), from asian musk shrews (suncus murinus) in india 16 ; thailand virus (thaiv), from bandicoots (bandicota indica) in thailand 17 ; and a newfound hantavirus, from chinese mole shrews (anourosorex squamipes) in vietnam. 18 virion and genome. the size of the negative-sense ssrna genome of the prototypical htnv is 6,533 nt for the l-segment, 3 ,616 nt for the m-segment, and 1,696 nt for the s-segment (figures 8.1 and 8.2 ). epizootiology. rodents (order rodentia) are the main natural reservoir of hantaviruses. nevertheless, strains have been isolated from birds in the far east 19 and from bats in china. 20 infection in rodents is asymptomatic, but the virus is expelled with saliva, urine, and excrement, most intensively during the first month after inoculation. (during this period, virus antigen can be detected in the lungs.) 4 the evolution of hantaviruses is closely related to that of its rodent host (figure 8 .2). 4, 6, 21 at least 34 species of rodents (rodentia), 2 species of lagomorphs (order lagomorpha), 7 species of insectivores (order insectivora), 1 species of predators (order carnivora), and 1 species of artiodactyls (order artiodactyla) are known to take part in hantavirus circulation on the territory of northern eurasia. 8, 21, 22 the main species of rodents, which are the hosts of hantaviruses in russia, are presented in table 8 .1. the infection rate of mouselike rodents and insectivores lies within the limits 3.3 6 0.5%. 23 hantavirus antigens have been detected in birds as well: the oriental turtle dove (streptopelia orientalis), coal tit (parus ater), marsh tit (parus palustris), daurian redstart (phoenicurus auroreus), nuthatch (sitta europaea), black-faced bunting (emberiza spodocephala elegans), eurasian jay (garrulus glandarius), hazel grouse (tetrastes bonasia), pheasant (phasianus colchicus), ural owl (strix uralensis), green-backed heron (butorides striatus), and grey heron (ardea cinerea). 19 hantavirus (magboi virus, or mgbv) was isolated in 2012 from the hairy slit-faced bat (nycteris hispida) in africa (sierra leone), 24 but the role of bats in the circulation of hemorrhagic fever with renal syndrome virus (hfrsv) is yet to be investigated in detail. in western siberia, the main natural reservoir of hfrsv is rodents of the hamsterlike (cricetidae) family-in particular, bank voles (myodes glareolus), with a susceptibility up to 70%; red-backed voles (myodes rutilus), susceptibility 9%; and, in the north, siberian brown lemmings (lemmus sibiricus), 14%. the infection rate of other rodents and insectivores is about 0.4à3.0%. 8, 22 in eastern siberia, the maximum susceptibility is demonstrated in grey red-backed voles (myodes rufocanus), 70%; house mice (mus musculus), 15%; water voles (arvicola terrestris), 8%; and tundra voles (microtus oeconomus), 8%. 8 in the far east, hfrsv was revealed to circulate among field mice (apodemus agrarius) with a susceptibility of about 35%; asiatic forest mice (a. peninsulae), susceptibility 30%; reed voles (microtus fortis), 4à18%; grey redbacked voles (myodes rufocanus), 12%; and other rodents (rodentia), 0.7à4.3%. 21, 22, 25 epidemiology. hfrsv infection starts by aerogenic penetration of the virus during the inhalation of waste products (saliva, urine, excrement) of latently infected animals. an alimentary pathway (with contaminated food and water) of the infection is also possible. 4, 8, 22, 26, 27 hfrs is distributed over eurasia (russia, belarus, ukraine, moldova, the baltic countries, the czech republic, slovakia, bulgaria, romania, serbia, slovenia, england, france, germany, belgium, hungary, denmark, fennoscandia, kazakhstan, georgia, azerbaijan, china, north and south korea, japan), as well as american and african countries. 7, 28, 29 during 2000à2009, in 58 of 83 regions in russia, 74,890 cases of hfrs were registered (table 8 .2). 8 annual morbidity of hfrs in russia is in the range from 2,700 to 11,400 cases (1.3à7.8%) and is decreasing. about 95% of cases take place in european forest landscapes. puuv associated with the bank vole (myodes glareolus) provokes about 90% of hfrs cases in russia (especially in bashkortostan, udmurtia, mari el, tatarstan, the chuvash republic, orenburg, ulyanovsk, and the penza region). 8, 30 morbidity in the urban population is higher (65%) than in the rural one. the peak of the disease occurs during julyàoctober in forests and in gardens and kitchens closely situated to the forests. 4 ,31à33 dobv associated mainly with field mice (apodemus agrarius) and small forest mice (a. uralensis) is of leading epidemiological significance in the central and southwestern sectors of the european part of russia (the voronezh, lipetsk, orel, and belgorod regions), as well as in georgia. 8, 31, 34, 35 puuv and tulv are associated with the common vole (microtus arvalis) and the bank vole (myodes glareolus) and are also distributed over this territory. 4, 8, 36 a similar situation is observed in other regions of the central federal district: in the moscow, yaroslavl, ryazan, tver, kaluga, vladimir, ivanov, kostroma, smolensk regions. hfrs morbidity in the moscow region is associated with puuv, 31 the infection rate of which is 12à57% among bank voles (myodes glareolus), 10à20% in the common vole (microtus arvalis), 11% in major's pine vole (microtus majori), and in 4à6% other rodent species. 1 in krasnodar krai, the black sea field mouse (apodemus ponticus) and major's pine vole (microtus majori) play the main role in human morbidity. 31, 37 human morbidity in the european part of russia is registered beginning at a relatively low level in marchàapril, decreasing to yet a lower level in mayàaugust, increasing in septemberànovember, and then increasing again during decemberàjanuary. 1 the hyperendemic territory is the southwestern ural region (especially the bashkortostan republic and the chelyabinsk and orenburg regions), the volga-vyatka economic region (especially the udmurt republic), the chuvash republic, and the tatarstan, mari el, samara, penza, saratov, and ulyanovsk regions. 4, 8 the main human morbidity occurs among those 20à40 years old (chiefly men). in russia, hfrs represents a significant part of all naturalfoci zoonotic diseases. the immune layer to hfrsv in the european part of russia is a mean 4.7%; in the bashkortostan republic, it reaches up to 40% (mean, 17%). 4 the immune layer among the populations of western and eastern siberia is about 2% for the entire region, 0.2% in krasnoyarsk krai, 1.1% in the irkutsk region, 3.1% in the omsk region, and 12.6% in the tyumen region. 1, 4 the far east provides about 2% of all hfrs cases in russia. 23 the highest morbidity was revealed in khabarovsk krai, primorsky krai, and the amur region. 1 in khabarovsk krai and primorsky krai, las in china and japan, -htnv is associated with grey red-backed voles (myodes rufocanus). 2, 3, 21, 37 the morbidity of seov (the third serotype) associated with the synanthropic brown rat (rattus norvegicus) and black rat (r. rattus) was examed in both the far east and the european part of russia. the researchers found that seov provoked hfrs more often among the urban population, whereas htnv did so more often among the rural population, of primorsky krai. 21 morbidity in the far east has a small uptick in mayàjuly and reaches its main peak in novemberàdecember. the immune stratum in the far east is about 1% (ranging from 0.3% in the amur region to 1.5% in primorsky krai). 1, 21 pathogenesis. capillary damage is the basis of hfrs pathogenesis. in the first part of the disease, toxicoallergic phenomena predominate, caused by viral infection of the walls of vegetative centers, venules, and arterioles. lesions on the sympathetic nodes of the neck are followed by hyperemia of the face and neck. irritation of the vagus nerve leads to bradycardia and a fall in arterial pressure. damage to the vascular permeability is accompanied by hemorrhages in mucous membranes and the skin. the cause of death is cardiovascular insufficiency, massive hemorrhages into the vital organs, plasmorrhea into the tissues, collapse, shock, swelled lungs, spontaneous rupture of the kidneys, a hypertrophied brain, and paralysis of the vegetative centers. 4, 22 clinical features. the incubation period is 4à30 days. hfrs starts with fever, headache, muscular pain, dizziness, nausea, vomiting, hyperemia of the face and neck, bradycardia, and a fall in arterial pressure. abnormalities of the central nervous system (cns) in the form of block, excitement, hallucinations, meningeal signs, and visual impairments often occur. hemorrhagic syndrome becomes apparent as plasmorrhea into the tissues, together with microthrombosis; exanthema; petechial skin rash; nasal, pulmonary, and uterine bleeding: vomiting blood, hematuria, and visceral bleeding. in some cases, pasternatsky syndrome, pain in the kidneys, oliguria, and albuminuria become morphologically apparent as interstitial and tubular nephritis. the duration of fever is 3à9 days. two-wave temperature dynamics is possible. 22, 38 analyses of 5,282 cases of hfrs etiologically linked with puuv in sweden during 1997à2007 found 0.4% mortality in the first three months of the disease. 39, 40 defense immunity remains for at least 30 years. 8, 22 diagnostics. laboratory diagnostics are based on the fluorescent antibody method (fam), enzyme-linked immunosorbent assay (elisa), and reverse transcription polymerase chain reaction (rt-pcr) testing. the virus can be isolated with the use of vero e6 (green monkey kidney cell line), 2bs (diploid human embryo lung cell line), a-549 (human lung carcinoma cell line), or rlc (rat lung tissue primary cell culture). 8, 22 control and prophylaxis. treatment of hfrs can be symptomatic, pathogenetic, or etiotropic (or any combination thereof). during the fever period, early hospitalization, disintoxical therapy, and strengthening of the walls of vessels are necessary. during the oliguria period, transfusion with desalinated human albumin, hemodes, a 5% glucose solution, and an isotonic nacl solution (under the control of the emitted volume of urine) are given. in case of shock, antishock therapy is applied, and hemodialysis is prescribed for kidney insufficiency. 4, 22 vaccination is the most effective approach to the prophylaxis of hfrs. the efficacy of vaccination was demonstrated in china and in north and south korea. nevertheless, it must be mentioned that vaccines in these countries are produced from htnv and seov stains and do not defend against puuv infection, which is the main etiological agent of hfrs in the european part of russia (where 98% of all russian morbidity occurs) 8 . for a long time, anti-hfrs vaccine was difficult to produce because there were no sensitive cell lines to accumulate hantavirus. however, the recent adaptation of puuv and dobv to the certified vero e6 cell line affords an opportunity to produce candidate vaccines against hfrs. experimental series of "combi-hfrs-vac" vaccine have passed compliance tests for medical immunoglobulin preparations for use in humans. 8, 41, 42 the genus nairovirus includes the ticktransmitted bunyaviruses, whose genome is the largest in the family bunyaviridae. the size of l-segments of the dugbe virus (dugv), a prototypical species of the nairoviruses, is 12,255 nt. the m-and s-segments are 4,888 and 1,716 nt, respectively (figure 8 . 3) . as with other bunyaviruses, the l-segment of the nairoviruses encodes an rdrp, the m-segment encodes a polyprotein precursor of the envelope glycoproteins gn and gc, and the s-segment encodes the nucleocapsid (n) protein. 1, 2 the genus nairovirus was established on the basis of antigenic relationships among viruses of the six antigenic groups of arthropod-borne viruses: the crimeanàcongo hemorrhagic fever (cchf), nairobi sheep disease (nsd), qalyub (qyb), sakhalin (sak), dera ghazi khan (dgk), and hughes (hugv) groups. 3à6 subsequently, a seventh, thiafora (tfa), group was assigned to the genus. 7, 8 currently, about 35 viruses are assigned to the genus nairovirus, now united in the aforementioned seven groups. 1 sequence analysis of previously unclassified bunyaviruses revealed that the nairoviruses actually number much more than 35 . three additional groups of nairoviruses-issyk-kul (isk), artashat (artsv), and tamdy (tam)-were established on the basis of phylogenetic analysis (table 8 .3). cchfv belongs to the nairovirus genus of the bunyaviridae family and is the etiological agent of crimeanàcongo hemorrhagic fever (cchf). history. cchf was first mentioned as "hunibini" and "hongirifta" by tajik physician abu-ibrahim djurdjani in the twelfth century. the viral nature of cchf was originally established in 1945 during an expedition to crimea headed by mikhail chumakov at the time of an outbreak. 1à3 the modern history of cchfv investigation starts in june 1944 with an epidemic of the disease in the northwestern steppe part of the crimean peninsula. more than 200 severe cases of the disease broke out, all exhibiting hemorrhagic syndrome, known in that time as "severe infectious capillary toxicosis." mikhail chumakov headed an expedition to the region, and much research revealed that the disease is transmitted by hyalomma plumbeum (marginatum) ticks of the ixodidae family. the disease 1 in 1963, the historical hodzha strain was isolated from a patient with hemorrhagic fever in uzbekistan, as was a set of strains from h. marginatum larvae and nymphs in the astrakhan region, near the caspian sea. 2, 3 in 1967, the similarity between the etiological agent of crimean hemorrhagic fever and that of congo virus, isolated from a patient in 1966 in zaire (congo), was demonstrated, so the virus was renamed cchfv. 4, 5 genome and taxonomy. like the genomes of all nairoviruses, that of cchfv consists of three segments of negative ssrna: a signed small (s) (1,672 nt) segment, a medium (m) (5,366 nt), and a large (l) (12,108 nt) segment. each segment has a single orf that encodes the nucleocapsid protein (n, 482 aa, s-segment), a polyprotein precursor of envelope glycoproteins gn and gc (1,684 aa, m-segment), and rdrp (3,945 aa, l-segment). genetic diversity among cchfv strains may reach 31% nt and 27% aa differences for m-segment sequences, a reflection of pressure on the immune system and adaptation to various ecologic zones with different prevalences of hyalomma tick species. the s-and l-segments are more conservative: the level of divergence of s-segment sequences is 20% nt and 8% aa, and that for l-segment sequences is 22% nt and 10% aa. phylogenetic analysis based on sequence data comparisons of s-segments shows that cchfv isolates from different regions can be clustered into seven phylogeographic groups: west african isolates (group i), as well as isolates from central africa (uganda and the democratic republic of the congo) (group ii); south africa and west africa (group iii); the middle east and asia (group iv) (the asian strain can be divided to two distinct subgroups: asia 1 (iva) and asia 2 (ivb)); europe and turkey (group v); and greece (group vi), a separate group detached from the rest of europe (figure 8.4) . 6à8 in general, the genotypic structure defined on basis of the s-segment analysis is correlated strictly with geography. cases of isolation of strains not typical for a given territory were attributed to possible transmission of the virus by infected ticks carried by migratory birds. the tree topology based on the l-segment comparison is, on the whole, similar to that generated on the basis of the s-segment. exceptions are the viruses from senegal, which represent a separate lineage in the s-segment analysis, and those clustered within group iii in the l-segment analysis. similarly, the division of group iv into group iva (asia 1) and ivb (asia 2) is not clear (figures 8.5 and 8.6) . in russia, most of the strains of cchfv that were isolated were isolated in the country's southern regions (astrakhan, volgograd, and stavropol districts). phylogenetic analysis showed that all of them are closely related to european and turkish strains (group v). 9à12 epizootiology. up to today, cchfv has been found to circulate in 46 countries in europe, africa, and asia. 4,13à15 cchfv was isolated from at least 27 species of mainly ixodidae ticks, but their roles in maintaining virus circulation are different (tables 8.4 and 8.5). the main significance for cchfv reservation and transmission belongs to ticks of the hyalomma genus: h. marginatum in the south of he european part of russia, h. anatolicum and h. detritum in the middle east and asia, and h. asiaticumin kazakhstan. according to our data, the viral load among imagoes of h. marginatum in the astrakhan region in 2001à2005 was 1.33%; among nymphs, the load was 0.2%. the presence of transphase and transovarial transmission of cchfv provides a reservation for viruses during the interepidemic period. three hostsfor larvae (ground birds, mainly corvidae; table 8.4 isolation of cchfv from ixodidae ticks mouselike rodents; and hares), nymphs (also ground birds, mouselike rodents, and hares), and imagoes (large mammals-mainly cattle, sheep, and camels)-provide a variety of ecological links of cchfv to vertebrates. 1,16à19 in nigeria, cchfv was isolated from midges (culicoides sp.) 4 the distribution of h. marginatum is limited by the isotherm of effective temperatures such that sum (σ t $ 10 c ) 5 3,000 c, or 120 days with mean temperature $20 c per year. 20 so, the northern boundary of the distribution of cchfv in the south of the european part of russia lies in the dry steppe subzone. 1 in russia and south africa, cchfv is often isolated from hares. 1, 21 cchfv was isolated from hedgehogs (atelerix spiculus) in nigeria. hares and mouselike rodents play the main role in cchfv circulation. 1, 21, 22 viremia in birds is not sufficient for vector transmission (although specific antibodies appear); nevertheless, ground birds are an important element of cchfv transmission because they are the hosts for the preimaginal phases of h. marginatum development. 16, 18, 23 during field investigations of chatkalsky ridge in kirgizia, nymphs and larvae of h. marginatum dominated among field-collected materials from birds. the highest number of ticks was found on rollers (coracias garrulus), crested larks (galerida cristata), tree sparrows (passer montanus), and blackbilled magpies (pica pica). in the astrakhan region, rooks (corvus frugilegus) are the main hosts for h. marginatum preimaginal phases. 16 during migrations, birds can take part in dispersing preimago ticks that carry the virus. for example, in spain in 2010, cchfv of african origin (probably introduced by migrating birds) was isolated from h. lusitanicum. 24 european birds overwintering in africa were also found to harbor ticks that carried the virus. 25 cchfv infection rates found as the result of an investigation of 40,711 domestic animal sera are presented in table 8 .6. 20 domestic animals are one of the main reservoirs of cchfv among vertebrates. viremia (2.6à3.7 (log 10 ld 50 )/20 mcl) sufficient for the infection of ticks was detected 5à8 days after experimental inoculation of sheep. viremia after up to 10 days post inoculation was detected in small gophers (citellus pygmaeus), long-eared hedgehogs (hemiechinus auritus), and wood mice (apodemus sylvaticus). experimental infection was revealed only in nymphs, and that is why hares and corvidae birds-the main hosts for nymphs-play the chief role in cchfv circulation. astrakhan 1 5 11 13 9 4 37 16 20 5 6 7 10 7 1 152 volgograd 0 18 9 3 3 2 6 16 30 7 2 3 0 0 6 105 dagestan 0 6 10 7 3 1 3 3 2 2 1 3 2 0 2 rostov 27 0 5 7 9 9 16 55 53 83 27 16 48 41 38 434 stavropol 10 48 21 54 30 41 38 41 63 80 66 28 26 24 32 602 krasnodar 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 total 38 85 59 97 77 76 139 200 234 193 119 67 97 75 79 1,635 of ixodidae (at first, h. marginatum) ticks in this region as the result of climatic changes. during 1999à2010, 13,838 cases of cchf 44 were recorded in russia, including 520 in stavropol krai, 45 307 in the rostov region, 46 276 in the kalmyk republic, 47 134 in the astrakhan region, 48 99 in the volgograd region, 49 41 in the dagestan republic, 5 in the ingush republic, and 1 in the karachaevoàcherkesskaya republic 50 (table 8 .7). in 2013, 80 cases of cchf were recorded on the territory of the southern federal district and the north caucasian federal district (table 8 .8, figure 8 .8). the absence of any recorded cases of cchf in krasnodar krai could be explained by a lack of attention to cchf diagnostics. a decrease in the proportion of severe clinical forms with hemorrhagic syndrome occurred after 2006. the drop could have been due to the introduction of high-grade express diagnostics methods into clinical practice and an intensification in seeking out and diagnosing those suspected of having cchf. at the same time, the disease extended its incidence into the new territories of the volgograd region, with nosocomial cchf cases recorded there once again. 52 pathogenesis. pathogenesis is defined by lesions of the vascular and nervous systems. 17, 51, 53 clinical features. the incubation period after transmissive cchfv inoculation (as the result of a tick bite) is 2à7 days, whereas that after contact inoculation is 3à4 days. the difference is due to a much higher quantity of virus entering the system during contacts inoculation. 17, 50, 53 cchf starts rapidly, with the temperature increasing to 39à40 c and the appearance of fever, skin hyperemia in the top half of the trunk, headache, lumbar pain, abdominal and epigastric pains, generalized arthralgia, conjunctivitis, pharingitis, and diarrhea. about 50% of cases have two obvious waves of increasing temperature, with the temperature decreasing in 6à7 days after the end of the incubation period. petechial rash appears in the majority of all cchf patients in 3à4 days after the incubation period and is a marker of the second increasing-temperature wave. hemorrhagic diathesis with nasal bleeding (in two-thirds of cases), bloody vomiting, blood in the sputum, and hematuria, all starting 3à5 days after the end of incubation period, are characteristic in 85% of cases. the duration of the hemorrhagic period is 8à9 days. meningitis symptoms and signs of psychosis (depression, sleepiness, lassitude, photophobia) could develop as well. lethality is 16à20% for transmissive inoculation and up to 50% for contact inoculation. nevertheless, lethality is decreasing as the result of the introduction of modern testing systems and treatment with ribavirin. the convalescent period is about a month. 17, 50, 51, 53 e.v. leshchinskaya has suggested the following clinical classification of cchf: (i) severe form with hemorrhagic syndrome (1.a. without band bleeding; 1.b. with band bleeding); (ii) without hemorrhagic syndrome (2.a. medium-severe form; 2.b. light form). 50, 53 diagnostics. diagnosis is based on the detection of both specific antibodies via elisa (igm after 8 days post disease progression and igg) and virus rna via rt-pcr testing (earlier than 8 days post disease progression). 43, 54 both tests must be conducted for a definitive diagnosis of cchf to be made. during the first week of infection with cchf, positive results via rt-pcr are obtained in 93% of cases; during the second week, the percentage is 40%. during the second week of the disease, positive results in igm via elisa are obtained in 93% of cases; during the third week, the percentage of positive reults in igg via elisa is 80%. 55à58 control and prophylaxis. ribavirin is the most effective drug prescribed today. 53 ,59à61 ribavirin is used for 5 days after symptoms first appear: 2,000 mg (10 capsules) or 30 mg/kg for the first time, then 600 mg 3 2 times a day if the weight of the patient is more than 75 kg or 500 mg 3 2 times a day if the weight of the patient is is less than 75 kg). the duration of treatment is 4à10 days. ribavirin must not be used by pregnant women, except when the disease is considerd life threatening. vaccine development is currently just in the experimental stages, 62à64 so prophylaxis involves early detection of sick humans and the prevention of further contact infections. nonspecific prophylaxis includes the eradication of ixodidae ticks on livestock and acaricide treatment of locations inhabited by domestic animals. in pastures with large numbers of ixodidae ticks, animals have to be led into box stalls and the humans leading them there must use special suits. history. artashat virus (artsv, strain leiv-2236ar) was originally isolated from ornithodoros alactagalis ticks (family argasidae) collected in the burrows of a small five-toed jerboa (allactaga elater) near arevashat village (40 02 absence of antigenic relationships with any known viruses, it was referred to as an "unclassified bunyavirus." 1à3 taxonomy. three strains of artsv were sequenced. 4 a full-length genome comparison revealed that artsv has 42à60% nt similarity to other nairoviruses. phylogenetic analysis revealed that the virus is a new species in the nairovirus genus and forms a distinct genetic lineage on the nairovirus tree, which was constructed for all three segments of the genome (figures 8.10à8 . 12) . the phylogeny of the nairoviruses is based mainly on analyses of the partial sequence of the conservative catalytic core domain of rdrp. 5, 6 the similarity of this domain of artsv to other nairoviruses is 42à65% nt and 58à70% aa. the phylogenetic tree constructed by the maximum-likelihood method on the basis of the amino acid alignment of the rdrp catalytic core domain of nairoviruses confirms the topology of artsv on a newly formed genetic lineage (figures 8.10à8.12 ). the nairoviruses on the tree can be divided into two main phylogenetic groups. the first group includes the nairoviruses, which are transmitted predominantly by ixodids: the crimeanàcongo hemorrhagic fever group (hyalomma and haemaphysalis, as well as dermacentor, rhipicephalus, and ixodes), the dugbe group (mainly amblyomma, but also hyalomma, rhipicephalus, and haemaphysalis), the sakhalin group (ixodes), and the tamdy group (hyalomma). the first group also includes erve virus (ervev), whose vectors are unknown. 7, 8 the second phylogenetic lineage includes the nairoviruses from the hughes, issyk-kul, dera ghazi khan, and qalyub groups, whose vectors are argasids: argas and ornithodoros. the tree topology of artsv shows that the virus is in the lineage of the nairoviruses transmitted predominantly by ixodidae ticks, although all isolations of artsv were obtained from the argasidae ticks o. alactagalis and o. verrucosus (table 8.9 ). it can be assumed that the adaptation of artsv to argasids is the result of the the narrow ecologic niche occupied by those ticks, which are ticks of the subgenera theriodoros and pavlovskyella. note that, although ervev, a european nairovirus, is phylogenetically close to the nairovirus transmitted by ixodids, the association of ervev with ixodes spp. ticks has not been established in endemic areas (southern europe). 8 ervev has been isolated from shrews (crocidura russula). 9 arthropod vectors. the adaptation of viruses to argasidae ticks facilitates the possibility of survival of viral populations in winter at low temperatures and in dry periods. the ability of argasids to fast (up to 9 years and more), the long life cycle of these ticks (up to 20à25 years), and their polyphagia and ecological plasticity determine the stability of the natural foci of arboviruses transmitted by argasids. these foci are confined mainly to the arid regions of the southern part of the temperate and subtropical zones. 1, 2, 10 the northern border of the range of argasids coincides with isolines denoting a frost-free period of 150à180 days per year and an average daily temperature above 20 c for no less than 90à100 days per year. 11 tick species from the subgenera theriodoros (ornithodoros alactagalis, o. nereensis) and pavlovskyella (o. papillipes, o. verrucosus, o. cholodkovskiy, o. tartakovskiy) are associated mainly with burrows of rodents. 11 this ecological peculiarity narrows the possibility of the spread of viruses that are adapted to ticks from the theriodoros and pavlovskyella subgenera. 2 it also applies to artsv associated with burrowà shelter biomes and found only in transcaucasia. history. caspiy virus (casv, prototypical strain leiv-63az) was originally isolated from the blood of a sick herring gull (larus argentatus) caught on gil island in the baku archipelago, off the western coast of azerbaijan in the caspian sea (40 17 0 n, 49 55 0 e; figure 8 .13) in 1970. 1à4 on the basis of electron microscopy, casv was classified as a member of the bunyaviridae family, but antigenic relationships with known bunyaviruses have not been found. thus, casv was categorized into the unclassified bunyaviruses. 5,6à8 at the same time, and in the same place, three strains of casv were isolated from ornithodoros capensis (family argasidae) ticks taxonomy. the genome of the prototypical strain leiv-63az of casv was sequenced, and it has been shown that casv is a member of the hugv group of the nairovirus genus. 11 the s-segment of casv is about 1,594 nt in length and has a single orf that encodes the nucleocapsid protein (n, 497 aa). the second start codon, in position 7, is located in the n-protein orf of casv. the identity of the amino acid sequence of the n-protein of casv with those of other nairoviruses is only 28%, on average. the cleavage site for caspase-3 (d285evd288) that has been found in the n-protein of cchfv is absent in casv. cleavage of n by caspase-3 is required for effective replication of cchfv. 12 note that caspase cleavage sites in the nucleocapsid protein are also necessary for replication of human influenza a viruses. 13 the m-segment of casv, like that of the other nairoviruses, has a single orf-encoded polyprotein precursor of the envelope glycoproteins gn and gc. the length of the gn/gc precursor of casv is 1,376 aa. according to the results of an analysis of polyprotein in the program signalp server 4.1, the first 32 aa constitute the signal peptide that is cleaved on the ssa/sy site. the cleavage site between pre-gn and pre-gc is in position 699 (vsg/ik). these data are confirmed by the location of transmembrane domains in mature proteins gn and gc that was defined with the use of the program tmhmm server 2.0. six potential sites of n-glycosylation are predicted in the mature gn protein of casv, only one in the gc protein. in general, the level of identity of polyprotein in casv is 25à27% aa with that of other members of the nairovirus genus (table 8. 3). the l-segment of casv has an orf (4,001 aa) that encodes the viral enzyme rdrp, which is the most conservative viral protein. the similarity of the rdrp of casv to that of other nairoviruses for which complete genome sequences were available is 38.8à43.0% aa. phylogenetic analysis based on the predicted full-length amino acid sequences revealed that casv is equidistant from other nairoviruses, and forms a distinct branch, on the trees (figures 8.10à8.12). for many nairoviruses, only short sequences of the catalytic core domain of rdrp are available in genbank. this domain of rdrp is very conservative and relevant to phylogenetic analysis. 1, 14, 15 the highest level of similarity (80% aa) that the rdrp core domain of casv has is with the same sequences in viruses of hug. on the dendrogram, constructed on the basis of a comparison of rdrp core domains, casv is located on the branch of the hug group (figures 8.10à8.12 ). note that viruses of this group (as well as casv) have been isolated from ornithodoros (carios) ticks that are associated with seabirds on the coasts and islands of the world's oceans. 2, 16 thus, the phylogenetic relationship of casv with hug group viruses reflects the ecological features of those coasts and islands. arthropod vectors. ornithodoros capensis ticks inhabit the coasts and islands of the atlantic, indian, and pacific oceans from the southern part of the temperate zone to the equator, as well as some large inland ponds. 3 3, 4, 17 o. capensis ticks feed on many bird species, mainly those of the order charadriiformes: gulls (family laridae) and terns (sturnidae), but also cormorants (phalacrocoracidae) and pelicans (pelecanidae). 4, 17 these argasid ticks have a life cycle made up of six to eight stages: egg, larva, three to five stages of nymphs, and imago. according to laboratory study, the cycle is from 43 to 83 days and so can be completed during a single breeding season. these ecological peculiarities provide stability to the natural foci of the viruses, which are adapted to the o. capensis tick viruses and their transcontinental transfer by migrating birds. 5 vertebrate host. in 1970, during the collection of field material on islands in the baku archipelago, an epizootic among herring gulls was observed. the first strain of casv was isolated from sick birds. migrations in search of food, including migration between the western and eastern coasts of the caspian sea, result in a sharing of the argasids and viruses ranging over the area. history. the prototypical strain leiv-858uz of the chim virus (chimv) was isolated from ornithodoros tartakovskyi ticks collected in july 1971 in the burrows of great gerbils (rhombomys opimus) in the vicinity of the town of chim in the kashkadarinsky region of uzbekistan) (38 47 0 n, 66 18 0 e; figure 8 .14). 1à3 isolation of chimv was carried out during monitoring of these arboviruses' foci on the territory of central asia and kazakhstan. chimv was investigated through serological testing with viruses from different families and with unclassified viruses isolated earlier in the ussr. because no antigenic relationships of chimv were (and still have not been) found, chimv was assigned to the category of unclassified viruses. 3, 4 later, four strains of chimv were isolated from the ticks o. tartakovskyi, o. papillipes, and rhipicephalus turanicus (rhipicephalinae) respectively collected in the burrows of great gerbils in the kashkadarya, bukhara, and syrdarya districts of uzbekistan in 1972à1976. 5, 6 three strains of chimv also were isolated from hyalomma asiaticum (hyalomminae) ticks and from the livers of great gerbils, which were collected in the floodplains of the or river and karatal river (dzheskazgan district, kazakhstan) in april 1979 (figure 8 .14). 7, 8 taxonomy. the genome of the prototypical strain leiv-858uz of chimv was sequenced, and, on the basis of sequence analysis, the virus was classified as a novel member of the nairovirus genus. 9 phylogenetic analysis based on a partial sequence of a catalytic center of rdrp placed chimv on the genetic branch of the qybv group. 9, 10 the amino acid sequence of this domain of chimv has an 87% identity with qybv, geran virus (gerv), and bandia virus (bdav), the other members of the qybv group. 11à14 all these data are consistent with the fact that viruses of the qybv group, as well as chimv, have an environmental connection to ticks of the ornithodoros genus and to the burrows of rodents. qybv has repeatedly been isolated from o. erraticus ticks, collected in burrows of the african grass rat (arvicanthis niloticus) in the nile valley and the nile delta in egypt. 13 to date, only short sequences of the rdrp of qybv are available in genbank, but recently we gave a genetic characterization of gerv, isolated in transcaucasia and, apparently, closely related to qybv. 11 the full-length amino acid comparison of chimv with gerv showed that their nucleocapsid proteins n (s-segment) have only a 55.6% identity. the similarity of complete amino acid sequences of rdrp (l-segment) is 74.8%. the similarity of the polyprotein precursor of gn/gc is 55.6%. the proteins of chimv have 30.3à42.4% aa (n-protein), 27.5à45.1% aa (gn/gc precursor), and 48.1à62.3% aa (rdrp) identities with their counterpart proteins in other nairoviruses. among these nairoviruses, chimv has the highest level of similarity with iskv, which is associated with bats in central asia (figures 8.10à8.12) . 15 arthropod vectors. most isolations of chimv were obtained from ornithodoros tartakovskyi ticks. these ticks are common in the irano-turanian and mountain provinces of asia (kazakhstan, the central asian republics, northeastern iran, and china (xinjiang)). the western border of the area in question is the eastern shore of the caspian sea (53à54 e), the eastern border is in xinjiang (87 e) , and the northern border is 44à47 n. the typical biotopes that o. tartakovskyi ticks inhabit are the foothills of dry steppes with loess soils. the ticks also inhabit meadow steppes and deserts (floodplain terraces and canals). o. tartakovskyi ticks prefer burrows of small diameter (inhabited by rodents, including jerboas, ground squirrels, small predators, and hedgehogs, as well as by turtles and birds). synanthropic biotopes are rarely inhabited. 16 vertebrate hosts. the great gerbil (family muridae, subfamily gerbillinae, genus rhombomys) is distributed from the shores of the caspian sea on the plains of central asia and southern kazakhstan, to the deserts of central asia, iran, and afghanistan, and on eastward to northern china and inner mongolia. great gerbils are typical inhabitants of sandy deserts and form a colony with complex multistory burrows that have a large number of entranceways and egresses (up to 200à500). these burrows are a specific biotope that exists for many decades, and they maintain natural foci (in particular, of plague) in arid areas. 6, 8 animal infection. the significance of chimv in the pathology of humans is unknown. antibodies to chimv have been found in camels (9.5%) in the kashkadarya region in uzbekistan. 5 this finding shows the ability of chimv to infect camels, as does qybv, but additional studies are necessary to clarify the pathogenicity of chimv in humans and cattle. 17 history. grnv (strain leiv-10899az) was isolated from ornithodoros verrucosus (family argasidae, subfamily ornithodorinae) ticks collected in a burrow of red-tailed gerbils (meriones (cricetidae) erythrurus) near geran station, goranboy district, azerbaijan; figure 8 .15). serological methods have failed to identify grnv, but the virus has been sequenced and classified into the nairovirus genus (family bunyaviridae). 1 taxonomy. the genome of grnv was sequenced by a next-generation sequencing approach. 1 full-length genome analysis revealed that the genetic similarity of grnv to other known nairoviruses is, on average, 30à40% aa for the nucleocapsid protein (n, s-segment), 27à33% aa for the polyprotein precursor of the proteins gn and gc (m-segment), and 48.0à74.8% aa for rdrp (l-segment). the highest level of similarity all three proteins of grnv have is to that of chimv (54.2à74.8% aa identity) and that of iskv (42.4à62.3% aa identity). 2,3 further analysis based on a comparison of partial sequences of the conservative core domain of rdrp of the nairoviruses showed that grnv and chimv were most closely related to qybv, which is the prototypical virus of the group of the same name. 4 the nucleotide sequence of the rdrp core domain of grnv has 74.3% nt and 97.1% aa identities with the counterpart sequence of qybv. the data obtained allow grnv to be classified as a virus of the qybv group (figures 8.10à8.12). the phylogenetic relationship between grnv and qybv corresponds to their similar ecological characteristics. qybv was first isolated in 1952 by r. taylor and h. dressler from argasid ornithodoros erraticus ticks collected in a rodent burrow in the nile river delta near qalyub village, egypt (30 n, 32 e). 5à7 complementbinding antibodies to qybv were found in humans (1.5%), camels, donkeys, pigs, buffalos, dogs, and rodents. 1, 7 the antigenic group of qalyub, a group that includes qybv and antigenic-related bdav, is one of the prototypical groups of the nairovirus genus. 5, 8 previously, qybv had been repeatedly isolated from o. erraticum collected in the burrows of rodents (arvicanthis) in africa. the second member of the qybv group, bdav, was isolated from o. sonari (a member of the o. erraticus group) collected in the burrows of rodents (mainly mastomys) in senegal. 9, 10 the isolation of gerv, which is closely related to qybv, is the first confirmation of the circulation of qybv group viruses in transcaucasia. arthropod vectors. the area of distribution of o. verrucosus ticks covers the southern part of moldova as well as ukraine and the caucasus region, and is limited by 47 30 0 n latitude. the area includes the southern part of russia (the krasnodar and stavropol regions), the northern and eastern foothills of dagestan, the foothills and lowland hills of georgia, the valleys of the hrazdan river in armenia, the foothills of the lesser caucasus mountains in azerbaijan, and the gobustan plateau and the absheron peninsula, also in azerbaijan. o. verrucosus ticks inhabit shelter biotopesin particular, the burrows of red-tailed gerbils (meriones (cricetidae) erythrurus), animals that are common in central asia, southern kazakhstan, and eastern transcaucasia. redtailed gerbils tends to inhabit desert and semidesert landscapes. their burrows are deep and may have 5à10 entranceways and egresses. history. iskv (prototypic strain, leiv-315k) was originally isolated from a pool of internal organs (liver, spleen, brain) of nyctalus noctula bats, and their ticks (argas (carios) vespertilionis) were collected near issyk-kul lake in kyrgyzstan in 1970 (figure 8 .16). 1, 2 subsequently, iskv was isolated from other bat species of the vespertionidae family (vespertilio serotinus, vespertilio pipistrellus, myotis blythii, rhinolophus ferrumequinum), and from birds, in different regions of kyrgyzstan and tajikistan. 3à11 two strains were isolated from anopheles hyrcanus mosquitoes and culicoides schultzei biting midges, respectively (figure 8.16, table 8 .10). 3, 12, 13 complement-fixation testing showed that iskv is closely related or identical to the keterah virus, which was isolated from scotophilus temminckii bats and a. pusillus ticks in malaysia in 1960. 14, 15 a strain that has a close, one-sided antigenic relationship to iskv, leiv-218taj (named garm virus), was isolated from a common redstart (phoenicurus phoenicurus) caught in the village of garm, tajikistan, morphological studies by electron microscopy characterized iskv as a member of the bunyaviridae family, and because no antigenic relation to any known viruses was found, it was assigned to the unclassified bunyaviruses. 16 taxonomy. the genome of the prototypical strain of iskv, leiv-315k, was sequenced, and, on the basis of sequence analysis, the virus was classified into the nairovirus genus. 17 like the genomes of other nairoviruses, that of iskv consists of three segments of rna (in negative polarity), each of which has a single orf-encoded nucleocapsid protein (n, 485 aa, s-segment), a polyprotein precursor of the envelope glycoproteins gn and gc (1,631 aa, m-segment), and a rdrp (3,950 aa, l-segment). a pairwise comparison of the full-length nucleotide and deduced amino acid sequences of the iskv orfs with those of other nairoviruses revealed 48.2à51.1% nt (39.0à42.1% aa), 37.3à39.7% nt (23.2à26.5% aa), and 43.1à47.0% nt (31.9à34.5% aa) identity for rdrp, the precursor of gn and gc, and the n protein, respectively (table 8.10) . phylogenetic analysis carried out for the fulllength amino acid sequences by the maximumlikelihood nearest-neighbor method showed that iskv occupies a new and distinct branch on the phylogenetic trees relevant to all three nairovirus proteins (rdrp, gn/gc, and n) (figures 8.10à8.12) . for the many known nairoviruses (i.e., qybv, dgkv, and hugv, as well as for a new nairovirus that was found in european bats by a metagenomics approach), there are only partial sequences of the conservative catalytic core domain of rdrp. 16, 18, 19 the level of identity for this domain of iskv with other nairoviruses ranged from 59.6à66.1% for the nucleotide sequence and 64.8à75.2% for the amino acid sequence (table 8 .10). the iskv rdrp core domain has the highest level of identity with qybv (66.6% nt and 74.5% aa). the phylogenetic tree constructed on the basis of the amino acid alignment of the rdrp core domain of nairoviruses confirms the topology of iskv on a new genetic branch of the nairoviruses (figures 8.10à8.12) . arthropod vectors. most isolates of iskv were obtained from argas vespertilionis ticks, and we can assume that these ticks are the main natural reservoir of the virus. the range of ticks of the a. vespertilionis group covers territory in central asia, africa, oceania, and australia ( figure 8.17) . vertebrate hosts. the natural vertebrate hosts of iskv are apparently bats-specifically, the genera nyctalus, vespertilio, rhinolophus, and myotis (family vespertilionidae). these bats are common in the temperate and subtropical zones of europe, asia, and north africa, and widespread iskv transmission and the appearance of an emergency are possible in all of their territories. human pathology. the first case of issyk-kul fever was registered in tajikistan in august 1975 when a staff member became ill after catching bats during surveillance for arbovirus. iskv was isolated from his blood on the second 21 the disease occurs with fever (39à40 c), headache (94%), dizziness (50%), hyperemia of the throat (48%), cough (25%), and nausea (31%). the outcome is generally favorable, and no deaths have been registered. 18 most of the cases were associated with the presence of bats in the attic of the residence. the primary route of human infection was apparently by argasid ticks, but respiratory or alimentary routes (via the feces and urine of bats) could not be excluded. furthermore, a laboratory experiment showed that iskv can be transmitted by aedes caspius mosquitoes. 22 the percentage of the population immune to iskv in the southern part of tajikistan is 7.8%. in kyrgyzstan, antibodies to iskv have been found in 0.7à3.2% of the human population. the highest percentage (9%) with antibodies to iskv was found in the southeastern part of turkmenistan. 12 history. uzun-agach virus (uzav), strain leiv-kaz155, was isolated from the liver of a myotis blythii oxygnathus (order chiroptera, family vespertilionidae) bat caught in the vicinity of the village of uzun-agach, alma-ata district, kazakhstan, during the virological sounding of territory in central asia and kazakhstan in 1977 (figure 8.18 ). 1à3 on the basis of virion morphology, uzav was classified into the bunyaviridae family. no serological study of uzav was ever conducted, but the place of uzav isolation, uzun-agach, is close to where iskv was originally isolated, namely, near issyk-kul lake, and the source of both viruses is the same: bats. 4, 5 taxonomy. the full-length genome of uzav was sequenced, and, on the basis of phylogenetic analysis, the virus was classified into the nairovirus genus. 6 the genome of uzav, like those of other nairoviruses, consists of three segments of ssrna with negative polarity. the l-segment encodes rdrp (3,988 aa), the m-segment encodes a polyprotein precursor of the envelope glycoprotein gn and gc (1,621 aa), and the s-segment encodes the nucleocapsid protein n (485 aa). a pairwise comparison of the sequence of the uzav genome with those of other nairoviruses showed that the virus is related most closely to iskv. full-length sequences of the l-and m-segments of uzav have, respectively, 69.3% nt and 64.1% nt identities with those of iskv. amino acid sequences of rdrp (s-segment) of uzav and iskv have 76.2% aa similarity. the similarity of the amino acid sequences of the precursor of gn and gc for uzav and iskv is 66.7% aa. a comparison of the s-segments of uzav and iskv revealed that they are almost identical (99.6%). thus, we can conclude that uzav is a reassortant virus that got an s-segment from iskv. phylogenetic analysis based on l-and m-segments placed uzav in the lineage of iskv (figures 8.10à8 .12). 6, 7 vertebrate hosts. the vertebrate host of uzav is apparently bats, but because only a single isolation was obtained, this assertion is speculative. the finding that uzav is a reassortant virus closely related to iskv suggests that uzav occupies the same ecological niche as iskv and therefore is associated with bats and their argasid ticks. myotis blythii oxygnathus, the bat from which uzav was isolated, is common in the southern parts of the russian plain and in western siberia, caucasia, kazakhstan, southern europe, northern africa, middle and central asia, iran, and iraq. bats are important natural reservoir of emerging viruses. 8à11 iskv and uzav are the first nairoviruses that appear to be associated with bats. sakhalin virus (sakv) has been isolated from ixodes (ceratixodes) uriae (family ixodidae, subfamily ixodinae) ticks, which are obligate parasites of auks (family alcidae). the prototypical strain of sakv (leiv-71c) was isolated in 1969 from i. uriae ticks collected in a colony of the common murre (uria aalge) on tyuleniy island near the southeastern coast of sakhalin island in the sea of okhotsk (48 29 0 n, 144 38 0 e; figure 8 .19). 1à4 subsequently, 52 strains of sakv were isolated from i. uriae ticks on tyuleniy island and iona island in the sea of okhotsk, the commander islands in the barents sea, and the southeastern coast of the chukotka peninsula in the bering strait (table 8 .11). 4à7 on the basis of virion morphology, sakv has been classified into the bunyaviridae family. sakv was the first of the eponymous viruses, which together have formed a basis for the nairovirus genus. 8 paramushir virus (pmrv), prototypical strain, leiv-2268, a virus of the sakv group, was originally isolated from ixodes signatus ticks collected in 1972 in a colony of cormorants (phalacrocorax pelagicus) on paramushir island (in the kuril islands) (50 23 0 n, 155 41 0 e; figure 8 .19). 9,10 later (in 1972à1987), 18 strains of pmrv were isolated from i. uriae ticks, collected in the nests of auks (family alcidae) on tyuleniy island in the sea of okhotsk and on the commander islands in the bering sea (table 8 .11). 11à14 at least five nairoviruses are included in the sakv group. 3,10,15à17 avalon virus (avav), which was isolated from engorged imagoes and nymphs of i. uriae collected in l. argentatus nests on great island, newfoundland, , in 1972, is apparently identical to pmrv. 15, 18 several strains of avav were isolated in 1979 in cap sizun, brittany, france. 19 clo mor virus (cmv) was isolated in 1973 from nymphal i. uriae ticks collected in a uria aalge colony of clo mor, cape wrath, scotland. 20 cmv was found to be closely related to sakv in a complementfixation test. two strains of cmv were isolated from i. uriae collected in seabird colonies on lundy island (england) and the shiant isles (scotland) ( table 8.12) . 18, 20 rukutama virus (rukv) (strain leiv-6269s), which previously had been included in the sakv group, is now classified into the uukuniemi virus (uukv) group in the phlebovirus genus. 9, 21 taxonomy. complete genomes of sakv (strain leiv-71c) and pmrv (leiv-1149k) were sequenced. 9 also, partial sequences of rdrp of tillamook virus (tillv, identical to sakv), isolated from i. uriae ticks on the pacific coast (oregon) of the united states, are available (table 8 .12). 18 a full-length genome comparison showed that sakh and pmrv respectively share 75.6% nt and 88.0% aa identities in rdrp (l-segment), 59.7% nt and 57.9% aa in the precursor of gn and gc (m-segment), and 62.3% nt and 62.2% aa in the nucleocapsid protein (s-segment). sakv n-protein ranges from 30% (casv, hugv) to 43% (cchfv) similarity to other nairoviruses. the similarity of rdrp and the precursor of gn and gc proteins of sakv to other nairoviruses ranges from 42.8% (casv, hugv) to 50.8% (cchfv), respectively, and from 25.9% (ervev, tfav) to 28.9% (nsdv, dugv), respectively. 9 arthropod vectors. it has been shown that the infection rate of infected ixodes uriae imagoes is 2 times higher than of the species' nymphs and 10 times higher than that of the larval stage. transovarial transfer of sakv has been found to be 10%. the infection rates of male and female ticks are approximately the same. the hypostome of male i. uriae ticks is vestigial; therefore, they cannot be infected by breeding on infected birds. the infection rate of i. uriae imagoes is at least 20 times higher than that of i. signatus imagoes. 4à6,22,23 some other species of ixodes ticks are parasites of seabirds and may be an additional reservoir of sakv. i. auritulus and i. zealandicus ticks are distributed from alaska to cape horn in south and north america. 24 laboratory experiments have demonstrated that aedes aegypti and culex pipiens molestus mosquitoes can be infected by sakv as they suck blood. the virus was found in mosquitoes on 9, 14, and 19 days after infection in titers 1.0, 1.5, and 2.0 log 10 (ld 50 )/10 μl, respectively. however, it was shown that infected mosquitoes could not transmit the virus to mice through a bite. 6, 22 vertebrate hosts. ixodes uriae ticks and their host, the common murre (uria aalge), are a natural reservoir of sakv. pelagic cormorants (phalacrocorax pelagicus) and their obligate parasites (i. signatus) likely have only an additional influence. antibodies to sakv have been found in the common murre (u. aalge), pelagic cormorants (p. pelagicus), fulmars (fulmarus glacialis), tufted puffins (lunda cirrhata), and black-legged kittiwakes (rissa tridactyla) in the far east. 4à6,22 a serological examination of birds via an indirect complement-fixation test revealed that the northern boundary of the range of sakv is the commander islands, where antibodies have been found in 2.2% of birds. the southernmost place where antibodies have been detected (1.1% birds) is kunashir island in the kuril islands. antibodies were found most often (in 4.1à17.8% of birds) in the central part of the basin of the sea of okhotsk (on sakhalin island, tyuleniy island, and iona island). antibodies were also found in the red-necked phalarope (phalaropus lobatus), sanderling (calidris alba), the long-toed stint (c. subminuta) (up to 8.4% of the population), fulmars (f. glacialis) (4.9%), leach's petrels (oceanodroma leucorhoa), tufted puffins (l. cirrhata) (4.6%), the common murre (u. aalge) (3.8%), japanese 5, 6, 22 neutralizing antibodies to avav, a virus closely related to pmrv, have been found in 27.6% of puffins (fratercula arctica), petrels (calonectris leucomelas), and herring gulls (larus argentatus) in canada. 24, 25 findings of antibodies to sakv in seabirds carrying out their annual seasonal migration to the southern hemisphere suggest the possibility of transcontinental transfer of the virus to the southern hemisphere. the closely related taggert virus (tagv) was isolated from ixodes uriae ticks in penguin colonies on macquarie island, a phenomenon that may indicate a transfer of viruses by birds and their ticks between the northern and southern hemispheres. human infection. three human cases of cervical adenopathy associated with avav were described in france. 25 serological examination of farmers in cap sizun, brittany, france, found only 1% of the population positive. 18 history. tamv (prototypal strain, leiv-1308uz) was originally isolated from hyalomma asiaticum asiaticum (family ixodidae, subfamily hyalomminae) ticks collected from sheep in the arid landscape near the town of tamdybulak subsequently 52 strains of tamv were isolated in uzbekistan, 4à7 turkmenistan, 8à11 kyrgyzstan, 12,13 kazakhstan, 11, 14, 15 armenia, 6, 16 and azerbaijan 8,17à19 in 1971à1983 (table 8.13) . most of the strains were obtained from h. asiaticum ticks, but several were isolated from birds, mammalians (including bats), and sick humans. on the basis of virion morphology, tamv has been classified into the bunyaviridae family. serological studies by complement-fixation and neutralization tests revealed no antigenic relationships of tamv with any known viruses. 2 taxonomy. three strains of tamv isolated in uzbekistan (leiv-1308uz), armenia (leiv-6158ar), and azerbaijan (leiv-10226az) were completely sequenced. 20 phylogenetic analysis of the full-length sequences showed that tamv is a novel member of the nairovirus genus, forming a distinct phylogenetic lineage (figures 8.10à8.12 ). the similarity of the amino acid sequence of tamv rdrp (l-segment) with those of other nairoviruses is 40% aa, on average. the similarity of the rdrp of tamv with that of the nairoviruses associated predominantly with ixodid ticks (cchfv, hazara virus (hazv), and dugv) is higher (40% aa) than that with viruses associated with argasid ticks (iskv and casv) (38% aa). the similarity of the tamv polyprotein precursor of cn and gc with that of other nairoviruses is less than 25% aa. the similarity of the amino acid sequence of the nucleocapsid protein (s-segment) of tamv is 33% aa with ixodid nairoviruses and 28% aa with argasid nairoviruses. phylogenetic analysis of the catalytic core domain of the rdrp of the nairoviruses confirms that tamv forms a novel group in the nairovirus genus (figures 8.10à8.12 ). 20 genetic diversity among the three sequenced strains of tamv is low. the prototypic strain leiv-1308uz, isolated in central asia, has 99% nt identity in the l-segment with leiv-10226az from transcaucasia. the l-segment of the strain leiv-6158ar has 94.2% nt and 96.3% aa identity with the l-segment of leiv-1308uz. the similarity of the m-segment of leiv-1308uz with those of leiv-10226az and leiv-6158ar is 93% nt and 89% aa, respectively. the similarity of the s-segment among the three strains is 93à95% nt. 20 arthropod vectors. h. asiaticum ticks are apparently a main reservoir of tamv. more than half (57%) of tamv isolations were obtained from h. asiaticum asiaticum ticks, 6% from h. asiaticum, 8% from h. anatolicum, 6% from h. marginatum, 6% from rhipicephalus turanicus, and 2% from haemaphysalis concinna. the infection rates of male and female ticks in endemic territory were 1:210 and 1:200, respectively. the infection rate of h. asiaticum nymphs was 20 times lower. 7, 10, 14, 16 furthermore, tamv was isolated from larvae of h. asiaticum, which were hatched from eggs in the laboratory, indicating transovarial transmission of the virus. h. asiaticum asiaticum ticks are the most xerophilous subspecies of the hyalomma genus (ixodinae subfamily), 21 a characteristic that allows tamv to be distributed over the karakum desert in turkmenistan, the moinkum desert in kazakhstan, and the central part of the kyzyl kum desert in kazakhstan and uzbekistan. 7 . animal hosts. the larvae of h. asiaticum feed on ruminants, hoofed animals, small predators, hedgehogs, birds, and reptilians. one of the major hosts of h. asiaticum preimagoes is the great gerbil (rhombomys opimus). wild animals, as well as sheep and camels, are the hosts for h. asiaticum imagoes and may be involved in the circulation of tamv (table 8 .13). human pathology. sporadic cases of the disease associated with tamv was registered in kyrgyzstan in october 1973, when tamv was isolated from the blood of a patient with fever (39 c), headache, arthralgia, and weakness. 16 h. asiaticum asiaticum ticks rarely attack humans, and no outbreaks of tamv fever have been registered; however, human infection by h. asiaticum ticks is still possible concinna (ixodidae, haemaphysalinae) during 1971à1975. 1,2 according to preliminary information, burv is not able to agglutinate erythrocytes of birds and mammals and has no antigenic relationships with 59 arboviruses from different groups of the togaviridae, taxonomy. the genome of burv was sequenced, and the virus was classified into the nairovirus genus, family bunyaviridae. the genome consists of three segments: an l-segment (orf, 11,919 nt; encodes rdrp); an m-segment (orf, 4,035 nt; encodes a polyprotein precursor of the envelope proteins gn and gc); and an s-segment (orf, 1,482 nt; encodes the nucleocapsid protein n). 3, 4 a comparison of rdrp sequences of burv with those of other nairoviruses demonstrated that the virus is distantly related to tamv (59% aa similarity). the similarity of the rdrp catalytic core domain of burv to that of tamv is 82% aa, compared with about 60% aa for viruses in other phylogenetic groups. the level of similarity for the nucleotides sequences of this part of the rdrp of burv is 68% nt with those of tamv and 45à50% nt with those of other viruses (figure 8 .10). 3 the m-segment of burv has a long orf and encodes a polyprotein precursor of the envelope glycoproteins gn and gc. 4 the size of the polyprotein precursor is 1,344 aa. the mature gn and gc proteins of nairoviruses are formed by complex processes involving cellular peptidases. by the netnglyc 1.0 server, 11 potential glycosylation sites were predicted, with only 5 within mature gn or gc proteins. 5, 6 the level of similarity of the amino acid precursor of gn and gc in burv is 45% with that of tamv and no more than 27% with viruses of other phylogenetic groups. phylogenetic analyses based on a comparison of the full-length polyprotein precursor demonstrated the position of burv on the tamv branch and was consistent with the rdrp data ( figure 8 .11). 3 the s-segment of nairoviruses encodes a nucleocapsid protein (n). 4, 7 the size of the burv nucleocapsid protein is 493 aa, corresponding to the average size of the n protein of other nairoviruses (480à500 aa). the level of similarity of the amino acid sequence of burv n protein with that of tamv is 44%, and that with the amino acid sequences of other nairoviruses is30à32%. phylogenetic analyses of burv n protein are represented in figure 8 .12. the phylogenetic position of burv is on the tamv branch, despite the virus's having the lowest level of similarity of the n protein compared with that of other virus proteins. arthropod vectors. as mentioned earlier, six strains of burv were isolated from the ticks haemaphysalis punctata (five strains) and haem. concinna (one strain) in 1971à1975. the rate of infected ticks was 2.2à2.6%. burv is associated with haem. punctata and haem. concinna ticks in pasture biocenoses. the virus is phylogenetically close to tamv, which is also associated with ixodes ticks in pasture and desert biocenoses. 8 the orthobunyavirus genome consist of three segments of single-stranded negative-sense rna designated as large (l), medium (m), and small (s) (figure 8 .22). 1 the l-segment of the prototypical bunv (6,875 nt in length) encodes the viral rdrp. 2 the m-segment (4,458 nt) encodes two surface glycoproteins (gn and gc) and a nonstructural protein (nsm). 3, 4 the s-segment (961 nt) encodes the nucleocapsid protein (n) and a nonstructural protein (nss). the nss protein is considered a pathogenic factor for vertebrates, because it may act as an antagonist of interferon, which is involved in blocking the host's innate immune responses. 5à7 6, 7 to olyka virus, isolated in 1973 from an. maculipennis mosquitoes collected in western ukraine; 8à11 and to chittoor virus, isolated in 1957 from an. barbirostris mosquitoes collected in brahmanpally, chittoor district, andhra pradesh state, india. 12 the african ngari virus (nriv) is reassortant between batv and bunv. 12, 13 in russia, batv was repeatedly isolated in different regions (figure 8 .23). anadyr virus (anadv), strain leiv-13395, was isolated by s.d. lvov from a pool of aedes mosquitoes collected in september 1986 in a swamp tundra landscape near the village of ukraine, and russia are members of the european group. two strains of batv-leiv-ast04-2-315 and leiv-ast04-2-336-isolated in russia were completely sequenced and placed into the cluster of the european strains. 14 within this group, they are phylogenetically close to strain 42, isolated in the volgograd region in 2003 from anopheles messeae (maculipennis) mosquitoes, for which the partial nucleotide sequences of the l-and m-segments are known. between the strains leiv-ast04-2-315 and leiv-ast04-2-336, there is very high level of nucleotide and amino acid identity of three segments of the genome: 99.6/99.0% (l-segment/rdrp), 99.9/100.0% (m-segment/ polyprotein predecessor), and 99.7/100.0% (s-segment/nucleocapsid). the levels of nucleotide identity of strain 42 with these strains on partial sequences of l-and m-segments are 98.6/98.8% and 100/100%, respectively; that is, for the m-segment, all available nucleotide polymorphisms are synonymous. the lowest observed genetic differences and the temporal and geographical proximities of the various strains of these viruses suggest a common origin as different isolates of the same strain of batv circulating in the southern part of russia. phylogenetic analysis of anadv (strain leiv-13395) revealed its similarity to batv. the l-segment of anadv is from 76.5% to 79.7% identical with those of the different batv strains (figure 8 .26, table 8 .15). the identity of the l-segment of anadv with the l-segments of other viruses of the bunyamwera group is 73.5% (bunv), 74.1% (cvv), and 73.9% (tenv). the amino acid and is about 82.5% with tenv and cvv. the amino acid similarity of the nucleocapside protein is 98.7% with that of batv from uganda. phylogenetic analysis of the nucleotide sequences of the s-, m-, and l-segments conducted with the use of a maximum-likelihood algorithm placed anadv (leiv-13395) on a distinct branch of the dendrogram that considers it a new representative of the bunyamwera group. arthropod vectors. batv has been reported in sudan, africa. 15 the distribution of batv in southeastern asia includes malaysia, india, sri lanka, thailand, cambodia, and japan, 5,16 while in europe batv is distributed over austria, germany, yugoslavia, moldova, ukraine, belarus, and other countries. 2,17à19 in central europe, batv was isolated from anopheles claviger, an. maculipennis (an. messeae), coquillettidia richiardii, aedes (ochlerotatus) punctor, and ae. communis. 6, 7, 20 a wide distribution of batv in different landscape belts of the european part of russia, as well as in siberia and the far east, was demonstrated: in the temperate belt the main source of batv isolation was the zoophilic anopheles genus, whereas in high latitudes (tundra, northern taiga) it was the aedes genus. 18,21à24 in the european part of russia, batv has been isolated in the northern (komi republic), middle (vologda region), and southern (leningrad, yaroslavl, and vladimir regions; 2, 6, 17, 18, 20 in the southern hyperendemic regions of russia, the main vector of batv is an. messeae. according to our data, the infection rate of an. messeae in the middle belt of the volga delta (astrakhan region) reaches 0.188% (approximately 1 infected mosquito out of 500). because this species of mosquito attacks mainly domestic animals, it serves as a biological barrier, reducing risk of infection to humas. in the northern areas (the subarctic, the northern taiga), batv circulation is due mainly to aedes mosquitoes: ae. communis complex and ae. punctor. under experimental conditions, batv was isolated from hibernating females of an. messeae. hibernation is one of the mechanisms by which batv survives during the winter. 20, 25 vertebrate hosts. in anthropogenic biocenoses of the southern regions of russia, domestic animals are the main vertebrate reservoir, because they (especially cattle) are the main hosts for an. messeae. batv-neutralizing antibodies were found in india among rodents (mus cervicolor (55.2%), rattus exulans (36.4%), rattus rattus (19.5%), bandicota indica (15.5%)) and bats (cynopterus sphinx) (2.6%). 2, 5 this indicator is significantly higher in india among domestic animals: goats (41.8%), camels (100%), cows (60.9%), and buffalos (23.3%). in finland, anti-batv antibodies occasionally were found among cows (0.9%), but not among reindeers. 19 the chittoor strain is associated with mild illness, but is pathogenic to sheep and goats. 12 batv was isolated from birds: crows (corvus corone), coots (fulica atra), and grey partridges (perdix perdix). 9 persistent avian infection was established experimentally with reactivation of viremia by cortisone six months after the acute infection period. 10 an investigation of 5,000 sera of domestic animals in russia during 1982à1992 revealed anti-batv antibodies among these animals significantly more often than among people (table 8 .16). the largest immune layer was found in populations of horses (up to 80%), cattle (35à60%), sheep (up to 80%), and camels in forestàsteppe, semidesert, and desert landscape belts. in contrast to the situation in finland, antibodies were found in reindeer sera in a tundra landscape belt of the chukotka peninsula. no examinations of vertebrates in natural biocenoses were conducted. epidemiology. epidemic outbreaks and sporadic cases caused by batv, as well as outbreaks of hemorrhagic infection caused by ngari virus, have been reported. 13, 15, 18, 26, 27 to date, no cases of laboratory infection are known. according to a serological examination of 10,000 people in the endemic regions of russia, about 3à10% withstand batv infection in an asymptomatic form. the highest infection rate was established in forestàsteppe and steppe belts. (however, as a rule, the rate is higher for domestic animals than humans.) some northern areas in russia became hyperendemic for no apparent reason. 18, 21, 22 pathogenesis. no pathogenetic mechanism during batv infection in humans has yet been described in detail. there are experimental data, however, on batv infection in primates: 28 green monkeys (chlorocebus sabaeus) were found to be carriers of the virus 50 days after inoculation (the observation period); the virus was pantropic, destroying small vessels and producing vasculitis and perivascular focal lymphohistiocytic infiltrates. clinical features. the disease etiologically linked with batv proceeds mainly as influenzalike disease complicated by meningitis, malaise, myalgia, and anorexia. 13, 15, 18, 26, 27 at the same time, ngari virus (reassortant between batv and bunv) infection in east africa appears as outbreaks of hemorrhagic fever. 13 diseases associated withtheclosely related ilev in africa and madagascar also proceed with hemorrhagic phenomena and with lethal outcomes. 29, 30 diagnostics. a highly specific test based on rt-pcr has been developed, as have elisa tests for the detection of specific anti-batv igm and igg. 24 genome and taxonomy. the genome of the ce group of viruses consists of three segments of ssrna with negative polarity. the l-segment of lacv, a prototypical virus of the group, is 6,980 nt in length, the m-and s-segments 4,527 and 984 nt, respectively. as in other bunyaviruses, the l-segment encodes rdrp, the m-segment a polyprotein precursor of the envelope glycoproteins gn and gc, and the s-segment nucleocapsid protein (n). two nonstructural proteins are found in infected cells: nss, which encodes by adding an orf in the s-segment; and nsm, which forms during the maturation of the gn and gc proteins from the precursor. 11 25, 26 but viruses of the ce serocomplex were isolated from ae. albopictus (a known vector for at least 22 arboviruses), which was imported from southeastern asia and spread into 30 states of the united states. 27, 28 transovarial transmission was established in ae. vexans 29 and cs. annulata. 16 overwintering of tahv was documented in cx. modestus and cs. annulata females. 16 mosquito species have been defined and classified only partially in connection with the huge volume of this laborious work. the majority of strains were isolated from pools of mosquitoes belonging to different species. of 250 strains that were isolated (1 strain was isolated from a wild population of the common house mouse, mus musculus), only 112 were isolated from strictly defined species (table 8 .18). the other 138 strains were isolated from aedes mosquitoes of unidentified species: 34% of strains were from ae. communis, 18% from the mixed pools, in which ae. communis prevailed. strains were isolated from other species significantly less often. only one strain was isolated from anopheles maculipennis (an. messeae) and culiseta alaskaensis. 30 the dynamics of the seasonal infection rate of mosquitoes was investigated for two years on the model of the northern part of the russian plain and the eastern part of fennoscandia. in tundra, the epizootic period begins with the second decade of july and proceeds to the beginning of august, when the activity of mosquitoes comes to an end. in forest tundra, the epizootic period begins with the first decade of july and proceeds for 1.5 months; in the northern taiga, this period lasts at least 2 months (julyàaugust); in the middle and southern taiga, the first strains began to be isolated in the second decade of june. the mosquito infection rate increases significantly in the third decade of july and reaches a maximum in the middle to end of august, when the total number of mosquitoes decreases. 30, 31 the data collected testify to an almost universal distribution of ce serocomplex viruses in all landscape belts, except the arctic, in all six physicogeographical lands examined in the north of russia, 32 located on a territory of more than 10 million km 2 . the infection rate of mosquitoes increases (р , 0.01) in moving from the subarctic (tundra) (0.0090 6 0.0018%) to the landscape belt of the middle taiga (0.0196 6 0.0020%). this indicator in tundra and in the forest tundra is close to that in the southern taiga of the russian plain (0.0122%), in north america (0.01%), and in the forest steppes of the russian plain (0.0100à0.0017%). in the steppe belt of the russian plain, the infection rate of mosquitoes appeared to be the smallest (0.001%). in the leaf forests of the russian plain (0.0148%) and of the former czechoslovakia (0.0210%), the infection rate of mosquitoes is comparable to that for landscape belts of the northern and middle taiga. to date, at least s63 ce serocomplex virus strains were isolated from mosquitoes in the central and southern parts of the russian plain. among them, 4 strains were isolated from the blood and spinal fluid of patients, and 3 strains from the internal parts of rodents (2 from the bank vole, myodes glareolus; and 1 from the wood mouse, apodemus sylvaticus). the infection rate of mosquitoes depends on the landscape belt and the particular season in which field material was collected. the rate decreases, as a rule, from the north to the south. data indicating an absence of viruses in semideserts can be explained by an insufficient quantity of mosquitoes collected, but in wet subtropical zones in azerbaijan ce serocomplex viruses were isolated from anopheles hyrcanus. 33 in the southern taiga belt and mixed forests, the infection rate of mosquitoes was defined to be from the third week of may to the second week of august and two peaks were noted: at the end of june (the emergence of the first generation of aedes mosquitoes) and at the end of july to the beginning of august (the emergence of the second generation of aedes mosquitoes). in the majority of the southern belts, the infection rate was registered from the second week of june until the end of august with a small peak in the first week of august caused by the emergence of the second generation of aedes mosquitoes and by the peak of activity of culex, coquillettidia, and anopheles mosquitoes. 17 in steppe and forestàsteppe belts, ce serocomplex viruses were isolated from mosquitoes collected in the rostov and orenburg regions, as well as in the foothills of the caucasus mountains (krasnodar krai). most of the strains were obtained from aedes mosquitoes, which play the leading role in virus circulation. in these regions, anopheles mosquitoes join the virus population maintenance (three strains were isolated), being ecologically connected with agricultural animals and, because of that connection, playing an important role as an indicator species in anthropogenic biocenoses. in the center and south of the russian plain, there is a mix of populations of inkv, tahv, khtv. 31, 32 vertebrate hosts. the principal vertebrate hosts of tahv in europe are lagomorpha (hares (lepus europaeus), rabbits (oryctolagus cuniculus), hedgehogs (erinaceus roumanicus), and rodents (rodentia)). experimental viremia has been established in lagomorphs, hedgehogs, ground squirrels (citellus citellus), muskrats (ondatra zibethicus), squirrels (sciurus vulgaris), martens (martes foina), polecats (putorius eversmanni), foxes (vulpes vulpes), badgers (meles meles), bats (vespertilio murinus), piglets, and puppies. 14, 15, 34, 35 in total, 251 strains of ce serocomplex viruses were isolated within all landscape belts of all physicogeographical lands (figure 8 .30, table 8 . 19 ). according to our data, the susceptibility of mosquitoes increased from the tundra to the northern and middle taiga; however, the highest indicators were noted to be in the forestàsteppe and the steppe of western siberia (in altai krai). identification of these strains revealed at least three viruses of the ce complex: 2 strains of tahv, 44 of inkv, and 183 strains of khtv. 30 in all landscape belts east of the yenisei river (central and northeast siberia and the physicogeographical lands bordering the north pacific ocean), only khtv strains have been isolated. west of the yenisei river, inkv strains predominated in the tundra and the forestàtundra of western siberia, whereas khtv prevailed in other landscapes located to the south. in the eastern part of fennoscandia and in the north of the russian plain, inkv and khtv strains were isolated in about equal proportions. 30 the pattern of distribution of tahv, inkv, and khtv over northern eurasia suggests that the emergence of the ancestor of ce serocomplex viruses probably is connected to oligocene chineseàmanchurian fauna of the deciduous forests of eastern siberia evolving into okhotsk fauna during the upper tertiary period. the okhotsk fauna, in its turn, extended in early glacial times to the north, the west, and partially to the east in tundra through ancient beringia and on into north america. the ancestral virus could then penetrate into north america together with this fauna and gradually extend in the southern direction, in the process laying the foundation for the appearance of some other viruses of the ce serocomplex now circulating mainly in north america. mercurator, nigripes, excrucians 1 0.9 maculipennis b 1 0.9 total 112 100 a one strain was isolated from the genus culiseta. b one strain was isolated from the genus anopheles. the introduction of the virus population to the western hemisphere probably occurred through two pathways around the central siberian plateau: (i) through the tundra lying to the north of the plateau and (ii) through southern taiga and forestàsteppe territories. these pathways can explain the modern predominance of khtv in the forestàsteppe belt of siberia and in a taiga belt west of the yenisei river. in moving to other ecological systems further to the west, khtv could have been transformed partially to inkv and tahv. the inkv population penetrated into the western part of the eurasian subarctic through the taiga belt and occupied that part of eurasia, whereas tahv proceeded into the deciduous forests of europe, where it now prevails. 36 epidemiology. cev is endemic in the united states in california, new mexico, texas, the southwestern part of virginia, tennessee, and kentucky. 26, 37 sporadic morbidity with cns lesions occurs in those states, but the main morbidity is linked to lacv, which is endemic in 20 states, predominantly the u.s. census bureauàdefined east north central states (ohio, wisconsin, minnesota, iowa, and indiana), where morbidity reaches 0.1à0.4%. 26 cases of lacv-associated encephalitis are within the distribution of the main vector-aedes triseriatus-eastward from the rocky mountains. 38 during the last few decades, natural foci in west virginia, north carolina, and tennessee, with sporadic cases occurring in louisiana, alabama, georgia, and florida, joined with previously known ones in wisconsin, illinois, minnesota, indiana, and ohio. thus, having traversed the distance from southeastern asia to north america, ae. triseriatus is now part of the north american virus circulation. 39 the clinical picture varies from an acute fever syndrome (in some cases with pharyngitis and other symptoms of acute respiratory disease) to encephalitis. lethality is about 0.05%. from 40 to 100 cases occur annually. generally, the virus attacks children age 10 and under (60%), a phenomenon that may be explained by the existence of a layer of immunity in up to 40% of adults. 40 jcv (in the united states and canada) and sshv (in the northern part of the united states and in canada) are associated with sporadic cases of fever and encephalitis. 26 domestic dogs are susceptible to lacv, which provokes encephalitis. 21, 34, 41, 42 the role of deer in virus circulation has been established as well. horizontal and vertical transmission of viruses provides an active circulation of the virus, a high rate of infection in mosquitoes, and stability of natural foci under the relatively rough conditions of the central and northern parts of the temperate climatic belt. 43 all three viruses (inkv, khtv, and tahv) of the ce serocomplex distributed in eurasia have significance in human pathology. 43, 44 these viruses were found in czechoslovakia in 1959, 4, 45 austria in 1966, 13 finland in 1969, 6, 46 romania in 1974, 12 norway in 1978, 24 the former ussr(in transcaucasia) in 1972, 47 and elsewhere in the european and asian parts of russia. 9,30,32,33,36,44,48à50 in europe, human disease associated with tahv presents as an influenzalike illness mainly in children with sudden-onset fever, headache, malaise, conjunctivitis, pharingitis, myalgia, nausea, gastrointestinal symptoms, anorexia, and (seldom) meningitis and other signs of cns lesions. 16,42,51à56 the circulation of ce serocomplex viruses was established in china, 57 where they provoke human diseases with encephalitis 58 as well as acute respiratory disease, pneumonia, and acute arthritis. 59 in north america (the united states and canada), lacv is the most important of these viruses, 60 but sshv also is associated with human disease. 61 between 1963 and 1981 in the united states, 1,348 cases of ce were reported. 60, 62 so, ce serocomplex viruses have circumpolar distribution. in russia, these viruses are found from subarctic to desert climes ( figure 8 .30, table 8 .18). 32, 44 according to our summary data for 8,732 sera, the number of people with specific antibodies to ce serocomplex viruses in the tundra and forestàtundra belts (27.8%) is significantly lower than the number in the north and middle taiga belts (48% and 47%, respectively). these data correlate with the infection rate of mosquitoes in those landscape belts. 31, 49 results obtained from serological investigation of the human population correlate with those obtained from virological investigation of the mosquitoes (figure 8 .31). the maximum immune layer of the healthy population is registered in the southern taiga. in the landscape and geographical zones located south of that landscape, a gradual decrease in this indicator takes place. specific antibodies to inkv are seen everywhere that this virus circulates. in forest-àsteppes, specific antibodies to tahv and inkv are marked out with an identical frequency. in semideserts, anti-tahv antibodies are found twice as often as anti-inkv ones. the small number of strains isolated in these natural zones precludes establishing a relationship between the circulation of viruses and an immune layer of the population. active circulation of ce serocomplex viruses on the territory of russia results in regular registration of the diseases caused by these viruses. more than 7% of all seasonal fevers are etiologically linked to such viruses, and in some natural zones (the southern taiga and the mixed forests), this indicator increases to 10à12%. in mixed forests, the main etiological role most often belongs to inkv (50.4%), and in semideserts (astrakhan region) to tahv (76.5%). the diseases caused by ce serocomplex viruses in the center and south of the russian plain start appearing during the middle of may and reach a maximum in almost equal titers of specific antibodies to more than one virus were revealed in 65 patients (35.5%) in a neutralization test. 31, 43, 49 diseases were registered from may to september: in may, 22 cases (12.02%); in june, 35 (19.13%); in july, 67 (36.61%); in august, 54 (29.51%); and in september, 5 (2.73%). the seasonal dynamics in all landscape zones were identical: the maximum number of diseases is noted in julyàaugust. diseases were registered everywhere in the form of sporadic cases and small outbreaks, but more often in the taiga and the deciduous forests of the european part of russia and western siberia. most patients were 15à40 years old, with those up to 30 years making up 52.5% of all people infected. 9 pathogenesis. a systematic destruction of small vessels, together with the development of vasculitis and perivascular focal lymphohistiocytic infiltrates, underlies the pathogenesis of the diseases caused by ce serocomplex viruses. lesions in the lungs, brain, liver, and kidneys are the most frequent complications. 31, 49 clinical features. the incubation period lasts from 7 to 14 days, but in some cases is only 3 days. three main forms of disease linked with ce serocomplex viruses have been proposed: (i) influenzalike; (ii) with primary compromise of the bronchiopulmonary system; (iii) neuroinfectious, which proceeds with a syndrome of serous meningitis and encephalomeningitis. analysis of the clinical picture of cases examined showed that 79.8% of cases proceeded without signs of cns lesion, 20.2% with a syndrome of acute neuroinfection, and 8.9% with radiologically uncovered signs of changes in the bronchiàlung system. a comparison of clinical forms and etiologic agents showed that inkv and tahv often cause disease without cns lesions (65.6% and 92.5%, respectively) and that inkv plays the leading role in acute neuroinfection (34.4%). the etiological role of khtv was established in 14 cases without cns symptoms of lesions. 63 eighty-three patients had an influenzalike form of the disease etiologically linked to ce serocomplex viruses. the incubation period was 7à14 days. the disease began abruptly, with a high temperature that reached a maximum of 39à40 c in 98.9% of patients on the first day. the duration of the fever was 4.48 6 0.30 days. one of the main symptoms was an intensive headache (3.62 6 0.26 days in duration) that developed in the first few hours and was often accompanied by dizziness, nausea (31.3%), and vomiting (21.7%). 43,63à66 a survey of patients revealed infection of the sclera (59.0 6 3.4%), hyperemia of the face and the neck (10.8 6 3.4%), and, in some cases (3.6%), a spotty and papular rash on the skin of the trunk and the extremities. violations of the upper respiratory airways were characterized by hyperemia of the mucous membranes of the fauces (95.2 6 2.3%)and congestion of the nose and a dry, short cough (13.2 6 3.7%). with regard to the lungs, 26.5 6 4.8% of patients exhibited rigid breathing a dry, rattling cough during auscultation, and a strengthening of the bronchovascular picture on roentgenograms. among cns symptoms, the most common were a decrease in appetite, a stomachache without accurate localization and with liquid stool, and a small increase in the size of the liver with a short-term increase in aminotransferase activity in the blood. inflammatory changes in the bronchiàlung system (bronchitis and pneumonia) occurred as well. in all cases in which it appeared, pneumonia had a focal character with full the etiological role of different ce serocomplex viruses has been established in 8% of 463 cases with acute diseases of the nervous system (serous meningitis, encephalomeningitis, arachnoiditis, acute encephalomyelitis, and seronegative tick-borne encephalitis (tbe)): inkv (56.7 6 8.1%), tahv (8.1 6 4.5%), and unidentified (35.1 6 7.8%). the age of patients with cns lesions was from 3 to 61 years, with the majority (51.5%) from age 21 to 30. serous meningitis was observed in 29 patients who arrived at the hospital a mean 3.3 days after symptoms appeared. the disease began abruptly. the majority (58.6%) of patients complained of a high temperature that reached a maximum the first day, the duration of the fever was 4.54 6 0.05 days, with a critical (37.9%) or steplike (62.1%) decrease. headache was noted in 100% of patients and was accompanied by dizziness in 31%. vomiting developed on the first (53.6%) or the second (46.4%) day and continued in 67.7% of patients. meningeal signs appeared in 96.5% of patients but were weak and dissociated in most cases, with only 37.9% of patients exhibiting rigidity of the occipital muscles. the duration of the meningeal signs was 3.50 6 0.4 days. the cells of the spinal fluid (investigated on the 4.57th 6 0.54 day of the disease) was lymphocytic, mostly reaching three digits and up to 500 cells (55.6%); the protein concentration was reduced (0.15 6 0.02 g/l) in 41.4% of cases but was within the normal range (0.31 6 0.01 g/l) in other cases. in 34.5% of patients exhibiting acute neuroinfection symptoms of bronchitis and focal pneumonia, their condition was confirmed radiologically. encephalomeningitis caused by inkv was characterized by an abrupt beginning and fast development of focal symptomatology (ataxy, horizontal nystagmus, and discoordination) against a background of common infectious and meningeal syndromes, including inflammatory changes to the spinal fluid. 43,63à66 the variability of the clinical picture of the diseases caused by ce serocomplex viruses and its similarity-especially at early stagesto that of other infections suggest the necessity of carrying out differential clinical diagnostics with a number of diseases. the influenzalike form needs to be differentiated, first of all, from influenza, especially in the presence of symptoms of neurotoxicity, as well as from other acute respiratory diseases (parainfluenza, adenoviral and respiratoryàsyncytial diseases), pneumonia (including a mycoplasma and chlamydia etiology), and enteroviral diseases. the main epidemiological features and clinical symptoms that lend themselves to carrying out differential clinical diagnostics for the influenzalike diseases described here are presented in table 8 .20. note that considerable difficulties arise in implementing differential clinical diagnostics of the diseases that proceed with acute neuroinfection syndrome (serous meningitis, encephalomeningitis), especially when those diseases occur in the same season (tables 8.20 and 8.21). 31, 44, 66 the main criteria in differential clinical diagnostics of the disease etiologically linked with ce serocomplex viruses are as follows (see tables 8.20 and 8.21): acute onset; high short-term fever (4à8 days, on average) reaching a maximum on the first day and decreasing critically at the end of the feverish period; and intensive headache, nausea, vomiting, and weakness. also observed are insignificant catarrhal phenomena (nose congestion, rare dry cough) or their complete absence. a radiograph of the chest reveals signs of bronchitis and focal pneumonia with poor clinical symptomatology. an examination of the liver shows that its size, as well as its aminotransferase activity, has increased. changes in urine, such as albuminuria and, in some cases, cylindruria, are frequently reported. finally, symptoms relating to the vegetative nervous system (hyperemia of the face and the neck, subconjunctival hemorrhage, bradycardia, and persistent tachycardia) can be observed, as can both cns lesions in the form of serous meningitis and encephalomeningitis in combination with compromise of the bronciopulmonary system, liver, and kidneys. diagnostics. specific diagnostics of the diseases etiologically linked with ce serocomplex viruses could be based on virological testing (using sensitive biological models of newborn mice or cell lines to isolate the strains) or on serological testing. in the presence of the sera taken from patients during the acute period of the disease (the first 5à7 days) and in 2à3 weeks, the best method of retrospective inspection is a neutralization test. a hemagglutination inhibition test is considerably less sensitive. both complement-binding reactions and diffuse precipitation in agar have no diagnostic value today. for serological reactions, it is necessary to utilize hktv, tahv, and inkv antigens simultaneously. (in reference labs, sshv antigen should be used as well.) a quadruple (or greater) increase in the titers of specific antibodies or the detection of specific antibodies in the second serological test in their absence in the first test are diagnostic criteria. elisa for igg indication and monoclonal antibody capture elisa (mac-elisa) for igm indication provide good diagnostic opportunities. control and prophylaxis. supervision of morbidity and of the activity of natural foci linked with ce serocomplex viruses offers the following instructions: (i) monitor the patient clinically and the disease epidemiologically. (ii) provide well-timed diagnostics and seroepidemiological investigations. (iii) track the number and specific structure of mosquito vectors and possible vertebrate hosts. history. khurdun virus (khurv), strain leiv-ast01-5 (deposition certificate n 992, 04.11.2004, in the russian state collection of viruses), was isolated from a pool of internal parts of the coot (fulica atra; order gruiformes, family rallidae), collected august 3, 2001 , in natural biomes in the western part of the volga river delta, in khurdun tract, ikryaninsky district, astrakhan region. 1 later, nine more strains of khurv were isolated from f. atra and the cormorant phalacrocorax pygmaeus; order pelecaniformes: family phalacrocoracidae) in 2001à2004 (figure 8 .32). at least six viruses associated with birds have been shown to circulate in the volga river estuary. 2,3 khurv has not been identified by any serological method, 1 including sera against viruses of the flaviviridae, togaviridae, bunyaviridae, and orthomyxoviridae families. 4 taxonomy. the genome of khurv was sequenced, and phylogenetic analysis revealed that it is a new representative of the orthobunyavirus genus (figures 8.33à8.35). 5 the genome consists of three segments of ssrna with negative polarity-an l-segment (6,604 nt), an m-segment (3,161 nt), and an s-segment (950 nt)-and has only 25à32% identity with those of other orthobunyaviruses. the terminal 3 0 -and 5 0 -sequences of khurv genome segments, determined by rapid amplification of cdna ends, are canonical for the orthobunyavirus (3 0 -ucaucacaug and cgtgtgatga-5 0 ). 6 the l-segment of khurv has a single orf (6,526 nt) that encodes rdrp (2,174 aa). the similarity of khurv rdrp with those of the orthobunyaviruses is 32%, on average. the similarity of the conservative polymerase domain iii (a, в, c, d, and e motifs) 7 in rdrp reaches 62% (in bunv). the м-segment of khurv is shorter than those of the orthobunyaviruses (3,161 nt vs. 4,451 nt for bunv). the м-segment of khurv has a single orf (2,997 nt), which encodes a polyprotein precursor (998 aa) of the envelope glycoproteins gn and gc. apparently, the m-segment of khurv does not contain a nonstructural protein nsm, which is common in most of the orthobunyaviruses. 8, 9 the putative cleavage site between gn and gc of khurv was found in position 319/320 aa (asa/en). this site corresponds to the cleavage site between nsm/gc of the orthobunyaviruses and the conservative amino acid a/е (vaa/ee in bunv). the size of the gn protein of khurv is the same as that of the other orthobunyaviruses, 320 aa. the similarity of khurv gn is 23à29% aa, on average, to that of the other orthobunyaviruses (28.5% aa to bunv). the size of the gc protein of khurv, 679 aa, is shorter than that of the other orthobunyaviruses (cf. 950 aa for the gc protein of bunv). the c-part (approx. 500 aa) of the gc protein, which includes the conservative domain g1 (pfam03557), has about 30% aa similarity to the c-part in the other orthobunyaviruses, whereas the n-part (approximately 170 aa) has no similarity to that of any proteins in the genbank database. the s-segment of khurv is 950 nt in length and encodes a nucleocapsid protein (227 aa). the similarity of the n protein to that of the orthobunyaviruses is 22à26 aa%. most orthobunyaviruses have an additional orf that encodes arthropod vectors. there are no known arthropod vectors of khurv; the virus has been isolated only from birds. more than 20,000 aedes, culex, and anopheles mosquitoes were examined during the survival period for arboviruses in this region, and no khurv isolations were obtained. the family ceratopogonidae of biting midges is a potential vector of khurv, but these insects have not been surveyed. vertebrate hosts. all isolations of khurv were obtained from birds. nine strains of the virus were isolated from coots (fulica atra). (one hundred seventeen birds were examined and were found to have an infection rate of 8.5%.) one strain was isolated from the pygmy cormorant (phalacrocorax pygmaeus). (two hundred eighty-nine cormorants, mostly ph. carbo, were examined and were found to have an infection rate of 0.3%.) the phlebovirus genus comprises about 70 viruses that are divided into two main groups based on their ecological, antigenic, and genomic properties: mosquito-borne viruses and tick-borne viruses. 1, 2 the genome of the phleboviruses consists of three segments of ssrna with negative polarity: l (about 6,500 nt), m (about 3,300à4,200 nt), and s (about 1,800 nt) (figure 8 .36). in general, the structure of the genome is the same for mosquito-borne and tick-borne phleboviruses, but the m-segment is shorter in tick-borne viruses and it does not encode the nonstructural protein nsm. 3 phylogenetically, the phleboviruses can be divided into two branches in accordance with their ecological features. the tick-borne phleboviruses comprise viruses of the uukuniemi group, the bhanja group, and the two novel related viruses severe fever with thrombocytopenia syndrome virus (sftsv) and heartland virus (hrtv), which form separate clusters and are unassigned to any group (figures 8.37à8.39). the uukv serogroup currently comprises 15 viruses, but the status of some of them may be revised with the accumulation of more genomic and serological data. history. bhanja virus (bhav) was originally isolated from haemaphysalis intermedia ticks that were collected from a paralyzed goat in the town of bhanjanagar in the ganjam district in the state of odisha, india, in 1954 and was assigned to the unclassified bunyaviruses. 1 in europe, the first isolation of bhav was obtained from adult haem. punctata ticks collected in italy (1967) and then in croatia and bulgaria. 2,3,4 palma virus (palv), a virus closely related to bhav, was isolated from haem. punctata ticks in portugal. 5 two viruses-kismayo virus (kisv) and forécariah virus (forv)-antigenically related to bhav were isolated in africa. 6, 7 these viruses have been merged into the bhanja group on the basis of their serological cross-reactions. 8, 9 in transcaucasia, bhav (strain leiv-1818az) was isolated from ixodidae ticks rhipicephalus bursa collected from cows in ismailli district, azerbaijan, in 1972 ( figure 8 .40). closely related to bhav, razv (strain leiv-2741arm) was isolated from ixodid ticks dermacentor marginatus collected from sheep near the village of solak in the razdan district of armenia ( figure 8 .40). 10, 11 serological methods (detection of antibodies in animals and humans) have shown that bhav circulates in many mediterranean countries, the middle east, asia, and africa. 12, 13 taxonomy. viruses of the bhav group are not antigenically related to any of the other bunyaviruses, but they were assigned to the phlebovirus genus on the basis of a genetic analysis of their full-length genome sequences. 14, 15, 16 weak antigenic relationships were found between bhav and sftsv, a novel phlebovirus isolated in china. 16, 17, 18 sftsv, in its turn, is antigenically related to viruses of the uukuniemi group. 19 the genomes of certain viruses of the the m-segment of bhav (3,307 nt) encodes a polyprotein precursor (1,069 aa) of the envelope glycoproteins gn and gc. like the m-segments of other tick-borne phleboviruses, that of bhav has no nsm proteins that are common to mosquitoes-borne phleboviruses. the predicted cleavage site between gn and gc proteins has been found by signal ip software (http://www.cbs.dtu.dk/services) to be in position 559/560 of the polyprotein precursor (motif mhmalc/cdesrl). a dipeptide cd in the cleavage site is also typical for sftsv and hrtv, which were associated with human disease in china and the united states, respectively. 17, 18, 22 other phleboviruses, including uukv and rvfv, contain a dipeptide cs in this position. the s-segment (1,871 nt) of bhav has two orfs (n and nss proteins) disposed in opposite orientations (an ambisense expression strategy) and separated by an intergenic spacer (139 nt) . the similarity of the nucleocapsid vertebrate hosts. the ungulates, including domestic cows, sheep, and goats, are apparently involved in the circulation of bhav. 24 usually, bhav infection in adult animals is asymptomatic, but it is pathogenic to young ones (lamb, calf, suckling mouse), causing fever and meningoencephalitis. 13 ,25à27 experimental infection of rhesus monkeys by bhav induced encephalitis. 28 several strains of bhav were isolated from the four-toed hedgehog (atelerix albiventris) and the striped ground squirrel (xerus erythropus) in africa. antibodies have been detected in dogs, roe deer (capreolus capreolus), and wild boars (sus scrofa). 12 human pathology. bhav infection in human is mainly asymptomatic, but several cases of fever and meningoencephalitis caused by bhav have been described. 29à31 history. gissar virus (gsrv) was isolated from argas reflexus ticks collected in a dovecote in the town of of gissar in tajikistan (38 40 0 n, taxonomy. the genome of gsrv (strain leiv-5995taj) has been sequenced. 4 phylogenetic analysis shows that gsrv is a member of the phlebovirus genus of the uukuniemi group (figures 8.37à8.39 ). gsrv is closely related to grand arbaud virus (gav), which was isolated from a pool of argas reflexus ticks collected in a dovecote near gageron in arles in the rhô ne river delta in the camargue region of france in 1966. 5 gav is classified as virus belonging to the uukuniemi group. 6 the identity of the nucleotide and amino acid sequences of gsrv and gav is 76% nt for the s-segment (94% aa for the nucleocapsid protein), 73% nt for the m-segment (82% aa for the polyprotein precursor of gn/gc), and 76% nt for the l-segment (87.5% aa for rdrp). arthropod vectors. regardless of their geographical distribution, gsrv and gav occupy a narrow ecological niche associated with ticks (argas reflexus) and birds (most likely, pigeons (columbidae)). in laboratory experiments, gsrv reproduced in a. reflexus ticks in 30 days with titers up to 2.0 log 10 (ld 50 )/20 mcl. 7 the distribution of argas reflexus ticks is limited between 51 n on the north and 31 n on the south. the a. reflexus metamorphosis cycle is about three years. the ticks inhabit pigeons' habitats, which are also used by other birds, such as swallows and swifts. a. reflexus larvae were found in europe on a rock swallow (ptyonoprogne rupestris), in egypt on a little owl (athene noctua), in israel on a rock dove (columba livia) and a fan-tailed raven (corvus rhipidurus), and in crimea on the western jackdaw (corvus monedula). the mass reproduction of mites in a dovecote has a negative impact on pigeons' bereeding behavior. worse, at night the ticks can go down to the living space and bite people if the dovecote is built into a house. 8 vertebrate hosts. the main vertebrates involved in the circulation of gsrv are apparently birds, particularly the columbidae. in laboratory experiments, gsrv was isolated from the blood of small doves (streptopelia senegalensis) 5, 9, 22, and 30 days after infection. the virus titer in the blood was 1.5à2.5 log 10 (ld 50 )/20 mcl, on average. serological examination of birds in tajikistan found antibodies to gsrv 2% of doves (columba livia). 7 history. khasan virus (khav) was isolated from haemaphysalis longicornis ticks collected from spotted deer (cervus nippon) in 1971 in the forest in khasan district in the south of primorsky krai, russia (figure 8.43 ). 1 morphologic studies showed that khav belongs to the bunyaviridae family. the virion of khav has structural elements (filaments up to 10 nm) that are typical for uukv, but no antigenic relationships between khav and uukv (as well as zaliv terpeniya virus, ztv) have been found. 1, 2 in a complement-fixation test, khav did not react with serum used in the identification of certain bunyaviruses, so it was categorized in with the unclassified bunyaviruses. 3 taxonomy. the genome of khav (strain leiv-prm776) was sequenced, and the virus was classified into the phlebovirus genus of the bunyaviridae family. 4 the genome of khav consists of three segments of ssrna whose size and orf structure correspond to the size and orf structure of the other tick-borne phleboviruses. a full-length pairwise comparison of l-segments revealed a 53.1% nt identity between khav and uukv and 45.3% between khav and rvfv. the predicted amino acid sequence of rdrp of khav has 48.6% and 35.3% aa identities with uukv and rvfv, respectively. as in other tick-borne phleboviruses, the m-segment of khav does not contain any nsm protein. the similarity between the m-segments of khav and uukv is 45.6% nt, and that between the polyprotein precursors of khav and uukv is 35.9% aa. the s-segment of khav has 35% nt (25.5% aa for the n-protein) identity, on average, with that of the uukuniemi group viruses and 35% nt (27.8% aa), on average, with the mosquitoborne phleboviruses. on phylogenetic trees constructed on the basis of the alignment of full-length genome segments, khav forms a distinct branch external to the uukuniemi group viruses (figures 8.37à8.39 ). at least 14 viruses with unsettled taxonomy are included in the uukuniemi group. 5 some of them can be considered variants of the species uukv, manawa virus (mwav), precarious point virus (ppv), and gav. two tick-borne phleboviruses, sftsv and hrtv, are more closely related to the bhanja group than the uukuniemi group. 6, 7 arthropod vectors. only a single isolation of khav was ever obtained, and the ecology of the virus has not been studied. haemaphysalis longicornis ticks, from which khav was isolated, are distributed in the far east of russia, the northeastern part of china, the northern islands of japan, korea, fiji, new zealand, and australia. 8 haem. longicornis ticks also are the main vector of sftsv (oterwise called huaiyangshan virus, hysv), which caused a large outbreak of febrile illness with a high mortality rate (30%) in 2009 in china. 9 vertebrate hosts. the principal vertebrate host of khav is unknown. khav was isolated from ticks collected on deer. 1 haemaphysalis longicornis ticks are repeatedly found on cows, goats, horses, sheep, badgers, and dogs. 8 history. the sandfly fever virus group includes naples and sicilian subtypes. 1 epidemics of the comparatively mild acute febrile disease of short duration brought on by these viruses in countries bordering the mediterranean have been known since the napoleonic wars. 2 the same disease was common among newly arrived austrian soldiers on the dalmatian coast each summer. 3 experiments conducted by an austrian military commission proved that the disease was caused by a filterable agent in the blood of patients and that the sandfly phlebotomus papatasi can serve as a vector to transmit the disease. 4 during world war ii, epidemics occurred among troops in the mediterranean and two antigenically distinct strains were isolated from the blood of patients in 1943 in sicily and naples. these strains have been designated the sandfly fever sicilian virus (sfsv) and sandfly fever naples virus (sfnv), with prototype virus tosv. 5,6 dr. a. sabin gave a clinical description of the disease and demonstrated that immunity developed to one type of virus does not protect from infection caused by the other type. later, several viruses related to sfnv (anhanga (anhv), bujaru (bujv), candiru (cduv), chagres (chgv), icoaraci (icov), itaporanga (itpv), and punta toro (ptv)) were isolated from humans and rodents in south america. 2, 3, 7 to date, viruses related to tosv have been found in all regions of the world, including the palearctic, neotropical, ethiopian, and oriental zoogeographical regions. 2 the prototype strain of tosv was isolated from phlebotomus papatasi sandflies in 1971 in monte argentario in central italy. 8 two viruses antigenically related to tosv-karimabad virus (karv) and salehabad virus (salv)-were isolated from phlebotomus flies collected in 1959 near karimabad village and salehabad village, respectively, in iran. 9, 10 several related viruses were isolated in the mediterranean: sandfly fever cyprus virus (sfcv; 11 adria virus (adrv, salehabad-like), isolated in saloniki (alternatively, thessaloniki), greece; 12 and massilia virus, isolated near marseilles, france. 13 epidemic outbreaks of sandfly fever whose agents could not be typified occurred in some central asian countries and in crimea during and after world war ii and in turkmenistan after the devastating earthquake of 1948. antibodies to sfsv, sfnv, and karv were found in the blood of humans in tajikistan, azerbaijan, and moldova. 14 antibodies were also found in wild animals in turkmenistan: the great gerbil (rhombomys opimus), the long-clawed ground squirrel (spermophilopsis leptodactylus), and the hedgehog (erinaceus auritus). three strains of sfnv and two strains of sfsv were isolated in 1986à1987 from the blood of patients in afghanistan. 14, 15 taxonomy. the genome of tosv consists of three segments of negative-polarity ssrna: l-segment (6,404 nt in length), m-segment (4,214 nt) and s-segment (1,869 nt). phylogenetic analysis revealed that viruses of the sfnv complex are divided into five genetic clades that differ in their geographical distribution: (i) from africa (saint floris virus and gordil virus (gorv)); (ii) from the western mediterranean (punique virus (punv), granada virus (grv), and massilia virus); (iii) tosv; (iv) viruses from italy, cyprus, egypt, and india; (v) strains from serbia and tehran virus. 16 distribution. sfnv and sfsv are distributed over those areas of the southern parts of europe and asia, and over those areas of africa, which are within the range of the vector. 15 ,17à22 tosv is distributed over italy; spain; portugal; the south of france; slovenia; greece, including the ionian islands: cyprus; sicily; and turkey. 13,17,23à32 both the naples and sicilian strains were isolated from the blood of patients with febrile illness in the vicinity of aurangabad, maharashtra state, in northern india. sandfly virus fever also circulates in western india, as well as in pakistan. 33 the cocirculation of two tosv genotypes was uncovered in the southeast of france. 13, 15, 33 a case of disease associated with tosv befell a tourist returning from elba to switzerland in 2009, and another struck an american tourist returning from sicily the same year. 27 tosv from france is genetically different from that in spain. 3, 13, 33, 34 periodic outbreaks of sandfly fever occurred in the first half of the twentieth century in some central asian republics, transcaucasia, moldova, and ukraine. arthropod vectors. the primary vector of sfnv and sfsv is phlebotomus papatasi; for tosv, the primary vectors are ph. perniciosus and ph. perfiliewi. the viruses can be transmitted by the transovarial route and therefore may not require amplification in wild vertebrate hosts. 35 the infection rate of sandflies can reach 1:220. 36 the active period of phlebotomus in the southern part of europe lasts from may to september. sandflies are peridomestic; the immature stages feed on organic matter in soil and do not require water, but are sensitive to desiccation and therefore are often found in association with humid rodent burrows. vertebrate hosts. the main vertebrates involved in the circulation of sfnv are rodents, particularly the great gerbil (rhombomys opimus) and the long-clawed ground squirrel (spermophilopsis leptodactylus), as well as a hedgehog (erinaceus auritus). the great gerbil is distributed over areas ranging from near the caspian sea to the arid plains and deserts of central asia. the northern border of the animal's distribution is from the 213 8.1 family bunyaviridae mouth of the ural river on northward to the aral karakum and betpak-dala deserts, to the southern coast of lake balkhash, and thence to northern china and inner mongolia. the habitats of rh. opimus are sandy and clayey deserts. tosv was isolated from the brain of the bat pipistrellus kuhlii. 8 animal and human pathology. sandfly virus fever does not cause disease in domestic or wild animals. the hosts of phlebotomus sandflies are usually rodents, which may develop antibodies. over 100 human experimental volunteers were infected at the time of world war ii. 36, 37 the incubation period is between 2 and 6 days, and the onset of fever and headache in those patients was sudden. nausea, anorexia, vomiting, photophobia, pain in the eyes, and backache were common and were followed by a period of convalescence with weakness, sometimes diarrhea, and usually leucopenia. viremia was present 24 h before and 24 h after the onset of fever. 37 tosv was established as the cause of one-third of previously undiagnosed human aseptic meningitis and encephalitis cases examined in central italy. sfcv was associated with a large outbreak in the ionian islands of greece. 28 adrv is associated with serious illness with tonic muscle spasms, convulsions, difficulty urinating, and temporary loss of sight. human disease frequently goes unrecognized by local health-care workers. studies of antibodies in people indicate that the most infections occur in children. when large numbers of unimmunized adults are introduced into an endemic area, the incidence of disease can be high. human exposure to sandflies can be reduced by repellents, air-conditioning, and screens on windows. because sandflies have a flight range of not more than 200 m, human habitats can be constructed at a distance from potential domestic sandflies' breeding places, such as chicken houses and quarters for other farm animals. 19 history. uukv was originally isolated from ixodes ricinus ticks collected in 1959 from cows in southeastern finland. 1,2 antigenically similar isolates (strains leiv-540az and leiv-810az) have been obtained from blackbirds (turdus merula) and i. ricinus ticks collected in the foothills of the talysh mountains in the southeast of azerbaijan in 1968 and 1969, respectively. 3à5 uukv is distributed in the mid-and southern boreal zones of fennoscandia and adjacent areas of the russian plain. twelve strains of uukv were isolated from i. ricinus ticks (the infection rate was 0.5%), and one strain from aedes communis mosquitoes, in landscapes in the mideastern region of fennoscandia. 6, 7 three strains were isolated from i. persulcatus ticks collected in belozersky district, vologda region, russia, in 1979. 8, 9 uukv was also isolated from the mosquitoes ae. flavescens and ae. punctor in the west of ukraine, as well as at the border between poland and belarus. 10, 11 twenty-eight strains of uukv were isolated from i. ricinus ticks collected in lithuania and estonia in 1970à1971. 6,7,12à14 uukv was isolated as well from birds and i. ricinus ticks in western ukraine and belarus. 11, 15, 16 in central europe, uukv was found in the czech republic, slovakia, and poland. 17à20 the prototypical strain leiv-21c of ztv was isolated from ixodes uriae ticks collected in 1969 in a colony of common murres (uria aalge) in tyuleniy island in zaliv terpeniya bay in the sea of okhotsk). 21, 22 in accordance with the results of electron microscopy, ztv was assigned to the bunyaviridae family. complement-fixation testing revealed that ztv is most closely related to uukv, but the two viruses are easily distinguishable in a neutralization test. 21, 22 more than 60 strains of ztv were isolated from i. uriae ticks collected in colonies of seabirds on the shelf and islands of the sea of okhotsk, the bering sea, and the barents sea (table 8 .23, figure 8 .44). 9, 21, 23, 24 two strains of ztv were isolated from i. signatus ticks collected on ariy kamen island in the commander islands, but their infection rate was less than 1:10,000 (,0.01%). 9 a similar virus was found in norway. 25 one strain of ztv (leiv-279az) was isolated from the mosquito culex modestus collected in 1969 in a colony of herons (genus ardea) in the district of kyzylagach in the southeastern part of azerbaijan (figure 8.44 ). 3 natural foci of ztv and uukv associated with bloodsucking mosquitoes (subfamily culicinae) are found in continental areas in the european part of russia, particularly murmansk region. 7 taxonomy. the viruses of the phlebovirus genus can be divided into two main ecological groups: those transmitted by bloodsucking mosquitoes (subfamily culicinae) and midges (subfamily phlebotominae), together called mosquito borne, and those transmitted by ticks (tick borne). uukv is a prototypical virus of the uukuniemi antigenic group, which includes at least 15 related tick-borne phleboviruses (figures 8.37à8.39 ). 26 the genome of uukv consists of three segments of ssrna: an l-segment 6,423 nt long, an m-segment 3,229 nt long, and an s-segment 1,720 nt long. the m-segment of uukv, and indeed, that of all tick-borne phleboviruses, is shorter than the m-segment of mosquito-borne phleboviruses, owing to the absence of the nonstructural protein nsm, which is common in the mosquitoborne phleboviruses. originally, ztv was described as a virus closely related to uukv. a full-length sequence comparison showed that the similarity of ztv to uukv is 77.3% nt identity of the l-segment (90.9% aa of rdrp) and 70.9% nt identity of the m-segment (81.5% aa). arthropod vectors. most isolations of uukv and ztv were obtained from ixodes ricinus and i. uriae ticks, respectively. the infection rates of nymphs and larvae of i. uriae are 5 and 13 times lower, respectively, than that of the imago. these rates indicate a high frequency (8à10%) of transovarial transmission of ztv. 7, 9 probably, ztv has a more pronounced ability to replicate in mosquitoes that are active in the subarctic climate zone (tundra landscapes) in july through the first half of august at temperatures sufficient for the accumulation of virus in the salivary glands. 7 islands. in the murmansk region, which lies to the north of the european part of russia, antibodies were found in 6% of common murres (u. aalge), 4% of black-legged kittiwakes (rissa tridactyla), and 1% of voles (microtus oeconomus). 7, 9 apparently, ruminants could be infected by mosquitoes or by eating fallen birds. on the north coast of the kola peninsula, antibodies were found in 6% of thick-billed murres (u. lomvia), in 7% of blacklegged kittiwakes, and in 1% of voles. 7, 9 in central and eastern europe, a number of vertebrate hosts are involved in the circulation of uukv: forest rodents (myodes glareolus, apodemus flavicollis) and terrestrial passerine birds-the blackbird (turdus merula), pale trush (t. pallidus), ring ouzel (t. torquatus), european robin (erithacus rubecula), hedge sparrow (prunella modularis), wheatear (oenanthe oenanthe), european starling (sturnus vulgaris), carrion crow (corvus corone), magpie (pica pica), brambling (fringilla montifringilla), hawfinch (coccothraustes coccothraustes), yellow bunting (emberiza sulphurata), turtle dove (streptopelia turtur), and ringnecked pheasant (phasianus colchicus). 20,28à32 viremia and long-term persistence of the virus were demonstrated in experimentally infected birds of many species. specific antibodies were detected in cows and reptiles. human pathology. an association was revealed between uukv and different forms of disease, including neuropathy. 33, 34 a serological survey of 1,004 people in lithuania concluded that antibodies existed in 1.8à20.9% of the population. human antibodies to uukv were detected in less than 5% of the human population in central europe 33à35 and 13à14% in belarus. 16 the people living in the tundra landscape had antibodies to ztv in 3.3% of cases, while in the forest no such antibodies were detected (via a neutralization reaction). (table 8 .24). in previous studies, rukv was mistakenly included in the sakhalin serogroup in the nairovirus genus. 1 taxonomy. the genome of komv (strain leiv-13856) and rukv (strain leiv-6269) were completely sequenced, and the two viruses were classified into the phlebovirus genus. 2,3 a full-length comparison showed that the genetic similarity between komv and rukv is 93.0à95.5% nt. among other tick-borne phleboviruses, komv and rukv are most closely related to mwav, which was isolated from argas abdussalami ticks in 1964 in pakistan. 4 the similarities of the genomes of komv and rukv to that of mwav are 67.1% nt for the l-segment (73.0% aa for rdrp), 59.6% nt of the m-segment (58% aa for the polyprotein precursor), and 66.8% nt for the s-segment (58.4% aa for the n-protein). in phylogenetic trees, komv and rukv were placed into the uukuniemi group (figures 8.37à8 .39). 5 the ecology and area of distribution of komv and rukv are the same as those of ztv, which is closely related to uukv. several strains of ztv isolated on the commander islands were sequenced, and no reassortants of ztv with komv were found. 6, 7 arthropod vectors. all isolations of komv and rukv were obtained from ixodes uriae ticks, the obligate parasite of alcidae birds. the commander islands are located on the border of the temperate and subarctic climatic zones, and many different viruses belonging to the bunyaviridae (ztv, sakv, pmrv), flaviviridae (tyuleniy virus, tyuv), and reoviridae (okhv) families have been isolated from i. uriae ticks collected from birds living in colonies there. 8à11 note that the komv infection rate of the i. uriae ticks in the commander islands is 10 times less than the ztv (1:900) and tyuv (family flaviviridae, genus flavivirus) infection rates of the same ticks. vertebrate hosts. the main vertebrate host of komv and rukv is apparently alcidae birds, especially the common murre (uria aalge), but their involvement in the circulation of komv and rukv has not been studied sufficiently. human pathology. uukv group viruses, in general, do not play a role in human infectious pathology, although serological studies have detected antibodies to various viruses of this group in people. the flaviviridae family (from the latin flavus, "yellow," as well as from yellow fever virus (yfv)) includes three genera: flavivirus, pestivirus, and hepacivirus. 1 the flaviviridae are small (40à60 nm) enveloped viruses. the genome is represented by ssrna the flavivirus genus includes more than 70 viruses classified into 15 antigenic groups. 1, 3 the flavivirus virion is spherical (50 nm) and consists of a nucleocapsid (30 nm) and a lipid bilayer envelope covering it. the lipid envelope contains two transmembrane glycoproteins: m (matrix protein, 8 kd) and e (envelope protein, 50 kd). the genome of the flaviviruses is a single molecule of rna about 11,000 nt in length and capped on the 5 0 terminus. the genomic rna encodes a long orf of a polyprotein precursor flanked by 5 0 and 3 0 untranslated regions. mature viral proteins are produced during a complex process of proteolytic cleavage of the polyprotein precursor by cellular and viral proteases. structural proteins (core, m, and e) occupy one-third of the rna (the n part of the polyprotein) on the 5 0 part of the genome, followed by nonstructural proteins (ns1-ns5b) (figure 8 .46). 2, 4 most of the flaviviruses are arboviruses; that is, they can be transmitted to vertebrate hosts by bloodsucking arthropod vectors (figure 8.47 ). approximately 50% of known flaviviruses are transmitted by mosquitoes, about 30% by ticks. the arthropod vectors of some flaviviruses are unknown. there is also a group of flaviviruses that infect only insects and not vertebrates. some flaviviruses (e.g., west nile virus, wnv) have ecological plasticity and can be transmitted either by mosquitoes or by ticks. flaviviruses are distributed over all continents, with mosquito-borne viruses found mainly in regions with an equatorial and tropical climate and tick-borne viruses found mostly in regions with a temperate climate zone. many flaviviruses are associated with birds, which can transfer them during the birds' seasonal migration. flaviviruses belongs to natural foci zoonoses. certain flaviviruses, such as yfv, dengue virus (denv), and west nile virus (wnv), pose a serious threat to humans. 5à7 history. the first hint that omsk hemorrhagic fever (ohf) was etiologically linked figure 8 .48) an area with a wide network of lakes. about 200 cases with two lethal outcomes ("atypical tularemia" and "atypical leptospirosis") were investigated (without the expedition produced prodigious results: the prototype strain ohfv/kubrin was isolated from the blood of one patient; the mechanism of transmission of the virus by the ixodidae tick dermacentor reticulatus was established; the epidemiological and clinical features of ohf, as well as its pathogenesis and pathomorphology, were described; and inactivated vaccine from mouse brain was developed and prepared for epidemiological trials. 5 later, the role of another species of ixodidae ticks (d. marginatus) as an ohfv vector was revealed. 8, 9 taxonomy. ohfv belongs to the phylogenetic branch of the mammalian tick-borne virus group (figure 8 .47). the ohfv genome has a length of 10,787 nt, and its organization is common to the flaviviruses. two genotypes of ohfv are known today: prototypical strains for the first one are ohfv/kubrin and ohfv/bogolubovska, which have an extremely small genetic distance between them; the prototypical strain for the second genotype is ohfv/uve. 10à12 only six nucleotide substitutions, which encode four amino acids, have been found in the entire genome. three of four amino acid changes were located in the envelope glycoprotein e. 11 phylogenetic analysis based on a comparison of partial sequences of the e gene available in genbank showed that ohfv isolates can be divided to three genetic lineages (figure 8 .49). the genetic diversity among strains of different lineage is up to 11.8%. arthropod vectors. the natural foci of ohfv are found in the forestàsteppe landscape zone of western siberia, an area with numerous bogs and a wide network of lakes within the omsk, novosibirsk, kurgan, and tyumen regions (figure 8 .48). the natural foci border the area of distribution of tbev, and the two virus's natural foci are intermingled. 13à15 the principal ixodidae tick vectors for ohfv are dermacentor pictus (in the northern forestàsteppe subzone) and d. marginatus (in the southern forestàsteppe subzone). 3, 8, 9 the infection rate of d. pictus in epidemic years reaches 8%, in interepidemic years 0.1à0.9%. the main host for preimago phases of d. pictus is the narrow-headed vole (microtus gregalis). this species of rodent is host to 70à90% of d. pictus nymphs and larvaein the northern forestàsteppe subzone. in 1959à1962, when the number of microtus gregalis voles fell significantly, there was a concomitant decrease in the number of d. pictus ticks in the center of an epidemic zone that was accompanied by a sharp decrease in the infection rate of ticks and an attenuation of the meadow natural foci of ohfv. in some of those years, however, a high number of ixodes apronophorus, all phases of which feed on the water vole (arvicola terrestris), become involved in the virus's circulation on a par with d. pictus ticks. ar. terrestris makes fodder migrations in juneàaugust from damp locales (where their infection takes place) to coastal meadows (where peak activity of the larvae and nymphs of d. pictus is observed during those months). small animals living in those meadows become infected as they feed on the d. pictus larvae and nymphs. in damp locales, i. apronophorus could infect muskrats. also, d. marginatus, whose optimum zone lies in a steppe landscape belt, plays some (though largely insignificant) role in the lake areas of the southern forestàsteppe subzone. 16 during epizootic and epidemic activity of ohf natural foci, gamasidae ticks, as well as aquatic organisms belonging to the hydracarinae, take part in ohfv circulation. their involvement is confirmed by the identity of isolated strains with those isolated from muskrats and sick humans. experiments with experimentally and spontaneously ohfvinfected gamasidae ticks testify to the ability of longitudinal (more than six months) virus preservation. 17 vertebrate hosts. the principal vertebrate host of ohfv, which is able to directly infect humans, is the muskrat (ondatra zibethicus). this species was introduced into western siberia from canada in 1928. their population density reached a modern-day high in the 1940s. close interactions among o. zibethicus and local populations of arvicola terrestris emerged. ar. terrestris has periods of rapid population growth followed by epizootics of tularemia, leptospirosis, and ohfv. muskrats suffered these epizootics together with other local species of rodents: microtus oeconomus, m. gregalis, myodes rutilus, apodemus agrarius, and ar. terrestris. 13 the ofv infection rate among muskrats is about 15% in both the autumnàwinter and the springàsummer periods. 16 latent infection was established in all rodents except the muskrat. 18 ohfv was detected in birds and in mosquitoes, but the role of these two animals in virus circulation is not clear. 18à21 epidemiology. ohfv is transmitted both by ixodidae tick bites and as the result of direct contact with infected muskrats, their flesh, and fresh fells. 1, 5 ohf morbidity during 1945à1949 reached 1.5à5.0%. then there was a gradual decrease down to single cases. most ohf cases (96.8%) were detected in the lake forestàsteppe, in the south of the forestàsteppe landscape zone, which occupies 14.5% of the territory where 15.3% of country people in the omsk region live. the northern forestàsteppe landscape zone is the youngest landscape of western siberia, having evolved in place of the former southern taiga landscape zone. 22, 23 in the south of western siberia, the following territorial zones can be marked out: (i) the 223 8.2 family flaviviridae preferred territory of tick-borne encephalitis virus (tbev) (the southern taiga); (ii) intermediate territory (the boundary of the southern taiga with the northern forestàsteppe); (iii) the preferred territory of ohfv (the northern and southern forestà steppe); and (iv) the territory of sporadic cases of ohf (part of the southern forestàsteppe and steppe). 13, 23 in the first zone, more than 90% of all cases of tbe in western siberia are registered and only single ohf cases are found; in the second zone, 1% each of cases of tbe and ohf; in the third zone, 4% of tbe and 96% of ohf; and in the fourth zone, 4% of tbe and single cases of ohf. 13 the seasonal incidence of ohf distinctly correlates with the activity of the principal ixodidae tick vectors. cases (a few) of ohf acquired by direct contact with muskrats occur mainly during the season in which the animals are hunted, in octoberàjanuary. in the springà summer season, ohf cases occur chiefly in rural areas. the age of patients ranges from 5 to 70 years, but cases occur mainly among middle-aged persons (40à50 years old). in the autumnàwinter period, ohf occurs mainly among muskrats trappers (60%), adult members of their families (28%), and children (12%). it appears that all patients infected directly from muskrats develop symptomatic illness. seroprevalence ranges from 0 to 32% in populations of endemic regions. 3, 7, 23 in the last decade of the twentieth century, an increase in ohf natural foci activity took place in the tyumen (1987), omsk (1988, 1999à2007), novosibirsk (1989à2002; regular epidemic activity took place on the territory of only four administrative districts), and kurgan (1992) regions. in the absolute majority of laboratoryconfirmed cases, the nontransmissive pathway (direct contact with muskrats) of the infection dominated. 17 pathogenesis is determined first of all by the destruction of capillaries, the vegetative nervous system, and the adrenal glands. 16, 24 clinical features. the incubation period of ohfv is 2à4 days long. the disease begins abruptly, with fever, head and muscular pain, hyperemia, and injection in the sclera. the body temperature increases up to 39à40 c and stays that way for 3à4 days, then decreases a little and critically falls on the 7th to 10th day after symptoms appear. from the first days of the illness, there are diapedetic bleedings, especially in the nose. recovery is usually complete, without any residual phenomena; lethal outcomes are possible, but are rare. 16,24à26 control and prophylaxis. ohfv survives up to 20 days in lake water. water can be contaminated by urine and feces of the infected muskrats or some other rodents. the water pathway in human infection has been discussed in the literature. 13, 14 prevention of the infection depends on the use of protective respirators and rubber gloves in processing muskrat pelts and on personal protective measures against tick bites. tbe vaccine offers a high degree of protection against ohf. 10, 23 cases of laboratory-acquired ohf have been reported in unvaccinated persons, and tbe vaccine is recommended for laboratory personnel working with either virus. 23 interferon and its inductors have shown a high efficiency in preventing ohf in experiments using animal models. 27 the genome of powv is a about 10,835 nt in length. the virus comprises two genetic lineages, formed by powv (lineage i) and the closely related deer tick virus (dtv, lineage ii) (figure 8 .51). 8 phylogenetic analysis based on partial sequences of the e gene showed that the population of powv in russia has a low genetic diversity. 9 the strains of powv isolated in russia have a high genetic similarity to the strains of lineage i isolated in north america. a full-length genome comparison revealed that far eastern isolates (leiv-3070prm, spassk-9, and nadezdinsk-1991) have a 99.5% identity with strain powv/lb from canada (figure 8.51) . arthropod vectors. powv was isolated from ixodidae ticks collected in the russian far east and in the u.s. states of california, colorado, connecticut, massachusetts, south dakota, and west virginia. serological investigations of wild mammals indicate that powv also circulates in the canadian provinces of alberta, british columbia, and nova scotia. 3,10à12 in north american natural foci, powv was isolated from ixodes cookei, i. spinipalpus, i. marxi, and dermacentor andersoni ticks. 3, 10, 11 in the far east, known vectors of powv are haemaphysalis longicornis, haem. concinna, haem. japonica, d. silvarum, and i. persulcatus ticks. 5, 9, 13, 14 transphase and transovarial transmission of powv in ixodidae ticks has been established. vertebrate hosts. in north america, powv was isolated from wild mammals: the woodchuck (mormota monax, the main reservoir), american red squirrel (tamiasciurus hudsonicus), deer mouse (peromiscus maniculatus), red fox (vulpes fulva), eastern gray squirrel (sciurus carolinensis), north american porcupine (erethizon dorsatum), striped skunk (mephitis mephitis), raccoon (procyon lotor), long-tailed weasel (mustela frenata), and gray fox (urocyon cinereoargenteus). 2, 4, 15 infection of wild vertebrates most often is inapparent. 2, 10 in the south of the russian far east (in primorsky krai), powv was isolated from aquatic birds: the common teal (anas crecca) and the mallard (anas platyrhynchos). 9, 13, 14, 16 epidemiology. human infections of powv were reported in canada (ontario and quebec), the united states (new york and pennsylvania), 2 and russia (primorsky krai). 14, 17, 18 nevertheless, human infection rarely develops. clinical features. the clinical picture of developing meningitis and encephalomeningitis includes high temperature, dryness in the gullet, drowsiness, headache, disorientation, convulsions, vomiting, difficulty breathing, coma, and paralysis, with 11% lethality in the severe phase of the disease. autopsy has revealed widespread perivascular and focal parenchymatous infiltration. in 50% of recoveries, consequent damage to the cns develops, which could lead to death in 1à3 years. 2, 18 control and prophylaxis. the vaccine against tbev is not effective against powv. 2 history. in 1931à1934, the russian military medical doctoràneuropathologist a.g. panov, together with his colleagues a.n. shapoval and d.a. krasnov, described a neuroinfection with a high level of mortality in the far east. this neuroinfection later was called "springà summer encephalitis." 1,2 during field expeditions in 1937à1940, the historical strain tbev/ sofjin was isolated from the brain of a patient with encephalitis who died in khabarovsk krai (figure 8.52) . in that period, the main vector of tbev-ixodes persulcatus tickswas established, epidemiological peculiarities of tbe were studied, and the first anti-tbev vaccine was developed on the basis of intracerebrally infected mouse brain and was successfully used in medical practice. 2 complex expeditions were undertaken by a number of prominent virologists (l.a. zilber (figure 2.9 strain tbev/leiv-1380kaz (the former aav) was isolated from ixodes persulcatus in the low-mountain part of southeastern kazakhstan (alma-ata region) in 1977. 11 preliminary investigation revealed a one-sided antigenic relation between aav and powv. 12 aav was associated with human cases of meningitis. specific antibodies to aav were found among ground squirrels (citellus fulvus), agricultural animals, and humans. later, the aav genome was sequenced (genbank id: kj 744033). 13 a full-length genome comparison showed that aav has the highest similarity (94.6% nt and 98.3% aa identities) to the tbev/ chita-653, tbev/irkutsk-12, tbev/aino, and tbev/vasilchenko strains belonging to the siberian genotype (figure 8.53) . recent genetic studies of tbev revealed two additional genotypes of this virus on the territory of eastern siberia (irkutsk region): for the first one, only a single strain is known today; for the latter, there are five strains in mongolia. 14 thus, tbev has a high level of genetic diversity in northern eurasia. tbev-sib genotype dominates in europe, western siberia, and eastern siberia, tbev-fe in the far east. 15, 16 the tbev-fe genotype, which was widely distributed in siberia and northeastern europe, is now being displaced by tbev-sib. tbev-fe strains are often pathogenic to laboratory mice, whereas tbev-sib frequently provokes severe and lethal disease. 15 local populations of all genotypes of tbev could be stable for a long time. 16 distribution. tbev is distributed within the areas of distribution of its main vectors: ixodes persulcatus and i. ricinus ticks (figure 8 .54-see details in the detailed work of e.i. korenberg 17 norway; 29à31 in the rest of europe, the czech republic, 8, 32 slovakia, 6, 33, 34 bulgaria, 35 hungary, 36, 37 poland, 38, 39 croatia, 40 latvia, 41 lithuania, 42 estonia, 43, 44 denmark, 31 germany, 45à48 austria, 49 slovenia, 50 france, 51 italy, 52,53 and spain 54 (table 8 .25); and in asia, the russian far east and siberia, 1,16,55 japan (hokkaido), 55 north and south korea, 56, 57 china, 58 mongolia, 59 kazakhstan, 13 and kyrgyzstan. 60 arthropod vectors. natural tbev infection has been observed in 16 species of ixodidae ticks. the principal arthropod vectors for tbev in russia are the ixodidae ticks ixodes persulcatus (in the far east, siberia, and the north of the european part of the country) and i. ricinus (in the south of the european part) (figure 8.54 ). 69 the northern boundary of i. persulcatus and i. ricinus lies within the limits of an effective temperature sum isoline of about 1,000à1,300 c (the middle taiga landscape belt). the most suitable climatic conditions for these ticks are within the south taiga. imago tick activity begins in the third d decade of april and reaches a maximum in the second and third decades of may or in the first and second decades of june, with activity beginning to decrease in the third decade of june. this time frame correlates with morbidity dynamics having an 8-to 10-day lag (figure 8 .55). 70 the ecological links of tbev during its circulation in natural foci are extremely diverse as the result of wide distribution of this virus (figures 8.52 and 8.54 ). ixodidae ticks, mainly i. persulcatus, are the natural reservoir of tbev and the core of natural foci. 12, 62, 71, 72 from the very beginning of the tick's larval stage, a suctional, tarlike liquid appears around the hypostome and becomes rosin. 62, 73 the quantity of virus in this rosin plug is comparable to that in the tick's body (10 3 à10 4 pfu/mcl). 74 the place of suction on the body of the host is significant for the development of infection; for example, suction in the axillary hollow results in the highest lethality (16.1%, 1.5 times more in comparison to suction in the neck and in the head. 73 ticks become infected as they suck blood from a vertebrate host with a level of viremia that is equal to or higher than the threshold required for infection. ticks can also become infected from an uninfected vertebrate host as they suck blood together with infected ticks. 73, 75 transovarial and transphase transmission of tbev has been described in the literature; nevertheless, the effectiveness of vertical transmission of tbev is low. (about 1% of progeny turn out to be infected). 52, 76 the sexual pathway of tbev transmission from male to female is quite effective (about 50%). 77à79 the aggressiveness and activity of tbev-infected ixodidae ticks increases with the tbev titer in their bodies. 62, 75 infected ticks have been found on the clothing of figure 8.55 trends in the incidence of tbe in russia, by month (as a percentage of the amount of disease for the year, according to long-term data). humans at a fequency 5à20 times higher than uninfected ticks have been found. 48, 62, 75 tbev has been isolated from the mosquitoes anopheles hyrcanus in kyrgyzstan 80 and aedes sp. in western siberia. 81 the strain tbev/malyshevo was isolated from aedes vexans nipponii mosquitoes collected in 1978 on the coast of petropavlovskoe lake in khabarovsk krai in the russian far east (48 40ʹn, 135 41ʹe ). 82à84 a preliminary investigation 82 concluded that this strain belonged to negishi (negv) virus, 85 and later the possibility was discussed that the strain belonged to a separate, malyshevo virus. then, phylogenetic analysis using a next-generation sequencing approach revealed that malyshevo is a strain of tbev and is closely related to tbev strains isolated in the far east: tbev/1230, tbev/ spassk-72, tbev/primorye-89. 13 tbev has been isolated many times fromticks and fleas of the superfamily gamasoidea living in nests of rodents and birds (table 8 .27), even during the winter period. 2,47,86à89 vertebrate hosts. hosts for the preimago stage of ixodidae ticks-asian chipmunks (tamias sibiricus), shrews (members of the soricidae family), bank voles (myodes glareolus), field voles (microtus agrestis), mountain hares (lepus timidus), and 74 species of birds (table 8 .28)-have great significance in tbev circulation. 10, 12, 62, 64, 71, 72, 90, 91 persistent tbev infection in bank voles and field voles has been found during the winter period. 26 infection among vertebrates occurs mainly by tick bites. in rare instances, alimentary transmission of tbev through milk containing viruses is possible. 34, 92 epidemiology. there are two basic modes of human infection by tbev: (i) as the result of being bitten by infected ixodidae ticks (the main mode); and (ii) as the result of consuming infected raw goat, sheep, and cow meat, milk, or dairy products (mainly in natural foci linked to ixodes ricinus). 23, 32, 93 the latter pathway of tbev distribution often involves whole families. as much as 70% of cases in belarus have been alimentary. 70 tbev can persist in milk at 60 c for more than 10 min, and some of the viruses can remain viable even after pasteurization at 62 c for 20 min. nor is tbev inactivated after 24 h at 4 c and ph 2.8. many laboratory infection cases (usually by aerosol) have been described. several hundred cases are recorded in europe (table 8 .25) and in russia (table 8.26 ) each year, with considerable interannual variation. 17,70,94à96 the highest level of tbe morbidity is registered in the baltic states (latvia, 6.2à10.8 per 100,000 population); lithuania, 6.5à13.5; and estonia, 10.4à13.5) and in slovenia (10.2à18.6) and the czech republic (5.0à10.0). in neighboring austria, where the vaccination rate is higher, the index is lower (0.6à1.2). 97 seasonal tbe morbidity in russia is connected with seasonal activity of the ixodidae tick vectors (figure 8.55) . the risk of infection depends upon the frequency of tick bites, which is different for populations living in the different landscape belts. results of an investigation of almost 200,000 people demonstrate that the highest risk is for the population living in the southern taiga belt, where about 20% of adults were found to have tick bites during one epidemic season (table 8. in rural localities of the southern taiga belt, about half of schoolchildren and about 80% of adults have antibodies to tbev. for comparison, only 14à20% of adult citizens of kemerovo, a city of about half a million in western siberia, and 2à3% of citizens of moscow have antibodies specific to tbev (table 8.29) . 98 a mathematical model for evaluating the infection rate and the probability of developing the disease as a function of the density of the tick population, its infection rate and biting activity, and the level of the immune human layer was developed by d.k. lvov and coauthors. 98à102 the same approach, which is also suitable for other arboviral infections, was used for landscape-epidemiological zoning of tbev natural foci in altai krai in the southern part of western siberia: more than 10,000 residents living in the different landscape belts on a territory about 250,000 km 2 were tested by serological methods (figure 8.56) . the tests produced a good fit between calculated and registered morbidity data (table 8.30) . pathogenesis. tbe can be realized in several pathogenetic variants. an inapparent clinical form is characterized by short-term localization of tbev in lymph nodes and immune cells, as well as by extranervous reproduction without viremia. infection is terminated by the development of stable immunity. about 95% of cases of infection are inapparent. 102 clinical fever is expressed as a common infectious process, but both the central and the peripheral nervous system are involved in the pathology. 103 neuroinfection is characterized by lesion of the envelope and substance of the spinal cord and cns. clinical features. the incubation period ranges from 1 to 30 days, but usually is 7à12 days. the onset of illness in typical cases is abrupt and with a headache. the temperature clinical symptoms of tbe, as well as the severity of the disease, are at least partially determined by biological properties of the virus. 104 there are two main clinical forms of tbe: the far eastern variety, associated with far eastern and siberian strains of the virus, and the european variety (also known as western biphasic meningoencephalitis or biphasic milk fever), associated chiefly with european strains. human disease of the first type is usually clinically more severe in the acute phase, but is associated with a lower rate of chronic cns sequelae. the first phase starts with sudden fever, flulike symptoms (pronounced headache, weakness, nausea, myalgia, arthralgia), and conjunctivitis. the second phase appears after 4à7 days of apparent recovery, but then the cns is affected (meningoencephalitis appears), accompanied with fever, retrobulbar pain, photophobia, stiff neck, sleeping disorders, excessive sweating, drowsiness, tremors, nystagmus, meningeal signs, ataxia, pareses of the extremities, dizziness, confusion, psychic instability, excitability, anxiety, disorientation, and/or memory loss. tbev produces diffuse degenerative changes in neurons, perivascular lymphocytic infiltration, and damage to purkinje cells in the cns. mortality ranges from 1% (tbev-eur), to 8% (tbev-sib), to 20à40% (tbev-fe). convalescence is prolonged, and neurological and psychotic sequelae often include paresis and atrophic paralysis of the neck and shoulders. 27, 45, 104 a chronic form of the disease occasionally combines with a progressive course (called kozhevnikov's epilepsy), in which progressive neuritis of the shoulder plexus, multiple sclerosis, and progressive muscle atrophy often develop. 105, 106 the chronic form is registered in 1à2% of all tbe cases and is said to be the result of virusàimmunity interactions. 19 many authors have noted a decreasing number of severe tbe cases. 103 diagnostics. laboratory diagnosis of tbe involves both serological (elisa, hemagglutination inhibition test (hit), neutralization testing) and virological methods (virus isolation using a biological model of intracerebrally inoculated newborn mice, 5à6 g mice, cell culture), as well as highly sensitive rt-pcr and real-time rt-pcr. control and prophylaxis. specific and nonspecific prophylaxis tools are highly efficient if they are utilized correctly. personal safety includes protection against ticks. vaccination against tbev has a long history of success. mass vaccination of populations in the endemic territory is necessary. a full course of vaccination provides 98% safety. 102 all vaccines produced in russia are effective in the entire area of distribution of tbev, independently of the strain used to prepare the vaccine. vaccination has reduced tbe morbidity down to single cases in austria, the czech republic, and slovakia. 107 single cases of tbev among vaccinated persons need to be investigated because possible causes are personal peculiarities of the immune system and errors in the control of vaccine production. 108 the presence of brain tissue in vaccines produced on the basis of intracerebrally inoculated newborn mice was a source of danger for a long time: demyelinating encephalitis could develop. this danger was eliminated after vaccines were developed which used tbev strains that reproduced in cell cultures. in the 1960s, cell culture vaccines against tbev were developed by e.n. levkovich history. japanese encephalitis virus (jev) was originally isolated by h. hayashi in 1933 from a patient who died with encephalitis and then, again, in 1935 from a patient who died with a fever in tokyo. 1, 2 before that, however, japanese encephalitis (je) epidemics was documented in japan in 1903 and onward as "ioshiwara cold." in the south of the russian far east, strains of jev were known since the end of the 1930s (figure 8.57 ). je played a role in the historical events of world war ii. american military personnel massed on okinawa and preparing to invade japan were demoralized by an outbreak of encephalitis among the indigenous people. a fictionalized account of the risk from je for american soldiers during world war ii underscores the military risk. 3 taxonomy. phylogenetic studies indicated that jev isolates be divided into five genotypes, the distributions of which overlapped (figure 8.58 ). genotypes i, ii, and iii are most prevalent and are spread throughout asia (japan, china, india, korea, malaysia, and vietnam), the far east of russia, and northern australia. genotypes iv and v are rarer and were isolated in indonesia and india, respectively. genotypes i and iii are found mostly in temperate zones, whereas genotypes ii and iv predominate in tropical zones. 4à6 genetic diversity between strains of the different genotypes ranges from 9.1% to 16.6%. arthropod vectors. jev circulation in the equatorial and subequatorial climatic zones is year-round and is seasonal in the tropical, subtropical, and temperate belts, with a peak at the end of summer and the beginning of fall. jev is brought from the equatorial and tropical climatic belts to the subtropical and temperate belt during the spring migration of birds. about 30 species of mosquitoes are able to transmit jev; nevertheless, only some of them are effective vectors. the main vector in japan, the philippines, the korean peninsula, china, the indochinese peninsula (except malaysia), indonesia, sri lanka, india, and nepal is epidemics usually develop after plentiful precipitation and a long rise in environmental temperatures until they are no less than 25 c (but within the range 25à32 c). 7 for a long time, the main vector for jev in the south of primorsky krai in russia was culex tritaeniorhynchus. in the 1940s, as a result of both improvements in agriculture and meteorological changes, this species of mosquitoes consisted about 80% of all field collections. in subsequent years, however, their numbers abruptly declined, and by the 1960s the species represented only 0.15à0.75% of all mosquitoes collected. cx. pipiens is an accessory vector, and aedes togoi transmits jev in seashore areas. jev was also isolated in 1989 from ae. vexans. 8, 9 vertebrate hosts. aquatic and semiaquatic birds (especially herons) have the main significance in the natural cycle of jev circulation. regular transfer of jev in migratory birds from endemic territories with year-round circulation of the virus to regions of the southern part of the temperate climatic belt (in particular, the southern part of primorsky krai, to the south from lake khanka 11 ) is likely. 10 jev transfer over hundreds of kilometers by infected mosquitoes is possible as well, especially in areas with a monsoonal climate (e.g., in australia through the torres strait 12à14 ). birds transfer jev from natural to synantropic biocenoses, where, thanks to culex tritaeniorhynchus mosquitoes willingly attacking wild birds, pigs, persons, synantropic birds, and domestic animals (chiefly pigs), these all join into jev circulation. 7 infection in pigs could be inapparent, or it could be clinically expressed with encephalitis and a lethal outcome. the level of viremia in infected pigs is enough to infect mosquitoes. such epizootics among pigs are, in effect, amplifiers for jev, serving as prerequisites for the development of epidemics, first of all among people living in the countryside, but then among city dwellers as well. antibodies to jev specifically were revealed among wild boars (83%), raccoons (59%), 14 and dogs (17%). 7 in the south of china, jev was isolated from both leschenault's rousette (rousettus leschnaulti), a species of fruit bat, and the little tube-nosed bat (murina aurata), 15 and anti-jev antibodies were identified in the blood of those animals. 16 jev preservation in bats could be one of the mechanisms of the year-round circulation of the virus in its natural foci, with activation in the spring and subsequent replication and spreading in the summer and autumn. in natural foci, birds are the principal vertebrate hosts contributing to transmission of the virus; in synantropic foci, pigs are the most important vertebrate hosts. 10,11 jev has been isolated from the grey-headed bunting (emberiza fucata), great cormorant (phalacrocorax carbo), japanese thrush (turdus cardis), azure-winged magpie (cyanopica cyana), japanese wagtail (motacilla grandis), barn swallow (hirundo rustica), and night heron (nicticorax nicticorax). natural foci are situated in meadows. of late, culex tritaeniorhynchus has become more abundant in connection with intensive rice cultivation, portending the possibility of increased jev circulation and epidemics. 17, 18 epidemiology. all the territory of japan, except for northern part of hokkaido, 7 is endemic, but most diseases are registered near islands in a closed sea, as well as in tokyo and adjacent prefectures. 3 before 1966, outbreaks of je emerged in japan practically every year, with 1,200à2,700 patients seen. later, morbidity began to decrease to tens of cases per year. in the 1970a and 1980s, morbidity fell to the level of single cases per year. the main cause of the decrease was a significant drop in the population of the main jev vector-culex tritaeniorhynchus mosquitoes-as the result of a reduction in the acreage of rice fields as well as water pollution in places of mosquito habitation. in addition, the program of mass vaccination carried out annually among children of school age and a change in the structure of pork farms lessening the availability of pigs played a significant role in the falloff in the mosquito population. je is a serious problem in 20 countries of southeast asia and oceania. 19 during the last few years, more than 50,000 cases per year were registered, with about 20% lethality. 19 morbidity increases annually in bangladesh, indonesia, laos, myanmar, north korea, and pakistan. 19, 20 in addition, , the occurrence of an epidemic in southeastern asian countries is becoming more and more likely because those countries are now seeking to increase their production of rice. the greatest risk of je is said to be in china, nepal, sri lanka, thailand, 21 laos, and vietnam. je is of the highest importance among all kinds of endemic encephalitis, potentially threatening nearly 50% of the population of our planet. 3 the disease especially affects military contingents, as it did the american army during the concentration of armies in okinawa 3 and the soviet army during the battle of lake khasan (also called the changkufeng incident) in the south of primorsky krai. precursors of jev circulated in indonesia and then evolved into six genotypes. 22 genotype iii is widespread in a moderate climatic belt and often provokes epidemic outbreaks in eastern and southeastern asia. genotype i originated in indonesia, circulated in thailand and cambodia in the 1970s and in south korea and japan in the 1990s, and has now completely replaced genotype iii. 23 genotype i got into japan in two ways: from southeastern asia and from mainland china. 24, 25 two island territoriesthe philippines and taiwan, in both of which genotype iii circulates-were free of genotype i-and the philippines remains free-but the genotype appeared in taiwan in 2008. 26 the evolution of jev led to the emergence of two new subclusters in 2009à2010; the two together have replaced genotype iii. until recently, the qinghai-tibet plateau, in china, was free of jev, but in august 2009 the virus was isolated from culex tritaeniorhynchus mosquitoes there. 27 during an epidemic in septemberànovember 2009, genotype i circulated in japan. 28 in nepal, on the northern border of india, je has been known since 1978, after which outbreaks were observed annually. 9 jev circulates in the north of australia as well. 12, 21 je claimed morbidity in the south of the russian far east (in primorsky krai) in 1938 during an expedition headed by p.g. sergiev and i.i. rogosin. epidemics of jev broke out in the region in 1938, 1939, and 1943. more than 800 cases were recognized between 1938 and 1943, with 68% reported in the extreme south of primorsky krai. the northern extent of this area is limited by the southern part of the ussuri lowland (about 42à43 n, 130à133 e). enzootic jev circulation without human morbidity has been documented, with the seroprevalence of residents estimated at about 10à20%. 11,18,29,30 je cases occur mainly in augustàseptember (but also when heavy rains are combined with high temperatures from april to september: $21 c in april, $23 c in june, $25 c in august, and $21 c in september). clinical features. the clinical picture of je varies from asymptomatic and easy feverish forms to an encephalitis syndrome. the ratio of clinical to asymptomatic forms is from 1:300 to 1:1,000, although the ratio in india in the 1970s and 1980s was from 1:20 to 1:30. 31à33 the start of the disease is sudden, with fever (80%), headache, vomiting (24%), and symptoms of cns destruction (most often, hemiplegia and articulation lesions)-in 12% of cases, and at the height of the illness in 65% of cases. about one-third of patients with cns lesions recover completely. 34 lethal outcomes are preceded by unconsciousness and then coma (20à44% of the total number of patients). death comes in two-thirds of cases during the first week, in one-fourth during the second week, and in the rest of the cases in one month, from the onset of symptoms. after the disease, residual phenomena in the form of paralysis and mental issues are quite often observed. 28, 32 control and prophylaxis. inactivated vaccines are used to immunize people, 19,29,33,35à37 live vaccines to immunize pigs and horses. 31 vaccination and protection of pigs from mosquito attack and protection of humans from mosquitoes (through the use of repellents, mosquito nets, bed curtains, etc.) are recommended during epidemics among people. mass vaccination has been carried out successfully in japan, south korea, china, and india. 19,28,33,35à37 live vaccine manufactured on the basis of the chinese strain sa 14à22 is is given in china, south korea, and other countries in government programs aimed at expanding immunization of children. 19 24 the complete genomes of tyuv and kamv (genbank id: kf815939 and kf815940, respectively) were presented in a 1973 article in the journal of medical entomology, 25 and it was established that kamv was a new virus within the tyuv group of the flavivirus genus. virion and genome. tyuv is a prototypical virus of the tyuleniy antigenic complex. the viruses of that complex belong to the ecological group of seabird tick-borne flaviviruses, which forms a distinct branch on the phylogenetic tree. 26 four species are known in the tyuleniy antigenic complex: tyuv (in russia and the united states), meav (in europe), srev (in oceania) and kamv (in russia). the genetic similarity between the seabird tick-borne flaviviruses and the mammalian tick-borne flaviviruses is about 42% nt. a full-length genome comparison showed that the similarity among the four viruses in the tyuleniy antigenic complex is 70% nt and 85% aa, on average. tyuv leiv-61c, isolated in the russian far east, has 86% nt and 97% aa identities with tyuv isolated on the pacific coast of the united states. kama virus (strain leiv-tat20776) has 70% nt identity with the other viruses of the tyuleniy antigenic complex (meav, srev, tyuv). the similarity of the polyprotein precursor of kamv is 74% aa with each of tyuv and srev, 78% aa with meav. 25 arthropod vectors. tyuv is distributed over the basins of the sea of okhotsk and the bering and barents seas. the infection rate of ixodes uriae in the pacific part of the virus's distribution is 4.5 times greater than in the atlantic part (table 8 .31). 16 ,18à23 outside of northern eurasia, tyuv is distributed over the west coasts of the united states (chiefly in oregon) and canada. 27, 28 the infection rate of nymphs and larvae of i. uriae is one-twentieth to one-half the infection rate of the imago. the infection rates of i. uriae females and males (the males have only a rudimentary hypostome and do not feed) are practically the same. 21 these data testify to the transphase and transovarial transmission of tyuv. (the efficiency of this type of transmission is about 5%.) attempts to isolate tyuv from i. signatus ticks were unsuccessful. the presence of antibodies to tyuv among local cows and indigenous people of the commander islands 19,21 indicates the possible role of sanguivorous mosquitoes (e.g., aedes communis, ae. punctor, and ae. excrucians) in infection. mosquitoes could also take part in virus circulation: their infection rate from the end of july to the beginning of august reaches 0.3% in nesting colonies of seabirds and 0.1% on the seacoast. experimental infection of tyuv on the model of aedes aegypti demonstrated the presence of the virus 4à31 days after inoculation, with 1.5à2.0 lg ld 50 /10 mcl on days 4à17; 3.0à3.5 lg ld 50 /10 mcl on days 23à27; and 1.5 lg ld 50 /10 mcl on day 31. the transmission of tyuv during the feeding of infected mosquitoes on mice was established 7à19 days after infection of the mosquitoes. in culex pipiens molestus, tyuv was detected 5à21 days (the period of observation) after infection, with 1.0à2.0 lg ld 50 /10 mcl. 20 vertebrate hosts. migratory seabirds play a role in the exchange of tyuv group flaviviruses between the northern and southern hemispheres. 18, 29 investigation with the help of indirect complement-binding reactions of sera samples from 2,500 birds collected in the far east revealed that the maximum tyuv infection rate takes place in brü nnich's guillemots (uria lomvia), common murres (u. aalge), and tufted puffins (fratercula cirrhata). lower rates were seen in pelagic cormorants (phalacrocorax pelagicus), redfaced cormorants (ph. urile), glaucous-winged gulls (larus glaucescens), kittiwakes (rissa tridactyla), northern fulmars (fulmarus glacialis), and sandpipers (scolopacidae). 17, 18, 20, 21, 23, 30 the presence of specific anti-tyuv antibodies among sandpipers-red-necked phalaropes 27, 28, 31 considering the annual migrations of these birds, tyuv can be found within the i. uriae area of distribution in nesting colonies of puffins. about 90% of adult and 10% of juvenile northern fur seals (callorhinus ursinus) on the commander islands have specific anti-tyuv antibodies, implying that these animals are involved in the circulation of that virus. a tyuv strain was isolated from the arctic ground squirrel (citellus (urocitellus) parryii) on the southeastern coast of the chukotka peninsula (63 n, 180 e). this event is one more argument for virus splash into the continent, with rodents included in virus circulation. in the tundra of the kola peninsula seacoast, antibodies specific to tyuv were detected among cattle (28.1%) as well as red-necked phalaropes (phalaropus lobatus), snow buntings (plectrophenax nivalis), ruffs (philomachus pugnax), and rodents: tundra voles (microtus oeconomus). 21 thus, in the atlantic part of its distribution, tyuv also tends to penetrate into the continent. experimental infection of kittiwakes (rissa tridactyla), herring gulls (larus argentatus), and brü nnich's guillemots (uria lomvia) was followed by the development of clinical features with cns lesions and lethal outcomes. 32 epidemiology. the indigenous population in the far eastern part of tyuv distribution has specific anti-tyuv antibodies: 8.4% in tundra on the coast of the chukotka peninsular, 4.2% in forestàtundra on the coasts of the sea of okhotsk and the bering sea, 7.4% -in taiga on sakhalin island, and 9.1% in tundra on the coast of the kola peninsula. 21 the development of fever in humans visiting nesting colonies of seabirds on the coast of the barents sea has been described in the literature. 33 ecological peculiarities of tyuv and kamv distribution. penetration of tyuv from the northern to the southern hemisphere is carried out by about 20 species of birds, mostly turnstones (arenaria interpres), that nest in the north of asia and overwinter in australia and new zealand. wedge-tailed shearwaters (puffinus pacificus) nest in the southern hemisphere and carry out an annual migration along the coasts of the pacific ocean up to northern eurasia and north america. 23, 34 close genetic relations found between tyuv and kamv have not been explained yet because information is lacking about ecological links between alcidae birds in the north and bank swallows in the central part of the russian plain. nontheless, the closeness demonstrates an ancient link between the flaviviruses and ixodidae ticks-obligatory parasites of colonial and burrow-shelter birds not only on the ocean coast, but also on the continental part of the distribution of those viruses. 19, 20, 23, 35, 36 meav and srev, which are genetically close to tyuv, 25,26 could be intermediate evolutionary branches between tick-borne viruses of seabirds and later mammalian viruses transmitted by ticks. 13, 15 the main vector of tyuv in subarctic regions-ixodes uriae, adapted to seabirds-is replaced by the ornithodoros capensis complex or argas spp. in the subtropics and tropics. 18, 27 the northern boundary of the argas genus distribution is limited by a july isotherm of 15à20 c and of the ornithodoros genus by 20à25 c in europe and 25à30 c in asia. 37 the vector of kamv-the i. lividus tick-has transpaleoarctic distribution, from the british isles in the west to japan in the east and from 62 n down to 43 s. this species of tick has an extrazonal distribution in the diggings of bank swallows (riparia riparia) made in the soft ground of steeps along the banks of rivers and lakes in taiga, leaf forest, forestàsteppe and 247 8.2 family flaviviridae steppe climatic belts. i. lividus ticks are typical parasites of-burrow-shelter birds and relate strictly to the life cycle of the host: after the appearance of birds in the nesting areas in may, larvae begin to feed. in june, nymphs feed on the nestlings; female imagoes also feed on the nestlings, but male imagoes do not. 38 given the presence of kamv-a virus closely related to tyuv-in the central part of the russian plain, it is worthwhile, and even necessary, to carry out a wider search for tyuv analogues on the continental part of northern eurasia. history. dengue fever (denf), etiologically linked to dengue virus (denv) (family flaviviridae, genus flavivirus), has been known in asia, africa, and america since the end of the eighteenth century. 1,2 wide epidemics of denf appeared in southeastern asia after world war ii. 3 according to who data, denf morbidity, including imported cases, has been detected in more than 100 countries of asia, africa, and europe. more than 2.5 billion people on earth are under the threat of denf. about 50 million people fall victim to denf annually. 4 american armies sustained heavy losses as the result of denf during world war ii, 3 as well as during 1960à1990 in vietnam, the philippines, somalia, and haiti. 5 simultaneous outbreaks of denf and chikungunya fever often occur. 6 the virus etiology of denf and its transmission by mosquitoes was established by p.m. ashburn and c.f. craig in experiments using volunteers at the beginning of the twentieth century. 7 denv-1 was isolated in 1944 from the blood of patients with fever on the hawaiian islands, 8 denv-2 in 1944 from the blood of patients with fever on new guinea, 8 denv-3 in 1956 from the blood of patients with fever in the philippines, 9 and denv-4 in 1956 from the blood of patient with fever during epidemics in manila. 9 taxonomy. four different serotypes of denv form a distinct phylogenetic lineage on the mosquito-borne flavivirus lineage (figure 8.47 ). genetic variation among different strains suggested that denv be divided into distinct genetic clusters considered as genotypes. the genetic diversity of denv is best exemplified in denv-2, the different strains of which are divided into four genotypes: asian 1, asian 2, american/asian and so-called cosmopolitan. 10 denv-3 strains are divided into five genotypes (iàv), 11 and denv-4 strains form three genotypes. 12 in general, a particular genotype is linked to specific geographical regions and that genotype may be used in describing imported cases of denv infection. arthropod vectors. denf belongs to natural-foci diseases. its vectors are anthropophilic species of mosquitoes: aedes aegypti and ae. albopictus in synantropic natural foci. humans are the only vertebrate hosts in synantropic natural foci, whereas wild mammals are involved in virus circulation in sylvatic natural foci. vectors in equatorial africa are ae. furcifer, ae. vittatus, ae. tailori, and ae. luteocephalus. vertebrate hosts. in southastern asia, the vertebrate hosts of denv are macaques (genus macaca) and surilis (genus presbytis) living in the rain forests of equatorial climatic belts; the main vector is aedes niveus; a circulation of denv-{1, 2, 4} has been identified. natural foci of denv were also found in the eastern part of equatorial africa, in senegal and nigeria. the vertebrate hosts are patas monkeys (erythrocebus patas); wild strains are considered possible precursors of epidemic ones. among humans, wild strains provoke slight clinical forms of dengue fever. 13à15 epidemiology. denf has an epidemic character involving tens of thousands of people in southeastern asia, oceania, the caribbean basin, central and south america, and africa. the transmission pathway is a mosquito bite, mainly by members of the aedes genus. these mosquitoes are able to transmit denv in 8à10 days after feeding on a sick person. about 60à70% of the human population falls victim to denf during epidemics. 15 denv continues to circulate actively and to provoke wide epidemics. for example, all four types of denv exist in sri lanka, with new clades replacing old ones, accompanied by a severe clinical picture. 16, 17 in the 1980s, a new wave of denf epidemics began to develop in sri lanka, india, pakistan, and central and south america. 18, 19 these epidemics were linked mainly to the relatively new denv-3, but to denv-1 and denv-2 as well. 20 in some cases-for instance, in myanmar 21 and china 1 -all four types of denv circulated simultaneously. clinical features. the incubation period is 2à7 days. the start of the disease is quick, with fever and with frontal and retroorbital headache. lymphadenopathia, rash in macule and papule forms (not always), leukopenia, skin hyperesthesia, changes in taste, loss of appetite, and muscle and joint pains gradually develop. then, after 1à2 days of normal body temperature, the second wave of fever develops, accompanied by a measleslike rash. the palms and soles are rash free. severe cns complications have been described to arise in endemic regions (e.g., brazil). 3 the hemorrhagic clinical form of denf, with shock and a high level of lethality (especially among children), was originally seen in the philippines in 1953. later, this clinical form was registered in india, malaysia, singapore, indonesia, vietnam, cambodia, and sri lanka, as well as on islands in the pacific. according to who data, more than 1.3 million patients had hemorrhagic denf from 1956 to 1992, with 14,000 lethal outcomes. starting from 1975, hemorrhagic denf has become the main cause of hospitalization and deaths among children in the countries of southeastern asia. 1 the hemorrhagic form of denf usually develops after a secondary infection by a type of denv different from the primary one. the primary type of denv is not neutralized, but fragments antigen binding (fab)associated enhancement of the infection occurs. for example, in french polynesia in 2000, two years after epidemics of denv-2, an outbreak etiologically linked to denv-1 emerged and hemorrhagic denf was detected among children 6à10 months and 4à11 years old. 16 five symptoms are characteristic of the hemorrhagic clinical form of dengue: high temperature, rash, hemorrhagia, hepatomegalia, and insults to the circulatory system. thrombocytopenia with blood condensation also occurs. 4 hemorrhagic denf can be without shock or can precede it. shock develops in 3à7 days of the disease, wheninsults to the circulatory system appear: the skin becomes cold, sticky, and cyanochroic; the pulse rate increases; and drowsiness appears. in the absence of antishock actions, patients die within 12à24 h. the severity of the disease depends on a number of factors: the infection titer in the blood, the type of denv, its biological properties, and more. 22à24 imported cases of dengue. there is a high risk of denv infection for visitors to endemic regions, with consequent penetration of the virus into nonendemic regions. 1, 25 denf has occurred in spain in the past (e.g., in cádiz in 1778). several tens of human cases are introduced into the country each year from equatorial and subequatorial regions. denv-1 and denv-2 caused a huge outbreak in greece in augustàseptember of both 1927 and 1928: in those periods, about 650,000 of 700,000 inhabitants of athens and piraeus contracted denf, including hemorrhagic forms and about 1,000 lethal outcomes. 26 penetrations of denv also took place in the netherlands in 2006à2007 27 and in japan, 28 france, 29 northern italy, 30 and germany in 2010. 31 during 2002à2011 in russia, among patients with fever from the risk group that visited tropicalàequatorial countries, 48 cases of denf were identified with the help of serological investigation (22 cases arrived from indonesia; 11 from thailand; 3 each from vietnam and india; 2 each from venezuela and the dominican republic; and 1 each from sri lanka, malaysia, singapore, sierra leone, and costa rica). 32à34 in 2013 in russia, 30 cases of denf were identified in moscow, 8 in st. petersburg, and 8 imported strains of denv were isolated. the risk of denf for europe has appeared again with the introduction of aedes albopictus and ae. aegypti mosquitoes in the countries of the mediterranean and black sea basins. 35 stable populations of both these species were found on the southeastern coast of the black sea (in krasnodar krai, russia, as well as in abkhazia). 36à38 control and prophylaxis. the main approach to prophylaxis is to struggle against mosquito vectors. during the 1950s and 1960s, a program against ae. aegypti mosquitoes that was unprecedented in terms of scale and expense was conducted in america, but it was stopped in 1970; as a result, in 1995 the number of ae. aegypti mosquitoes was estimated to be same as that before the program began. 39 the struggle against mosquito vectors in singapore turned out to be more successful, but still did not prevent denf morbidity. 40 investigations into four-component vaccines are far from completion today. 22, 41 express methods of denf diagnostics are used in airports. 42 who issues a reference guide for the diagnosis, treatment, prophylaxis, and control of denf. 43 (table 8 .32, figure 8 .60). further serological investigations with the help of hit revealed that sokv belongs to the flaviviridae family, and with the help of complement-fixation testing (but not neutralization testing), to the entebbe bat serogroup. 1à3 a prototypical strain of this serogroup was isolated from a kenyan big-eared free-tailed bat (tadarida lobata) collected near entebbe, uganda, in july 1957. 5 taxonomy. the genome of sokv was sequenced, and genome analysis showed that the virus is related most closely (71% nt and 79% aa identities) to entebbe bat virus (entv). sokv has about 50% nt and 55% aa identities with other flaviviruses, except viruses of the rio bravo (rbv) and modoc (modv) groups (,50% similarity). 6 no arthropod vector of entv and sokv has been established; however, phylogenetic analysis based on a full-length genome comparison placed sokv and entv together on a distinct branch of mosquito-borne flaviviruses related to yfv and sepik virus (sepv) (figure 8.47) . arthropod vectors. according to serological data, domestic animals do not take part significantly in sokv circulation, although antibodies to sokv were detected among cows and sheep. isolation of sokv from birds that were known not to have made contact with obligatory parasites of bats, as well as the presence of positive sera from humans and domestic animals, suggest the participation of mosquitoes in sokv circulation. transmission of the virus by bats could be carried out by argas vespertilionis and ixodes vespertilionis. 7à10 vertebrate hosts. more than 20 flaviviruses were isolated from bats (order chiroptera); about half are unique to these mammals. 11 24 ; and yokose virus (yokv). 25 the insectivorous bats vespertilio pipistrellus, from which sokv was isolated, belong to the evening bats family (vespertilionidae), which is active during the evening and at night. their daylight shelters are situated mostly in house garrets. v. pipistrellus is distributed over europe, the mediterranean, the caucasus region, and central asia. a part of the population overwinters in africa, where infection by local viruses (e.g., bbv, dbv, entv) could occur. experimental infection of sparrows (passer montanus) resulted in sokv being detected in internal parts of infected birds on the 8th and 25th days after inoculation. 26 epidemiology. there are no laboratoryconfirmed human cases of sokv infection. nevertheless, the proximity of sokv hosts (bats) to human habitats, as well as the presence of encephalitis and hemorrhagic fever agents among the flaviviruses, suggest that sokv may be dangerous to humans. complement-binding specific anti-sokv antibodies were detected among humans in kyrgyzstan and turkmenistan (6.2% and 4.0%, respectively), testifying to recent infection events. 1à4,7,9,10,16,27à31 history. wnv (family flaviviridae, genus flavivirus), theetiological agent of west nile fever (wnf), was first isolated during research on yfv in 1937 from the blood of a native of uganda who was suffering a mild fever. 1 the strain isolated, b956, belongs to genetic lineage ii. (see "taxonomy" next.) strain eg101, isolated from the sera of a child without clinical signs in egypt, 2 is the prototype for african genetic lineage i, widely used for investigations. wnv belongs to the jev group, has the broadest antigenic properties, and, on theoretical grounds, appears to be the most ancient member of the flavivirus genus. 3 lowpassaged wnv strains are known by many investigators to be common causes of laboratory infection, apparent or inapparent. 4 taxonomy. phylogenetic analysis revealed that different geographic isolates of wnv could be grouped into two major genetic lineages (figure 8.61 ). lineage i includes strains from africa, southern and eastern europe, india, and the middle east. lineage ii includes isolates from west, central, and east africa, as well as madagascar. lineage 1 can be subdivided into three clades: clade 1a consists of strains from europe, africa, the united states, and israel. the topotypic isolates of wnv in australia-kunjin virus (kunv)belong to clade 1b, and clade 1c is formed by isolates from india. 5 subsequently, two genetically divergent rabensburg strains-97à103 (isolated in the czech republic) and leiv-krnd88-190 (isolated in russia)-were proposed to form novel lineages iii and iv, respectively. 6à8 a fifth lineage was formed by strains from india. 9 phylogenetic analyses based on complete genomic sequences revealed that the various lineages differed from each other by 20à25%. a putative novel sixth lineage has been detected in spain in 2006, but only a partial sequence of the ns5 gene of this isolate is available in genbank. 10 world distribution. the distribution of wnv in northern eurasia, and indeed, in the whole world, covers vast territories within the equatorial, tropical, and temperate (the southern part) climatic belts in africa, europe, asia, australia, and north america (the last starting from 1999). in africa, it is very difficult to find a country or landscape in which wnv has not been detected by either a virological or serological approach. the isolation of this virus from a wide array of species of birds, mosquitoes, ixodidae and argasidae ticks, and domestic animals as well as humans testifies to the ecological plasticity of the virus and therefore to its ability to adapt to different ecological conditions. two genetic lineages circulate in africa: the first, which dominates, and the second. sporadic morbidity and epidemic outbreaks permanently take place in a number of african countries, especially the republic of south africa, where a wide outbreak with at least 3,000 human cases occurred in 1974 after an active period of rain. according to a report from the pasteur institute, during the last 10à15 years alone, epidemic outbreaks were registered in algeria (in 1994, with more than 50 cases and 8 deaths, and in 1997, with 173 cases), in tunisia (during 1997à2003, with 173 cases), morocco (in 1996 and 2002; the epidemic reached both humans and horses), in senegal (in 1993), and in kenya (in 1998). 11 new centers of infection continue to be arise in africa-for example, in 2009 in morocco, where morbidity among people and horses was observed and 3.5% of birds had specific anti-wnv antibodies, 12 and in 2010 in the republic of south africa, where there were a number of lethal outcomes. 13 the wide distribution of wnv in africa and its circulation among populations of the majority of the continent's species of local and migrating birds indicates that the virus is able to penetrate to southern europe and western siberia through the birds' migration pathways. most of the birds nesting in or migrating through the volga delta overwinter in africa. 14 thus, africa is the main source of penetration of wnv genotypes i and ii into southern europe and western siberia. in asia, a peculiar third genotype of wnv appears to be circulating in the indian subcontinent. 11 a prototypical strain of wnv genotype 3 was isolated from xculex vishnui mosquitoes in southeastern india, and human morbidity was identified in india, pakistan, and israel. taking into account the fact that most of the birds from western siberia and many from eastern siberia overwinter in india and other countries of southern asia, there is a high probability that wnv genotype 3 has penetrated into siberia. also in asia, both epidemics and sporadic cases etiologically linked with the first genotype of wnv have arisen regularly in israel since at least1958. one such outbreak was observed in 1999à2000. 15 surveillance in south korea does not indicate any wnv circulation in that country. 16 in australia and oceania, the kunjin variant of the first genotype of wnv appears to be circulating. 17à19 kunv could be introduced into northern eurasia (in eastern siberia and the far east) by migrating birds overwintering in southeastern asia and australia. 11, 14 in 2011, an outbreak among horses in new south wales, australia, was identified. 20 in central europe, for a long time only two strains of wnv were known: one isolated in from aedes cantans in 1972 in western slovakia and the other isolated from ae. vexans, ae. cinereus, and culex pipiens in 1997 in the czech republic, near the austrian border. anti-wnv antibodies were identified in the czech republic among 1.4à9.7% of birds, including crows, daws, turtle doves, common kestrels, ducks, coots, and thrushes. later, two strains of the so-called rabensburg genotype of wnv were isolated from cx. pipiens in 1997 and 1999 in the czech republic. 21à23 the strain belonging to the second lineage of wnv was isolated from a goshawk in hungary. 7 in 1996 in tuscany, italy, usutu virus (usuv), which is closely related to wnv, was isolated during an epizootic episode among birds, especially thrushes (turdus merula), and then, again, in 2001 in austria. later, this virus was found in hungary, switzerland, and germany. 24 practically all of the southern european countries are endemic for wnv. 25, 26 especially tragic events unfolded in romania, where there was an epidemic in julyàoctober 1996 with a peak at the end of august to the beginning of september in the southeastern part of the country, downstream of the danube river. six administrative units and bucharest were affected, among other jurisdictions. human morbidity reached 12.4%, and 835 patients with cns insult were hospitalized. the number of patients with fever was at least 10 times more, and the number of infected individuals 100à300 times more. the outbreak, which dragged on until 2000, 27 testifies to the development of a city epidemic form of wnf. the virus belonged to the first genotype of wnv and probably was brought to romania by birds from africa. wnv distribution in europe indicates an especially high risk of a wvf outbreak in deltas of the large rivers-the rhô ne in france and the danube in romania-through which the main migratory paths of birds overwintering in africa lie. 14 in the recent past, wnv has been active in europe in italy, 28, 29 greece, 30, 31 spain, 10 poland, 26 the czech republic, 3, 22 and france. 22 infected mosquitoes were imported into great britain from the united states by airplane travel. 32 as for north america, before 1999 that continent was free of wnv. penetration of wnv into america most likely happened by infected mosquitoes in the holds of ships from ports in the mediterranean sea or black sea. 11 fifty-six cases of human wnf were revealed in new york city and its surroundings at the end of julyàseptember 1999, with a peak in the second half of august. seven cases (12.5%) had a lethal outcome. the virus was found in culex sp. and aedes vexans mosquitoes caught in septemberàoctober in new york city and in the states of new jersey and connecticut. positive results were obtained by rt-pcr during an investigation of brain tissues of dead birds: crows, seagulls, storks, herons, ducks, cuckoos, pigeons, jays, robins, hawks, and eagles. the genomes of the strains that were isolated were found to belong to the first genotype and were close to the strains isolated in 1996 in romania and in 1998 in israel. 33 in 1999, wnv was registered in the united states, probably translocated there by migrating birds or by infected mosquitoes inhabiting the holds of visiting ships. wnv was found in by 2003à2004, practically all the territory of the united states, southern canada, and latin america became endemic with high morbidity and mortality. 34 the greatest morbidity in the united states was found in the states of northdakota, south dakota, and nebraska. 27, 35 the number of diseased individuals reached 4,000à9,000 cases in separate years. during 1999à2006 in the united states, more than 16,000 wnf cases were identified, with more than 600 (4%) succumbing to the disease. the economic damage was estimated in billions of dollars. 36, 37 today, wnv continues to circulate in the united states. 38, 39 morbidity grew in the states of louisiana and mississippi after hurricane katrina. 40 in montana, the infection rate of people living in close proximity to a colony of pelicans (pelecanus erythrorhynchos) is five times higher than in other regions of the state. 41 in a sea park in texas, grampuses (orcinus orca) contracted encephalitis and died, 42 and previous episodes of polyencephalomyelitis were revealed among seals (phoca vitulina). also in texas, three new genetic clades of wnv were found, testifying to rapid evolution of the virus on the american continent. 43 in 2012, an epidemic arose again, accompanied by a large number of lethal outcomes. in texas, a state of emergency was declared. northern eurasia. in northern eurasia, on the basis of the results of multiple investigations, the distribution of wnv includes moldova, ukraine, belarus, armenia, azerbaijan, georgia, kazakhstan, tajikistan, kyrgyzstan, uzbekistan, turkmenistan, the south of the european part of russia (the desert, semidesert, steppe, and forestàsteppe landscape belts), and western siberia. 11, 35, 44 the first data on wnv isolation were obtained from hyalomma marginatum ticks collected in the astrakhan region in 1963. data were also obtained in azerbaijan from a blackbird (turdus merula) and a european nuthatch (sitta europaea) and, later, from a herring gull (larus argentatus) and argasidae ticks (ornithodoros coniceps) parasitizing it. 14 wnf morbidity is now a permanent feature in the astrakhan region, kazakhstan, central asian countries (republics of the former ussr), ukraine, and azerbaijan. virological, entomological, zoologicoornithological, and epidemiological investigations of wnv in the astrakhan region and the kalmyk republic were conducted especially actively. 8,39,45à61 virus activity in the volga river delta was found at least as far as 50 years ago. 11, 35, 60 but interactions between wnv, on the one hand, and animal and vector populations, on the other, were not investigated in detail as well as genetic characteristics of the virus; indeed, the latter began to be studied well only during the first decade of twenty-first century, when suckling mice and vero-e6 cell culture were used to isolate the virus and serological investigations were employed to detect viral rna (neutralization testing, elisa, hit) and to sequence genes (rt-pcr). wnv endemic territories in southern russia were known from the moment the virus was isolated in the astrakhan region in 1964. (the number of cases confirmed by elisa in the southof the european part of russia is presented in table 8 .33.) sporadic cases with a moderate clinical picture and minor outbreaks were observed in the area practically annually, as well as in other southern regions of the former soviet union. the immune structure to wnv among humans in the ussr was also known, with the most immunity occurring in the south of russia, mainly the astrakhan region (figure 8 .62, table 8 .34). all this familiarity with wnf is why an outbreak in 1999 in volgograd was not exactly unexpected, 62 even though it originally was identified by regional experts as an enterovirus infection. still, laboratory-confirmed wnf cases reached more than 500 that year, and according to our estimations, the number of infected patients exceeded 200,000 (table 8.35) . mortality (about 10%) was also unusually high. large deltas of european rivers such as the rhô ne, danube, and volga rivers are known to be transit hubs for migrating birds and places of introduction of viruses linked with birds. 14 the main natural focus in russia is the volga delta. the volga delta and contiguous territories around the northern caspian basin have been endemic for wnf for many years (tables 8.33à8 . 35) , and other arboviruses have been ecologically linked with aquatic and semiaquatic birds frequenting the region. ninety percent of these species of birds overwinter on the african continent. up to 100,000 birds pass over the region daily during their seasonal migrations via the volga delta main line of the eastern europe migratory route. (see figure 3.2 .) the problem is that the volga delta is the place from which viruses are introduced into anthropogenic biocenoses in close vicinity to human habitation. one consequence of this scenario was epidemic outbreaks in the astrakhan and volgograd regions in 1999à2001. the volga delta consists of three basic belts, each with its own unique ecosystem features (figure 8.63) . the lower volga delta borders the caspian sea and is characterized by extensive exposed spaces with water. the water depth usually does not exceed 1.0à1.5 m, a situation that is highly conducive to the mass propagation of mosquitoes and one that also provides nesting opportunities for aquatic and semiaquatic birds. near where it empties into the caspian sea, the volga bed turns significantly to the west, so the western part of the delta, including both the reed bed of the northwestern caspian coast (up to lagan in the kalmyk republic) and some flooded islands, is more extensive than the central and eastern parts. the extreme eastern part of the delta lies in kazakhstan. a number of hunters and fishermen could be infected in the lower delta of the volga. the middle volga delta is more distant from the sea, has powerful currents, and consists of shallow lake ecosystems with reeds and shrubs. water ecosystems adjoin semidesert ones. within the limits of this zone, wild biocenoses combine with anthropogenic areas around a number of settlements, whose inhabitants keep cattle, sheep, and camels. wnf is widely registered among the native population. the upper volga delta adjoins the volgaà akhtuba lowlands and semideserts. large cities, including astrakhan, are located within the limits of this zone. some species of wild birds that are common in the middle delta also occur in this zone, coming into close contact with domestic animals and synanthropic birds. analysis of retrospective data collected before 1999 revealed that the main locus of native-population morbidity by wnf is in the volga delta (table 8 .35). viruses could be introduced into the northern part of the volgaàakhtuba lowland up to volgograd and maybe even higher. thus, in the future it will be necessary to control the introduction of the virus into the volgaàakhtuba lowland from astrakhan to volgograd. arid landscapes occupying contiguous terrian to the west of the volgaàakhtuba system and the volga delta are situated within the boundaries of the caspian seaàturanian basin physicogeographical area (figure 8.63) . every year at the end of july, a group of specialists from the d.i. ivanovsky institute of virology in moscow has traveled to the astrakhan region and the kalmyk republic to organize and conduct a joint scientific expedition with local centers of sanitaryàepidemiological inspection for ecologo-virological monitoring of the northwestern caspian region (figures 8.64à8.66) . the main goal of the expedition is to contain the ecological and epidemiological situation after suppression of wnv circulation in the previous epidemiological season as the result of a combination of natural factors. the plan for the collection of field material took into account the results of previous expeditions, when key milestones and marker species of mosquitoes and wild and domestic animals were identified. in particular, the researchers planned to investigate the role of the ixodidae tick hyalomma marginatum (figure 8 .67) in wnv and other arbovirus circulation in anthropogenic and wild biotopes. both federal and local heads of various services, as well as virologists, epidemiologists, veterinarians, hunters, and frontier guards, were supplied with materials containing evaluations of ecologo-virological monitoring of their respective territories in the previous epidemiological season. practical recommendations were given for prophylaxis of wnf, cchf, and other arboviral diseases. field materials-bloodsucking mosquitoes, ixodidae ticks, internals (blood, serum, liver, spleen, and brain) of wild birds and mammals, and sera from donors and domestic animalswere collected on the territory of the astrakhan region and the kalmyk republic from the end of july to the beginning of august 2000à2004 within the boundaries of the volga delta, the volgaàakhtuba valley, and adjacent arid landscapes. field materials were collected in the biotopes of the west volga coast and the east akhtuba coast, including internal wateràmeadows of the upper and lower volgaàakhtuba zones, hydromorphic and adjacent meadowàsteppe biotopes of the upper and meddle belts of the volga, the volga avandelta, the territory of the sarpa lakes, and the east side of ergeny (see figures 8.64à8.66 ). during 2000à2004, the expedition collected 504,731 bloodsucking mosquitoes (of the order diptera and family culicidae: genera culex, aedes, coquillettidia, and anopheles); 11,266 ixodidae ticks (of the taxon acari and family ixodidae: genera hyalomma, rhipicephalus, and dermacentor), mainly h. marginatum; internal parts of 2,794 birds and 67 hares (lepus europaeus); sera from 4,500 human donors (2,500 in the astrakhan region and 2,000 in the kalmyk republic); and sera from 5,300 domestic animals (2,900 in the astrakhan region and 2,400 in the kalmyk republic) (figure 8.68 ). the field materials that were collected were stored and transported to the d.i. ivanovsky institute of virology in liquid nitrogen in dewars, in accordance with all requirements for the handling and transport of infectious samples. internal parts of 2,794 wild birds were investigated by virological methods (table 8 .36). twelve wnv strains (tables 8.36 and 8.37) were isolated. according to the bioprobe method used, the total wnv infection rate among wild birds is about 0.4%, with the highest level (0.7%) reached in the middle and rt-pcr testing for any indication of wnv rna was carried out on 108 samples of internal parts collected from wild mammals on the territory of the northwestern caspian region. positive results are presented in tables 8.42 detected in anopheles messeae (0.028%), a common visitor to houses with domestic animals in anthropogenic biocenoses, as well as in an. hyrcanus (0.026%) in rushes in natural biocenoses. as is illustrated in figure 8 .73, the highest intensity of wnv circulation takes place among sanguivorous mosquito populations in anthropogenic biocenoses on the territory of the volga delta (figure 8.74 ). rt-pcr testing was carried out for the detection of wnv rna in 11,266 samples of hyalomma marginatum ticks (taxon acari, wnf cases began to be registered starting in june 2001, with the maximum reached in august (figure 8.76) . durint the first three 27 .0% of patients in the latter group had intracranial hypertension syndrome. there were two cases of severe disease: a 71-year-old patient with seromeningitis and an 8-year-old child with neurotoxic syndrome during the acute period. all of the cases had a favorable result: no lethal cases were registered. sera from 2,884 farm animals collected in the astrakhan region during 2001à2004 were tested by hit and neutralization testing in order to detect specific anti-wnv antibodies. in addition, hit-positive sera underwent neutralization testing. anti-wnv antibodies were found by hit in all species investigated: horses (mean positive result for the entire observation period, 9.8%; coincidence with neutralization testing, 94.1%), cattle (6.4%; 72.0%), camels (5.2%; 41.7%), pigs (3.1%; cattle are the main host of anopheles messeae, and cowsheds offer favorable conditions for the mosquitoes to reproduce. cattle-specific antigens could often be found in the intestines of culex pipiens females (but not an. messeae females), which inhabitat damp basements. town utilities adjoin with farm utilities in all settlements of the astrakhan region, so cattle are the hosts both for an. messeae and for cx. pipiens. both species of mosquitoes are active vectors of wnv in anthropogenic biocenoses. horses were the only species of farm animals with clinically expressed wnf. in contrast to cattle, whose pastures are situated close to human settlements, horses browse far from settlements, often grazing in natural biocenoses. a significant portion of horse livestock in the astrakhan region are of the kushum breed, bred for meat and racing, and browse freely all year. pedigree horses (don, akhaltekinsky and arabian race horses) are kept in bloodstock farms in a stall, or they browse locally. draft horses are kept in settlements. horse-specific antigens have been found in the intestines of replete females of all mosquitoes species (except for culiseta annulata, which are relatively fewer). the total (2001à2004) distribution of hitpositive horses increases from the upper volgaàakhtuba to the lower, with the highest number found in the middle belt of the volga delta (where the epicenter of the natural foci is located). pigs are the animals closest to human settlements, so pig-specific antigens are often found in the intestines of replete females of the anthropogenic mosquito species anopheles messeae and culex pipiens. pigs are kept in individual yards or on pig farms. the latter are situated far from human settlements. as they are in cattle housing, an. messeae are the main mosquito species on the pig farm; nevertheless, all mosquitoes collected here by probe were negative for wnv. in 2003, we collected sera on the pig farms, and all probes were hit negative. in 2004, we collected sera both on pig farms and in individual yards. sheep are the most numerous species of farm animal in the astrakhan region. sheep pastures are in the dry steppe, where conditions are favorable for the ixodidae tick hyalomma marginatum. only a couple of species of mosquito could live in the saltish, dry steppe il'mens: aedes caspius and cx. modestus. the latter is an active vector for wnv. a stable and low level of infection rate among sheep (about 2%) reflects the low level of intensity of wnv circulation in arid landscapes of the astrakhan region. kalmyk racing camels inhabit more arid landscapes than sheep inhabit; consequently, one might expect a lower level of seropositive camels. however, hit often demonstrates a high percentage of positive results: 33.3% in 1989 and 13.9% in 2001. so, we instead collected sera from camels during 2002à2004 in semiwild pastures, and the percentage of seropositive results decreased. the coincidence between the results of hit testing and neutralization testing is presented in table 8 .46. horses are the best marker of wnv circulation, because they have the largest percentage of hit-positive results and the greatest coincidence between hit and nt results. kushum race horses are the most significant marker. monitoring the infection rates among farm animals will be continued, taking into account the relationships and phenomena described. it has been found that wnv can remain viable during interepidemiological periods in overwintering imagoes of sanguivorous mosquitoes (e.g., anopheles messeae, culex pipiens and culiseta annulata) as well as overwintering imagoes of the ixodidae tick hyalomma marginatum. the scheme of wnv circulation on the territory of the northwestern caspian region is presented in figure 8 .77. after the 1999à2006 outbreak of wnf in four administrative units in southern russia, a significant outbreak with more than 500 cases arose in the summer and autumn of 2010. the disease spread up to 500 km to the north and northeast from an earlier known endemic area and now includes an additional two administrative units (tables 8.47 the orthomyxoviridae includes six genera of enveloped viruses with a segmented, negative-polarity ssrna genome. the genome of the orthomyxoviruses consists of six (thogotovirus and quaranjavirus), seven (influenza c virus), or eight (influenza a virus, influenza b virus and isavirus) segments. 1,2 all orthomyxoviruses encode three enzymes formed of viral rdrp: pb1 (figure 8.79) , pb2, and pa. these proteins are about 30% similar among viruses of different genera. common structural proteins are np, associated with genomic rna; matrix protein; and two envelope proteins: hemagglutinin, or ha (possesses hemagglutinating activity) and neuraminidase, or na (also called sialidase) in the influenza viruses. viruses of the thogotovirus and quaranjavirus genera are transmitted by arthropod vectors, predominantly ixodidae and argasidae ticks, respectively. viruses of the influenza a virus, influenza b virus and influenza c virus genera are important human pathogens transmitted by a respiratory route. 1 genus isavirus has only one species: infectious salmon anemia virus, which strikes fish in the salmonidae family. genus influenza a virus has just one named species: influenza a virus, represented by numerous antigenic and genetic subtypes. the genome of influenza a virus consists of 8 segments of ssrna that encode 11 or more proteins. 1à5 influenza a viruses are divided into distinct subtypes based on the antigenic and genetic properties of their ha and na proteins. sixteen subtypes of ha (ha1à16) and 9 subtypes of na (na1à9) have been found worldwide in aquatic birds. two additional subtypes of ha (ha17 and ha18) and na (na10 and na11) are seen in new world bats. 4,6,7 h17 and ha18 form a clade distinctly history. influenza as a human disease was originally described in 412 b.c. by hippocrates (figure 8 .82) in his book epidemics, but the "father of medicine" did not consider influenza to be an infectious disease. instead, the famous english physician thomas sydenham (figure 8.83 ) was the first who suggested the infectious nature of the disease. 1, 2 the term "influenza" has been around since the first half of eighteenth century and derives from the italian "influenza di freddo" ("influence of the cold") or from spanish "influencia de las estrellas" ("influence of the stars"), the latter reflecting the contemporaneous belief in astrological reasons for the emergence of disease. 3 up to the nineteenth century, the archaic terms "catarrhus epidemicus," "cephalgia contagiosa," "febris catarrhalis" and "febris comatose" had wide currency. 4 the english word "grippe" (related to the russian "грипп") is related to the german "greifen" ("to catch hold") and derived from the french "gripper" ("to catch hold," "paralyze"); the word gained currency at the beginning of nineteenth century. (cf., e.g., the passage from volume 1, chapter 1 of tolstoy's famous novel war and peace: "she was, as she said, suffering from la grippe; grippe being then a new word in st. petersburg, used only by the elite."). 5 before the nineteenth century, influenza a epidemics were described only qualitatively. subtypes of the etiological agent were retrospectively revealed for the 1889à1892 epidemic (h2n2), the 1897à1900 epidemic (h3n8), and the 1918à1919 pandemic (h1n1, the so-called spanish flu) 5à9 -retrospectively only because influenza a virus wasn't found until 1930 by richard shope (figure 8 .84) on the model of swine (sus scrofa) flu. 10, 11 human flu was found two years later 12,13 by a group of english scientists: wilson smith (figure 8 .85), christopher andrewes (figure 8 .86) and patrick laidlaw (figure 8.87) . during the pandemic of 1918à1919, it was suggested that the etiological agent of influenza a was the socalled afanasievàpfeiffer bacillus," 14à16 named after the russian bacteriologist mikhail afanasiev (figure 8 .88) and the german bacteriologist richard pfeiffer (figure 8 .89)-the modern haemophilus influenzae bacillus. 17, 18 three influenza a pandemics were described after the discovery of the etiological agent: the avian flu has been known under the name "lombardian disease" since the beginning of the nineteenth century. 31à34 in 1878, the italian veterinarian edoardo perroncito (figure 8 .90) described a highly contagious disease (previously named "exsudative typhus of chickens") among chickens, with 100% lethality in the vicinity of turin. 35 the terms "classic fowl plague" and "bird pest" came into wide use in 1901, when a large epizootic outbreak in tyrol province, italy, did away with the population of farm birds there. 33 the term "braunschweig disease" was used to identify an analogous disease among guinea fowls in europe. in 1901, the italian scientists eugenio centanni and ezio savonuzzi demonstrated that the etiological agent of classic fowl plague is a filtrated substance. 34 nevertheless, classic fowl plague wasn't identified as influenza a virus until 1955, by werner shäfer (figure 8 .91) on the example of the historical strain a/chicken/brescia/1/1902 (h7n7). 36, 37 w.b. becker was the first who identified influenza a virus among wild birds when he subtypes of influenza a virus in northern eurasia. at present, we know that numerous avian influenza viruses are abundant in the bird populations of northern eurasia. however, until the end of the 1960s, these data were absent. at that time in the former ussr, avian influenza a virus was being isolated only from poultry. one of the first avian viruses isolated in the ussr-a/duck/ukraine/1/1963-was destined to play an important role in the development of the theory of influenza virus evolution. 43 in 1960à1964, a group of researchers in the ukrainian soviet republic isolated several influenza virus strains from ducklings affected with sinusitis. the first three strains were isolated in 1960 in crimea and in the kharkov astrakhan region 95 24 49 31 11 25 73 16 1 1 5 22 18 67 70 508 volgograd region 380 32 15 15 3 12 63 2 5 411 57 institute of virology in moscow. as early as 1964, the duck strains ya-60, b-60, z-61, and c-61 were analyzed with respect to their antigenic specificity by hit and were found to be antigenically distinct from the human h1 and h2 viruses. 47 after the appearance of the h3 pandemic virus in 1968, some of the ukrainian duck strains were shown to be antigenically 48, 49 moreover, hit testing also showed that the b-60 and bv1 strains of the virus reacted with human sera, including those collected in 1881à1886 and in 1905à1908. on the basis of this phenomenon, the authors suggested that an avian virus similar to the strains b-60 and bv1 was the precursor of the human pandemic strain and that this antigenic variant had appeared in humans several times in the past. 48 formerly known as ya-60, strain a/ duck/ukraine/1/1960 was shown 50 to belong to the h11n2 subtype, whereas a/duck/ ukraine/2/1960 was identified as h3n6 and a/duck/ukraine/1/1963 as h3n8. the highly pathogenic h5n2 and h7n2 strains were isolated from chickens in the moscow region. 51, 52 several virus strains producing enteritis in chickens were isolated in 1972 and in 1974 in chicken farms and identified as h6n2 strains, 51,53,54 an unusual antigenic formula for a pathogenic virus affecting poultry. six h3n2 isolates were obtained in a chicken farm in kamchatka from chickens affected with rhinitis, conjunctivitis, and laryngotracheitis. 51, 55 in 1977, isolates identified as h3n1 viruses were isolated from sick chickens and ducks in the russian federation 25 and uzbekistan in the former ussr. 26 in 1984, h8n4 strains were isolated in the western part of the ukrainian soviet republic from the lungs of ducklings affected with pneumonia. the isolation was the only one of an h8 influenza virus in the ussr (lvov dk, unpublished data). in 1970, a large-scale series of virus isolations from wild birds, combined with some serological studies, was initiated as a part of the coordinated program of the national committee on the studies of viruses ecologically linked to birds together with the virus ecology center of the d.i. ivanovsky institute of virology. by the end of the 1970s, the pattern of circulation of avian viruses in the territory of the ussr was identified. 3, 11, 26, 30 in the ensuing years, the pattern of the influenza a virus subtypes (including h15 and h16) circulating in northern eurasia was amplified (figure 8.92 ). blood sera collected in the spring and autumn of 1970 near lake khanka and peter the great bay (both in primorsky krai) from 262 birds-mainly mallards (anas platyrhynchos), common teals (an. crecca), baikal teals (an. formosa), garganeys (an. querquedula), falcated ducks (an. falcata), pintails (an. acuta), grey herons (ardea cinerea), coots (fulica atra), black guillemots (cepphus grylle) and blacktailed gulls (larus crassirostris)-were hittested against h1, h4, h5, h6, h10, and h11 avian influenza viruses. no antibodies were found in the sera of grey herons and coots, nor were any found against h11 in any species. antibodies against all the other subtypes tested were encountered occasionally in the sera of gulls, black guillemots, and ducks. in some species, such as teals, falcated ducks, and black guillemots, antibodies against several subtypes were detected. 27 in 1972, sera were collected from gulls, cormorants, murres, and tufted puffins in the commander islands. antibodies against h2, h3, h5, and h7 viruses were detected. 28 in 1970à1972, sera from gulls, cormorants, and murres were collected in the kamchatka, sakhalin, and magadan regions and antibodies to h1, h2, h3, h5, h6, and h7 viruses were detected. 30 antibodies against h1, h3, h4, h5, and h7 were identified in sera taken from arctic terns (sterna paradisaea), black-throated loons (gavia arctica), mallards (anas platyrhynchos), common teals (anas crecca), tufted ducks (aythya fuligula), greylag geese (anser anser), skuas (stercorarius sp.), and a blue whistling thrush (myophonus caeruleus) collected in the white sea basin in the estuary of the pechora river in the arkhangelsk region of russia in 1969à1972. 56 the serologic studies suggested a wide range of avian influenza viruses circulating in wild birds in northern eurasia. this suggestion was confirmed and extended by the isolation of virus strains from other wild birds. many avian species proved to be hosts of h1 viruses. a virus belonging to the h1n3 subtype was isolated in 1977 from a tern in the southern part of the caspian sea basin. 57 in 1978, an h1n4 strain was isolated from a common teal (anas crecca) in the russian republic of buryatia in eastern siberia. 41 several h1n1 viruses were isolated in kazakhstan in 1979 from waterfowl, including the common teal (an. crecca), garganey (an. querquedula), shoveler (spatula clypeata), and coot (fulica atra), 58 as well as in 1980 from tree sparrows (passer montanus) and hooded crows (corvus cornix). 41 in 1979, an h1n1 virus was isolated from a hawfinch (c. coccothraustes) in mongolia. 59 in the same year, an h1n2 strain was isolated from a black-headed gull (larus ridibundus) on an island in the northern part of the caspian sea. 41 the avian viruses belonging to the h2 subtype seem not to be abundant in russia. in fact, for a long time the only virological evidence of the presence of this subtype in russia was the isolation of an h2n3 virus in 1976 from a pintail (anas acuta) in primorsky krai. 60 however, serological data suggested that h2 viruses circulated in wild birds not only in primorsky krai, but also in other regions of the far east, including the commander islands as well as the kamchatka, sakhalin, and magadan regions. 54, 61 avian influenza a viruses belonging to the h3 subtype are widespread in northern eurasia. an h3n2 virus was isolated from a common murre (uria aalge) in 1974 on sakhalin island, 62 and another h3n2 strain was isolated in 1976 from a pintail (anas acuta) in primorsky krai. 63 two h3n2 strains were isolated in 1974 in the ukrainian soviet republic from unusual hosts for avian viruses: the white wagtail (motacilla alba) and the european turtle dove (streptopelia turtur). 64 h3n2 strains were also isolated from grey crows (corvus cornix) in 1972 in the volga basin and from a shelducks (tadorna ferruginea) in 1979 in kazakhstan. 65 an h3n2 virus was isolated from a tree sparrow (p. montanus) in 1983 in the ukrainian soviet republic. 66 in 1972à1973, h3n3 and h3n8 viruses were isolated from ducks and herons in khabarovsk krai. one of the viruses closely resembled a strain isolated a year later in central asia. this resemblance demonstrated that h3n3 viruses circulated in regions fairly distant from one another. 67 in 1972à1973, h3n8 viruses were isolated in khabarovsk krai from wild ducks (anas sp.), tufted puffins (fratercula cirrhata), and horned puffins (f. corniculata) 65 and in the arkhangelsk region in the pechora river estuary (white sea basin) from arctic terns (sterna paradisaea) and black-throated loons (gavia arctica). 68 in 1978, h3n8 strains were isolated in the republic of buryatia from a mallard (an. platyrhynchos) and a pintail (an. acuta), 65 as well as in khabarovsk krai from the common murre (u. aalge) 67 and from black-headed gulls (larus ridibundus). 69 avian viruses of the h4 subtype were isolated in 1970à1980 mostly in a narrow belt stretching from the lower volga, through kazakhstan, and on to the south of eastern siberia. several h4n6 strains were isolated in 1976 from slender-billed gulls (chroicocephalus genei) in the volga delta 70 and from great black-headed gulls (ichthyaetus ichthyaetus) on the islands in the northern part of caspian sea. 41 in 1977, h4n8 virus was isolated from the black tern (chlidonias niger) in central kazakhstan. 71 in the republic of buryatia, h4n6 strains were isolated in 1978 from the common goldeneye (bucephala clangula). 41 isolations of h5 influenza viruses from wild birds were scarce. in 1976, several h5n3 strains were isolated from terns (common terns and little terns) and a slender-billed gull in the volga river delta. 70 a detailed description of the penetration of the h5n1 strain of of highly pathogenic avian influenza (hpai) a into northern eurasia and its further dissemination is presented shortly. the strains belonging to the h6 subtype seem not to be abundant, but their geographic distribution is wide. an h6n2 strain was isolated in 1972 from the arctic tern (sterna paradisaea) 68 in the arkhangelsk region (white sea basin). one h6n4 strain was isolated in 1978 from the pintail (anas acuta) in primorsky krai, 41 and an h6n8 strain was isolated from the common tern (s. hirundo) in 1977 in the caspian sea basin. 57 in 2010, two h6n2 strains were isolated on kunashir island (the southernmost of the kuril islands) and four were isolated on sakhalin island. an h7n3 strain was isolated in 1972 from a sandpiper (a member of the scolopacidae family) in the arkhangelsk region of russia. 68 one strain of h8n4 was isolated in 2001 in the republic of buryatia, and one strain in 2003 in mongolia. an h9n2 strain was isolated from a mallard (anas platyrhynchos) 72 in primorsky krai in 1982 and in khabarovsk krai in 2013. over 40 h10n5 strains were isolated from a wide array of bird species near alakol lake in east central kazakhstan in 1979. the strains were isolated from several species of ducks (anas sp.), from shorebirds (members of the order charadriiformes), to passerine birds (members of the order passeriformes), to coots (fulica atra), plovers (members of the family charadriidae, subfamily charadriinae), and chukars (alectoris chukar). 41 this situation is a rare case of an isolation of closely related viruses from an extremely wide array of avian species. the viruses identified as h11n8 strains were isolated in 1972 from the arctic tern (sterna paradisaea) and the red-throated diver (gavia stellata) in the estuary of the pechora river in the northern part of european russia. 54 several h11n6 strains were isolated from the common teal (anas crecca), the european widgeon (an. penelope), and the european golden plover (pluvialis apricaria) in 1979 in eastern siberia. 41 in 1987, h12n2 strains were isolated from mallards, a pintail, and european widgeons south of issyk-kul lake in kyrgyzstan. 72 two strains of h12n2 were isolated from wild ducks (subfamily anatinae) in kyrgyzstan. the results of virus isolation and serological studies in the territory of the ussr in 1970à1980 suggested a wide circulation of avian influenza viruses in wild birds and enabled researchers to construct a map of avian influenza viruses encountered in different regions of northern eurasia. the general pattern of distribution of influenza virus subtypes in wild birds was fairly evident by the end of the decade. virus isolation was continued in the ensuing years, and it brought 290 8. single-stranded rna viruses several major results. isolations were performed mostly in the central and southern parts of european russia, in western and eastern siberia, and in the russian far east. 72 overall, 1,005 strains were isolated from wild birds in russia in 1980à2013 (table 8 .49). about 250 samples were taken yearly from 50 to 100 birds in each geographic region. the mean percentage of successful isolations ranged from 3.5% to 5.7%. over 50% of the isolates were h13 viruses (h13n2, h13n3, h13n6, and h13n8) isolated mostly from gulls and shorebirds in the northern part of the caspian sea. the viruses of the h3 subtype (over 25% of the total number of isolates) were isolated in several regions. many strains isolated in 1979à1985 from great black-headed gulls (ichthyaetus ichthyaetus), herring gulls (larus argentatus) and caspian terns (hydroprogne caspia) on the island of maly zhemchuzhny in the northern part of the caspian sea were not identified at the time of isolation with respect to the subtype of their ha. as it turned out, the strains belonged to the subtype h13, was first described in 1982, 73 and in 1989 the mysterious caspian isolates were identified 74 as h13n2, h13n3, and h13n6. to characterize the h13 subtype molecularly and antigenically, the complete nucleotide sequence of the ha of the strain a/great black-headed gull/astrakhan/ 277/84 was used for comparison with the has of two american strains isolated from a gull and a pilot whale. 75 virus isolation studies in the northern caspian basin were continued in the 1990s and 2000s. materials were collected from wild birds in the area of the northern coast of the caspian sea (including maly zhemchuzhny island) from the delta of the terek river in the north caucasus region to the emba river in western kazakhstan. most of the strains that were isolated belonged to the h13 subtype, including h13n2, h13n3, h13n6, and h13n8 isolates; besides these strains, only single isolates belonging to the h4n3, h4n6, h6n2, and h9n2 subtypes were isolated. 76, 77 in 1990, a new, previously unrecognized, subtype of influenza virus h14 ha was described 78 on the basis of the characterization of two strains isolated in 1982 from mallards (anas platyrhynchos) in the ural river delta. the h14n5 and h14n6 subtypes were isolated from mallards and gulls in astrakhan. 76 a partial sequencing revealed that ns gene of the h14 strains isolated from the gulls was closely related to the ns gene of h9 and h13 strains isolated previously from gulls and terns in the caspian sea basin and to the h9n4 strain isolated in the russian far east. the ns gene of an h14n5 strain isolated from a mallard was much more distantly related to the ns gene of the viruses isolated from gulls. 76 the results suggest that reassortment events play a significant role in the evolution of h14 viruses, with the ns gene being an important determinant of the range of the host. a large-scale isolation of avian influenza viruses from fecal samples was performed in 1995à1998 in eastern siberia and the far east by a group that included both russian and japanese researchers. 79 scientific contacts between russian and japanese researchers of avian influenza a virus were ongoing during the eighth russianàjapanese consultations at a conference titled "protection of migratory wild birds in the asiaàpacific region" held at the russian ministry of natural resources in moscow april 01à05, 2011. at the conference, the d.i. ivanovsky institute of virology took the initiative to renew the international meetings on medical ornithology at the level of experts of asiaàpacific countries that had been taking place regularly during the 1970 and 1980s. as a result, the first international meeting for medical ornithology in the asiaàpacific region was held in tokyo, japan, on june 23, 2011. the meeting was devoted to the topic of hpai h5n1 distribution in asia. a second meeting was conducted in moscow at the d.i. ivanovsky institute of virology march 15à16, 2012 (figure 8.93) . 80 in the summer of 2000 in a valley in the sayan mountains in southeastern siberia, the strains h3n8, h7n1, h7n8, h13n1, and h13n6 were isolated. 81 the h3n8 and h7n8 strains were isolated from ruddy shelducks (tadorna ferruginea) and common redshanks (tringa totanus), the h7n1 strains from common pochards (aythya ferina), and the h13n1 strains from northern shovelers (anas clypeata) and great crested grebes (podiceps cristatus). the h13n6 strains were isolated from all of the aforementioned species, as well as from teals, ducks, and terns. in 2000à2002, the subtypes h3n8, h4n2, h4n6, h4n8, h4n9, h5n2, h5n3, h9n2, and h13n6 were isolated in the same region; 1,750 samples were taken from 48 bird species. 72 a strain isolated from the muskrat (ondatra zibethicus) 81 in 2000 in the republic of buryatia was identified as an h4n6 virus closely resembling the h4n6 strains isolated from ducks in the same year and the same region. 72 the has of the h4 strains (including the muskrat strain) isolated in buryatia formed a separate group of the eurasianàaustralian branch in the phylogenetic tree of h4 ha (figure 8.94 ). they had a c-terminal proline residue in their ha1 subunit, in contrast to the serine residue of most eurasian strains. the ha genes of the h5n2 isolates turned out 82 to have cleavage peptides lrnvpqretr/gl identical to the ones of the low-pathogenic strains isolated from ducks in hong kong and malaysia. in contrast, the has of h3 and h4 strains isolated from teals in 2002 and from mallards in 2003 near lake chany in novosibirsk region western siberia, were related to the has of the european h3 and h4 strains. 83, 84 interestingly, the has of the h3 strains were closely related to the ha of a/duck/ukraine/1/1963 (h3n8). 83 however, unlike the has of h3 and h4, the has of h2 strains isolated in the same area in 2003 from mallards resembled the has of h2 strains isolated in 2001 in japan from mallards (anas platyrhynchos). 84 in 2003, influenza a virus strains belonging to a rare subtype h8n6 were isolated in mongolia from the great cormorant (phalacrocorax carbo), white wagtail (motacilla alba), and magpie (pica pica). 85 penetration of hpai h5n1 into northern eurasia: reasons and consequences. during longitudinal wide-scale monitoring of influenza a viruses among wild bird populations in northern eurasia, several h5n2 and h5n3 strains were isolated in 1976 and 1981 in the caspian sea basin. 70, 74 more recently, in 1991à2001, strains belonging to the same subtypes were isolated in siberia, and their features proved to be relevant to h5 virus circulation. onn the one hand, the has of the strains isolated from teals in 2001 in primorsky krai, as well as the has of strains isolated from a mallard in lake chany in western siberia in 2003, were shown to be closely related to has of h5 strains isolated in 1997 in italy from poultry. 79, 82 on the other hand, the ha of the h5n3 strain isolated from a wild duck as early as 1991 in altai krai in southwest siberia was closely related to the ha of a/duck/malaysia/f119-3/ 1997 (figure 8 .95). the ha of the altai (1991) and lake chany (2003) viruses had a monobasic ha1àha2 cleavage site, and, accordingly, it had a low-pathogenic avian influenza (lpai) phenotype. 72, 79, 82, 86 besides the amino acid sequence of the ha, the sequences of other genes of the h5 viruses isolated in russia proved to be relevant. the np genes of the h5n2 and h5n3 strains isolated in primorsky krai in 2001 formed a separate cluster in the phylogenetic tree, together with the np genes of the h4n6 strains isolated from common shelducks (tadorna ferruginea) and common pochards (aythya ferina) in the republic of buryatia in 2000, the h2n3 strain isolated from the northern pintail (anas acuta) in primorsky krai in 1976, and the 43, 72 however, they were very distantly related to the np genes of h3n8, h6n1, and h5n1 strains isolated from poultry and humans in southeast asia in 1996à2001 and to the np genes of h4n8 viruses isolated from wild ducks in the caspian sea basin in the european russia in 2002. by contrast, unlike the np genes, ns genes of the strains from primorsky krai were closely related to the ns genes of the h5n1 and h4n8 viruses isolated in southeastern asia in 1997à2001, as well as to the ns genes of an h4n8 virus isolated in the caspian sea basin in 2002 (figure 8.97) . 43, 72 an abundance of influenza a subtypes in the avian populations of northern eurasia provides excellent conditions for gene exchange. the extent of the exchange is demonstrated by the relatedness of different genes of the russian isolates to the genes of european strains, on the one hand, and south asia isolates, on the other. 72, 76, 83, 84 the exchange is to a certain extent restricted by host specificity, but this restriction is not rigid, and the virus genes frequently traverse interspecies barriers. avian migration routes crossing russian territory are an important factor in the gene flow. the extensive intra-and interspecies contacts in the natural habitats of wild birds in russia stimulate rapid virus evolution and the appearance of new variants through reassortment events and, presumably, through the postreassortment adjustment of genes, thereby restoring the functional intergenic match. 87, 88 another factor may be the occurrence of avian influenza viruses in lake water, first registered in 1979 in eastern siberia. 41 this phenomenon might provide a means for the temporal as well as territorial transfer of genes, as suggested by the recent detection of influenza 89 thus, the sequencing data suggest that there exists an extensive exchange of genes of the avian influenza viruses circulating in europe, siberia, and southeast asia along the avian migration routes connecting europe, through the russian territory, with southeastern asia, the cradle of potentially pandemic reassortant viruses. after the highly pathogenic h5n1 viruses began disseminating from southeastern 82 our second prediction was that overwintering migrating birds could transmit the hpai virus into northern eurasia during their spring migration. we discussed two possible routes by which the birds might introduce the virus: the dzungarian (indianàasian) migration route and the asianàpacific route. preparing for these two possibilities, we increased our surveillance in the southern part of western siberia (through the russian foundation for basic research project 03-а04-49158) and in primorski krai (through the international scienceàtechnical center project 2800) in the spring of 2004. in april of 2005, a wide epizootic outbreak emerged at kukunor lake (also called qinghai lake) in qinghai province, china, and from this location the virus could spread through the dzungarian gate, which links the northwestern mountain ranges of tibet with the western siberian lowland. our second prediction was confirmed as well, when hpai h5n1 first appeared in northern eurasia, in western siberia (novosibirsk region, russia) in the summer of 2005 (figure 8.98 ). although the official start of the epizootic among poultry was dated july 10, 2005 (table 8 .50), that one occurred among wild birds about 2 weeks before was retrospectively established. 5 the outbreak spread quickly and caused over 90% lethality among poultry. the virus isolations in the area were performed independently by two groups of researchers. a number of strains were isolated in zdvinsky district, novosibirsk region, by a group of researchers from the d.i. ivanovsky institute of virology in moscow. the materials for isolation (cloacal and tracheal swabs, pools of internal organs, and blood) were taken from dead, sick, and healthy birds at the farm where the epizootic occurred and from wild birds in the vicinity. 90, 91 three strains were isolated from dead chickens (gallus gallus domesticus), two strains from sick or dead ducks (anas platyrhynchos domesticus), and one strain from a healthy great crested grebe (podiceps cristatus). all of the strains were deposited into the russian state collection of viruses functioning under the auspices of the d.i. ivanovsky institute of virology ( 93 several features of the primary structure of virus proteins, such as lys627 residue in pb2 and glu92 residue in ns1, characteristic of highly virulent variants of h5n1 viruses, correlated with the high pathogenicity of the novosibirsk isolates. a deletion in the na gene in amino acid positions 49à60 indicated that the strains belonged to the genotype z, which dominated in 2004 in southeastern asia. 94 the other group of strains was isolated by a team of researchers from the state research center of virology and biotechnology vector (also known as the vector institute) in koltsovo, novosibirsk region. two strains were isolated from chickens and one strain from a turkey in the village of suzdalka, dovolnoe district, in july 2005. the viruses were isolated from homogenates guangdong province, china. 95 the viruses were highly pathogenic to chickens in a laboratory test. 96 our third prediction was that the virus would move with the migrating birds to their overwintering locations. as it turned out, coincident with this prediction, epizootic outbreaks occurred along the main migration routse in the urals, the russian plain, europe, africa, central asia, and india figure 8 .99), 102 indicating the distribution of the virus through the eastern european flyway of birds (figure 8 .100), connecting western siberia, the russian plain, eastern europe, the middle east, and africa. 54 our fourth prediction was that the virus would return in birds migrating from their overwintering places to northern eurasia in the spring of 2006, with a widening of the epizootic. dramatic events occurred june 10à28, 2006, at uvs-nuur lake, which is situated on the boundary between the great lakes depression of mongolia and the tyva republic of russia (figure 8.98 ). an estimated 3,000-plus birds died in the russian part of this lake, which is only about 1% of the total area of the lake. the species most affected was the great crested grebe (podiceps cristatus); as also affected were coots (fulica atra) and cormorants (phalacrocorax carbo). terns and gulls were involved in the epizootic to a significantly less extent. the absence of poultry farms in the vicinity of uvs-nuur lake precluded outbreaks among poultry. the tyva strains appeared to be the beginning of a new genetic lineage in the qinghaiàsiberian genotype 2.2. the lineage was designated as a tyvaàsiberian subgroup 104 (figure 8 .99) that was isolated not only in siberia, but also in europe. it is believed (table 8 .51) from dead and sick poultry, and all the isolates were identified as hpai h5n1 (table 8 .52) with a high level of sequence similarity to the qinghaiàsuberian genotype 2.2 (figure 8.99) . this outcome implied a common source of infection for all the local outbreaks ( figure 8.101) , and subsequent epidemiologic investigation demonstrated a link to live-bird markets in moscow, where the affected farmers had purchased poultry several days before. a complete genome analysis of the prototype a/ chicken/moscow/2/2007 revealed 105 group of strains is shown with the use of braces: designations common to all strains in the given group are shown outside the braces; the variable part of the designations is cited inside the braces; the asterisk "*" means "any designation." only mutations that are found in all the strains of the given group are listed in the table. b bold font indicates substitutions with respect to hpai/h5n1/2.2 consensus; the frame -substitutions unique to northern eurasian strains (tables 1à2)-that is, they did not occur among northern eurasian strains previously; the frame with grey background -substitutions unique to all hpai/h5n1/2.2 genotypes (strains isolated in both northern eurasia and other places); {kc-substitution that takes place in the strains of the given epizootic outbreak only; {£c-substitution that takes place in the strains of both the given and later or previous epizootic outbreaks. valley ecosystem in the north or south caucasus in the winter of 2007 and was introduced into the live-bird market through contaminated poultry cages or contaminated grain. in september 2007 , an outbreak was detected in the northeastern part of the basin of the sea of azov on a chicken farm called "lebyazhje-chepiginskaya" in the krasnodar region of russia (figure 8.98) . the virus isolates-a/ chicken/krasnodar/300/2007 from poultry and a/cygnus cygnus/krasnodar/329/2007 from a sick whooper swan (cygnus cygnus) found in a "liman" (shallow gulf) near the farm-were closely related to each other (they had two synonymous nucleotide substitutions in pb1, two synonymous in pb2, one nonsynonymous in m1, two nonsynonymous in na, and one nonsynonymous in ns1) and belonged to the iranànorth caucasian subgroup of qinghaiàsiberian genotype 2.2 (figure 8 .99). the isolated strains contained 10 unique amino acid substitutions with respect to a qinghaiàsiberian consensus in pb2, pa, ha, na, and ns1, suggesting that regional variants were continuing to emerge. 106 in december 2007, a poultry farm called "gulyai-borisovskaya" in the rostov region became infected (figure 8.98) . unfortunately, the infection was not reported in time, and infected poultry manure was spread on adjacent fields, where wild terrestrial birds could be infected. 107 this exposure is thought to have contributed to the infection of a number of species. including rooks (corvus frugilegus), jackdaws (corvus monedula), rock doves (columba livia), common starlings (sturnus vulgaris), tree sparrows (passer montanus), house sparrows (passer domesticus), and more. surveillance of these species by rt-pcr detected h5 virus in 60% of pigeons and crows, in around 20% of starlings, and in 10% of tree sparrows, all without clinical features. these results were confirmed by viruses isolated from wild birds and poultry (table 8 .51). birds whose infection was confirmed by rt-pcr and virus isolation seemed reluctant to move and had ruffled feathers. on necropsy, the birds were observed to have had conjunctivitis; hemorrhages on the lower extremities and in muscle, adipose, intestine, mesentery, and brain tissue; and changes in the structure of the pancreas and liver. wide involvement of wild terrestrial birds in virus circulation, presumably from the exposure to infected chicken manure, distinguished this outbreak from others. genome analysis ( the qinghaiàsiberian clade includes viruses that have infected and caused severe disease and mortality in humans, but currently they do not appear to be transmitted efficiently in humans. upon analyzing representative viruses in our collection for their potential to replicate in mammals, we found that isolated strains replicated effectively in mammalian cell culture lines bhk-21, lech, vero e6, mdck, and spev. 5, 108, 111 pb2 has consensus k627 that promotes virulence in mammalian cells. 93 on the basis of the amino acid sequence of ha receptor-binding sites of qinghaiàsiberian isolates containing e202, q238, and g240, its affinity of qinghai siberian isolates for α2 0 -0 à3 0sialic acids was predicted. however, a double mutation q238 l and g-240 s or just a single mutation e-202 d could switch ha receptor-binding affinity from avian to human receptors. 113 all the qinghaiàsiberian isolates are sensitive to amantadine, rimantadine, and oseltamivir, as has been confirmed by both direct biological experiments in vitro 114 54 the first overwintering area could be the source for the iranànorth caucasian subgroup, the second for the tyvaàsiberian subgroup. returning to their nesting areas in northern eurasia in the spring of 2006, wild birds afforded a mixed virus population the opportunity to spread (figure 8.100) . 5, 24, 28, 42, 43, 108 a decrease in the potential of isolated strains to reproduce in vitro (figure 8 .102) is more evident in poultry (tcid 50 5 11.847à0.272 3 t) than in to wild birds (tcid 50 although hpai h5n1 has penetrated into northern eurasia through the dzungarian flyway of wild birds, this fact did not exclude the possibility of the virus transferring through other flyways -(e.g., through the far eastàpacific flyway). 54 indeed, in april with wild waterfowl. one initial theory of the introduction of the virus to poultry was from the birds' exposure to hunted ducks, but the direct interaction of wild birds with poultry seems more likely. the isolates (see table 8 .51) from dead chickens and the common teal (anas crecca) collected in the vicinity of epizootic farms were identical and indicated a direct role of migrating birds in the introduction of the virus. the teal, which appeared to be the most likely source of infection of poultry, had no obvious behavior changes but did have hemorrhagic lesions in the intestines on necropsy. it is interesting to underline the fact that common teals were the source of isolation of h5 (figure 8.99) . 117, 118 fortunately, both clades (2.2 and 2.3.2.1) of hpai h5n1 that had penetrated into northern eurasia had low epidemic potential because their receptor specificity did not switch from α2 0 à3 0 -to α2 0 à6 0 -sialoside affinity, a fact that was revealed by the primary structure of the ha receptor-binding region and direct testing in sialoside-based experiments in vitro. 5, 80 thus, we discuss the epizootic event provoked by hpai h5n1 in northern eurasia during 2005à2010 as a model of an emer-gingàreemerging situation in need of permanent ecologo-virological monitoring. influenza a viruses among mammals. the circulation of influenza a viruses among swine (order artiodactyla: family suidae, genus sus) was originally established in 1930 by richard shope (figure 8 .84): his investigations not only established the viral etiology of swine flu and isolated the first historical strain a/swine/iowa/15/1930 (h1n1), but also serologically demonstrated the close relation between human infection agents and those of swine. 11 shope's findings gave rise to a number of isolations of swine respiratory disease agents. many of these agents later turned out not to be influenza a virus; for example, "kö be porcine influenza virus," isolated in germany; 119 "infectious pneumonia of pigs;" 120,121 "beveridgeàbetts virus" 122 (more often, these pathogens belonged to chlamydia sp.); and "hemagglutinating virus of japan," 123,124 which initially was named "influenza d virus" and was later identified as sendai virus (sev) (family paramyxoviridae, genus respirovirus). 125 nevertheless, a number of strains isolated at the end of 1940s in korea (strain oti), 126 and in the 1950s and 1960s in lithuania (prototype a/swine/kaunas/353/ 1959), 127 estonia, 128 poland, 129 and russia 130 were identified as influenza a (h1n1) virus. also, in the middle of twentieth century, influenza a strains closely related to a/ swine/iowa/15/1930 (h1n1) were isolated in czechoslovakia 131,132 and hungary. 133 finally, after the beginning of the "asian flu" pandemic in 1957, swine influenza a (h2n2) virus strains were isolated initially in china 134 and later in czechoslovakia 135 the principal peculiarity of pigs is the presence of both α2 0 à6 0 -sialosides (typical of human cells) and α2 0 à3 0 -sialosides (typical of avian cells) on the surface of respiratory tract cells. this feature permits both human (or adapted swine) and bird influenza a virus strains to circulate simultaneously, giving rise to conditions favorable to the reassortment and emergence of virus variants with suddenly appearing new properties. 42,136à143 avian influenza a virus strains have been demonstrated to initiate productive infection in swine under experimental conditions. 31,144à147 the great number of reassortment forms of influenza a viruses isolated from swine constitute evidence of the extremely high reassortment potential of the swine viral population. thus, a/swine/england/191973/1992, isolated from nasal swabs of sick pigs in great britain in 1992, belongs to the unique h1n7 subtype, which was formed by the reassortment of a/ussr/90/1977 (h1n1) (the source of pb2, pb1, pa, ha, np, and ns segments) and a/equine/prague/1/1956 (h7n7) (the source of na and m segments). 148 151 the most evident illustration of the reassortment potential of swine populations is the emergence of the pandemic "swine flu" h1n1 pdm09 in 2009 as the result of the reassortment of two swine genotypes of the h1n1 subtype: the "american swine genotype" (the source of pb2, pb1, pa, ha, np, and ns segments) and the "european swine genotype" (the source of na and m segments) (figure 8.104 ). 24à29 using different receptor-mimicking sialosides (table 8 .55), we investigated the evolution of receptor specificity in influenza a (h1n1) pdm09 virus during pandemic and postpandemic epidemiological seasons. different types of sialoside specificity spectra are presented in figure 8 .105. to compare α2 0 à3 0 -and α2 0 à6 0 -sialoside specificities, we introduced the special parameter w 3/6 , which is the ratio of the optical density for flat α2 0 à3 0 -sialosides (3 0 sl and 3 0 sln) to the optical density for flat α2 0 à6 0 -sialosides (6 0 sl and 6 0 sln): if w 3/6 is ,1 (w 3/ 6 , 1.00), then α2 0 à6 0 -specificity dominates. in contrast, if w 3/6 . 1.00, then α2 0 à3 0 -specificity dominates. (strains with w 3/6 % 1.00 have approximately equal α2 0 à3 0 -and α2 0 à6 0specificities.) 152 the sialoside specificity of the first pandemic strains isolated in our study, a/california/04/2009 (h1n1) pdm09, demonstrates dual affinity to both α2 0 à3 0 -and α2 0 -6 0 -sialosides (figure 8.106) . therefore, such strains might be able to effect swineàhuman and humanàhuman transmission, and their pathogenicity is higher than that of seasonal influenza viruses (w 3/6 % 1 pigs could be the source of influenza a virus not only in humans, but also in synantropic animals. s. agapov published an article on the pathogenic properties of influenza a virus specimens isolated from brown rats (rattus norvegicus) in pigsties. 161 experimental infection of swine influenza a virus strains in rodentsmice (subfamily murinae) and hamsters (subfamily cricetinae)-has been described in a number of publications. 3,133,146,161à163 rodents have become a widely used laboratory model for influenza a virus. productive infection in laboratory mice (order rodentia: family muridae, genus mus) was revealed in a pioneer publication 13 of w. smith (figure 8 .85), c. andrewes (figure 8 .86) and p. laidlaw (figure 8.87 ). adapted to mice, influenza a virus strains are widely used to investigate infectious process, pathology, and the efficiency of antivirals. 161,164à168 in 2000, the strain influenza a/muskrat/ buryatia/1944/2000 (h4n6) was isolated from muskrat (ondatra zibethicus) hunted in the selenga river delta, near where it empties into lake baikal. despite mountain relief along the lake coast, the delta represents a sandbank wedge overgrown with low reeds where the conditions are conducive to a mass nesting of ducks and a high density of population of muskrats. as a result, there is a high level of interaction between the populations of aquatic birds and muskrats. in particular, a/muskrat/buryatia/ 1944/2000 (h4n6) has the highest homology with a/pochard/buryatia/1903/2000 (h4n6). the strain from muskrat turned out to be virulent to mice without any preliminary adaptation, like the majority of h4 strains from siberian ducks. it was suggested that virulence was promoted by an r220g mutation in ha. 72, 81 the russian state collection of viruses contains the influenza a/sciurus vulgaris/ 6su-6 0 sln 6-su-6 0 -sialyllactose: 6-su-neu5acα2-6galβ1-4glcβ primorje/1004/1979 strain with an undetermined subtype isolated from a red squirrel (sciurus vulgaris). 5 weasels (order carnivora: family mustelidae) are another sensitive group of hosts for influenza a viruses. the sensitivity of the domestic ferret (mustela putorius furo), an albino form of the forest polecat (mustela putorius), to the virus was explored even in the earliest scientific publications devoted to influenza a virus. 13, 14 today, ferrets are the best animal model of influenza a virus infection. in particular, sera of infected ferrets (as well as infected rats) are widely utilized for influenza a virus subtype identification. in 1985, japanese scientists demonstrated that the epidemic strain a/kumamoto/ 22/1977 (h3n2) was able to provoke disease in the european mink (mustela lutreola), 169 and perhaps it was this virus that caused a respiratory disease epizootic on japanese fur farms during 1977à1978. in 1984à1985, during an epizootic among minks in sweden, six strains of influenza a (h10n4) virus (prototype a/ mink/sweden/e12665/1984) were isolated and turned out to have an avian origin. 170 in 2007, an influenza a/stone marten/germany/r747/06 (h5n1) strain was isolated from the internals of a stone marten (martes foina) that was found dead in a place where there was mass mortality of birds in germany. 171, 172 the circulation of influenza a virus among cats (order carnivora: family felidae) was originally established in 1942 by the japanese virologists j. nakamura and t. iwasa: strain a/cat/fusan/1/1942 (known as "chiba virus") 173 turned out to be an avian strain of the h7n7 subtype. 168 in 1970, c.k. paniker and c.m. nair described the successful experimental infection of adult cats and eight-monthold kittens by a/hong kong/1/1968 (h3n2), of the "hong kong flu" pandemic strain. 174 a number of h5n1 strains from felidae members-tigers (panthera tigris), 175à177 leopards (p. pardus), 176 and domestic cats (felis catus) 178à180 -were described after 2005. the first experiment involving the infection of dogs (order carnivora: family 178 this strain had an avian origin, but provoked lethal pneumonia in dogs. 186 it is noteworthy that influenza a virus can be isolated from nasal swabs of dogs during inapparent infection, 187 so this virus might be more widely distributed among dogs than is usually considered. influenza a virus is often the cause of pericarditis in dogs. 188 the circulation of influenza a viruses among horses (order perissodactyla: family equidae, genus equus) was originally explored in 1956 by a group of czechoslovakian scientists headed by bella tumova (figure 8 .107). in that year, a widespread epizootic emerged among horses (equus ferus caballus) and the historical strain a/equine/prague/1/1956 was isolated. 189 a subtype of this strain was given an initial designation h eq1 n eq1 and later was identified as h7n7 (but, for a long time, veterinarians designated this subtype as equine influenza type 1). 146 later, influenza a (h7n7) strains were isolated in other european countries 190 and the united states. 191 during the "asiatic flu" pandemic of 1958à1961, a number of strains of influenza a (h2n2) were isolated from sick horses in the moscow region of the former ussr 192 hungary. 133, 163 it was shown that these strains were significantly different from a/equine/ prague/1/1956 (h7n7), belonged to the h2n2 subtype, and had a human origin. equine influenza a type 2 was originally found in 1963 in miami, florida, in the united states, when the prototypical strain a/equine/ miami/1963 was isolated and designated as subtype h eq2 n eq2 . 193 later, this subtype was identified as h3n8 and was multiply isolated 194à196 in both north and south america. in the former ussr, influenza a (h3n8) virus strains were isolated from horses in the ukrainian soviet republic during a widespread epizootic in 1970 in the vicinity of kiev. 31 the russian state collection of viruses contains the influenza a/equine/mongolia/3/ 1975 (h5n3) strain, which originates from birds and over came the interspecies barrier to penetrate into the equine population. the circulation of influenza a virus among camels (suborder tylopoda: family camelidae, genus camelus) was originally established by d. k. lvov 59 (figure 2 .36) in 1980. in december 1979, an epizootic of "contagious cough" among bactrian camels (camelus bactrianus) emerged in mongolia. thirteen strains were isolated from nasal swabs; 59 145, 198 tajikistan, 199 and the ukrainian soviet republic in the former ussr. 31 the circulation of influenza a viruses among cattle has been confirmed by multiple serological data. 31,200à204 the first isolation of influenza a strain from sick sheep (ovis aries) (order artiodactyla: family bovidae, subfamily caprinae) was carried out in 1959 by a group of hungarian scientists under the direction of g. takatsy during an epizootic among farm animals. 133, 163 the strain a/sheep/hungary/b111/59 (h2n2) isolated by takatsy was later utilized by j.l. mcqueen and f.m. davenport for experimental infection in lambs, but they observed no clinical symptoms. 205 the circulation of influenza a viruses among deer (order artiodactyla: family cervidae) was originally established by t.v. pysina and d.k. lvov when they isolated the a/rangifer tarandus/chukotka/1254/77 (h6n2) strain from slowed reindeer (rangifer tarandus) in the chukotka peninsula. 206 the russian state collection of viruses in the d.i. ivanovsky institute of virology contains the strains a/ deer/primorje/1201/78 (h1n1), isolated from red deer (cervus elaphus) in primorsky krai, and a/rangifer tarandus/yamal/865/90 (h13n1), isolated from reindeer (r. tarandus) on the coast of the barents sea. specific antibodies towards influenza a (h1n1) and a (h3n2) were detected in the sera of red deer (c. elaphus) and elks (alces alces) in the north of germany. 207, 208 s.q. li established the presence of about a 10% immune layer toward influenza a (h1n1) and a (h3n2) among cervidae in the northeastern provinces of china. 209 the strain influenza a/whale/pacific ocean/19/1976 (h1n3) (or, alternatively, a/ whale/po/19/1976) from a whale belonging to the balaenopteridae family (order cetacea, suborder mysticeti) and bagged in the south pacific ocean was isolated by a group of soviet virologists under the direction of d.k. lvov 210 (figure 2 .36) in 1976. this strain turned out to be reassortant between human and avian virus variants. 211 two strains of influenza a virus were isolated by a group of american virologists under the direction of r. webster 212 (figure 2 .20) from slowed long-finned pilot whales (globicephala melaena) near portland, maine, in the united states in 1984: a/whale/maine/1/84 (h13n9) (from periapical lymph nodes in the lungs) and a/whale/maine/2b/84 (h13n2) (from the lungs). further molecular genetic investigation, carried out by a russianàamerican group of scientists, revealed that influenza a variants in gulls (family laridae) were the source of these strains. 75 a number of influenza a virus strains were isolated on the coast of north america: h4n5, 213 h4n6, 214 and h7n7. 215, 216 thus, one could expect to find influenza a viruses among seals in northern eurasia as well. pathogenesis. epithelial cells of mucous membranes are the main targets of influenza a viruses. degeneration, necrosis, and further apoptosis, followed by tearing away of the epithelial cell layer take place as a result of the infection. nevertheless, the main element of influenza a virusàinduced pathogenesis is lesions on the system of vessels; the lesions emerge as the result of the toxic effect of the virus, an effect that includes the multiple formation of active oxygen forms. the latter provoke the generation of hydroperoxides, which interact with lipids and phospholipids of the cell wall to oxidize their peroxide, thereby hindering transport across the cell membrane. 217à219 a subsequent increase in the permeability of vessels, the fragility of their walls, and a violation of the body's microcirculation result in hemorrhagic manifestations, from nasal bleeding to hemorrhagic hypostasis of the lungs and hemorrhages in the substance of the brain. 219, 220 frustration of the circulation, in turn, defeats the nervous system. the pathomorphological picture is characterized by the existence of lymphomonocytic infiltrates around small and average-size veins, hyperplasia of glial elements, and a focal demyelinization that testifies to the toxic and allergic nature of the pathological process in the cns during influenza. 219, 221, 222 the most significant factors involved in cell tropism of the influenza a virus are the receptor assembly on the surface of the potential target cell and the ability of cell proteases to cleave ha into two subunits (ha1and ha2) followed by fusion peptide rescue. 223à227 for example, for avian influenza a virus variants, there is an obvious threshold in the virulence level: so-called lpai and hpai. hpai strains strike vascular endothelial and perivascular parenchymal cells as well as the cardiovascular system, quickly reproduce high titers in practically all internal organs, and cause systemic disease leading to death of a bird 1à7 days after infection. lpai strains, to the contrary, reproduce in low titers, have a narrow tropism toward mucous in the digestive and respiratory tracts (figure 8 .108), and cause enteritis or rhinitis with low mortality. (however, bird diseases connected with lpai also cause significant damage to agriculture and can break the interspecies barrier, resulting in diseases that are dangerous to people). wild aquatic and semiaquatic birds, which are natural reservoirs of influenza a viruses, can have inapparent disease during either lpai or hpai infection. 5,24,27,28,39,41à43,53,226,228à230 the ability of ha to be cleaved by proteases depends on the amino acid composition of the proteolytic cleavage site: lpai strains contain only one or two positively charged basic amino acids (k or r), whereas hpai strains have an enriched amount of basic amino acids. 5,24,27,28,39,41,228à230 nevertheless, pandemic strains with extremely high virulence in humans have only single basic amino acids within the limits of the proteolytic cleavage site (table 8 .58). still, it is noteworthy that lpai could provoke human disease as well. except for the amino acid composition of the proteolytic cleavage site of ha, the efficiency of the cleavage process depends on glycosylation of ha in the vicinity of this site. 231, 232 amino acid substitutions that switch virus tropisms from avian to mammalian cells in different influenza a virus proteins have been described: e627k, 112 144, 146, 219, 221 the classic diagnostic approach is to isolate the virus with the use of sensitive biological models (ferrets, developing chicken embryoa, and cell lines). influenza a virus infection could be retrospectively detected by hit 239 or neutralization testing, but the most effective diagnostic methods are rt-pcr and biological microchips. control and prophylaxis. vaccination, together with the forced slaughter of livestock. is the most effective and accessible approach to influenza a prophylaxis among domestic animals. each country chooses its own strategy for combining these methods. for example, in russia only livestock in small and individual farms is to be vaccinated whereas birds in poultry farms are not vaccinated, but are killed if either hpai or lpai is detected. 32 the genome of the quaranjaviruses consists of six segments of negative ssrna. segments 1à3 encode the proteins of a replicative polymerase complex (polymerase basic protein 2, or pb2; polymerase acidic protein, or pa; and polymerase basic protein 1, or pb1, respectively). the pb1 protein (polymerase 1 basic protein, rdrp) is one of the most conservative proteins of all viruses with a segmented rna genome. the amino acid sequence similarity of the pb1 protein among the viruses of different genera in the orthomyxoviridae family is 25à30%, on average, but the similarity of the functional domains of rdrp (pre-a, a, b, c, d, and e motifs) is 40à50% (figure 8.110) . the envelope glycoprotein gp (ha, segment 5) of the quaranjaviruses has a very low similarity to the homologous protein (ha, segment 4) of influenza viruses. however, it has some similarities tgo the surface glycoprotein of the baculoviruses. 1 the amino acid sequences of thogotovirus genus members have about 20% identity with qrfv and tlkv. two other segments of the genome (segments 4 and 6) of the quaranjaviruses encode two proteins whose function is unknown. these proteins are probably structural proteins, which act as nucleocapsid (n) and matrix protein (m), respectively, but currently their function is not well known. other viruses of the quaranjavirus genus have been found in south africa, nigeria, egypt, iran, afghanistan, and oceania. the quaranjaviruses are associated with argasidae ticks (argas arboreus, a. vulgaris, ornithodoros capensis), which are obligate parasites of birds. 3 tlkv has been classified into the quaranfil group of the orthomyxoviridae family on the basis of its antigenic reactions. 4à14 taxonomy. like the other members of the quaranjavirus genus, tlkv has a genome that consists of six ssrna segments. 13 the pb1 protein amino acid sequence of tlkv has 86% and 84% identities with qrfv and jav, respectively (table 8 .61). the similarity of the pb2 and pa proteins of tlkv to those of orf virus (orfv) is 70%, on average. the envelope glycoprotein (gp, segment 5) of the quaranjaviruses has very low similarity to the homologous protein (ha) of influenza viruses. however, it has some similarities to the surface glycoprotein of the baculoviruses. 4 the similarity of the gp of tlkv to that of qrfv is 72% nt and 80% aa (table 8 .62). segment 5 of tlkv has one orf and encodes a protein with unknown function (524 aa). its similarity to the same protein of qrfv is 85% aa. segment 6 encodes a protein 266 aa long, which has no homology with any of the virus's proteins that are deposited in the database genbank. the similarity of this protein in tlkv and the same protein in qrfv is 60%. figures 8.110 and 8.112 show the results of phylogenetic analysis based on a comparison of pb1 and the envelope protein (gp and ha, respectively). on the phylogenetic trees, tlkv is grouped with qrfv and jav within the quaranjavirus genus. 13 arthropod vectors. natural foci of tlkv associated with argas vulgaris ticks in kyrgyzstan are located below the northern border of the area of distribution of argasidae ticks (43 % on). this boundary coincides with the line of a frost-free period of 150à180 days a year and an average daily temperature above 20 for no less than 90à100 days per year. the ability of these ticks to withstand prolonged starvation (up to 9 years), as well as their long life cycle (25à30 years), polyphagia, and ability to transfer viruses transovarially, provides stability of the virus's natural foci. 1à3,15à18 animal hosts. tlkv was isolated from argasidae ticks collected in the nesting burrows of birds. complement-fixation testing of the birds from these colonies revealed that qrfv have been found in 2.6% of the human population. 11 the genus thogotovirus currently includes four viruses: thogoto virus (thov), dhori virus (dhov), araguari virus (argv), and jos virus (josv). 1, 2 the viruses of thogotovirus are arboviruses, transmitted mainly by ixodidae ticks; therefore, the genus had previously been called orthoacarivirus, to emphasize these viruses' association with ixodids (taxon acari: order parasitiformes, family ixodidae). thov was originally isolated from the ticks rhipicephalus (boophilus) decoloratus and rh. evertsii collected from cattle in thogoto forest, nairobi, kenya, in 1960. subsequently, it was isolated from human, cows, camels, and ticks in many countries in africa. 3, 4 the genome of the thogotoviruses consists of six segments of negative-polarity ssrna that encode seven proteins. (segment 6 encodes two forms of matrix protein.) 1, 2 the most conservative proteins of the replicative complex (pb1, pb2, pa) of thogotoviruses have 25à30% identity with those of the influenza a virus genus. history. dhori virus (dhov) was originally isolated from hyalomma dromedarii ticks collected from camels in india. 1 dhov has also been isolated in egypt, portugal, russia, and transcaucasia. 2à7 in russia, several strains of dhov were isolated from h. plumbeum ticks, anopheles hyrcanus mosquitoes, and lepus europaeus hares, all in the volga river estuary. 5, 7 one strain of dhov was isolated from the cormorant phalacrocorax carbo in maly zhemchuzhnyi island in the caspian sea (45 00 0 n, 48 18 0 e; figures 8.113 and 8.114 ). 4 the prototypical strain of batken virus (bknv), leiv-k306, was isolated from hyalomma marginatum ticks collected from sheep near the town of batken in kyrgyzstan in april 1970. 8 other strains of bknv were isolated from a mixed pool of aedes caspius and culex hortensis mosquitoes in kyrgyzstan 9 and from ornithodoros lahorensis and dermacentor marginatus ticks in transcaucasia. 10 antigenic studies showed that bknv is closely related to dhov, but differs from it. 8 taxonomy. the similarity of the structural homologous proteins of the thogotoviruses (thov, dhov, argv, and josv) ranges from 25% (m-protein, segment 6) to 45% (np, segment 5). the envelope protein ha (segment 4) has 35à45% identity, on average. the similarity of the nonstructural proteins (pb1, pb2, and pa) ranges from 60% to 74%. bknv has a high similarity to dhov. the proteins are 96% (pb2, pa, np, m) and 98% (pb1) identical. the similarity of the envelope protein ha of bknv to that of dhov is 90%, a percentage that explains the antigenic differences between these two closely related viruses. because the homology of the other structural and nonstructural proteins of bknv and dhov is 96à98%, it can be concluded that bknv is a variant of dhov, typical to central asia and transcaucasia. a phylogenetic analysis based on a comparison of the pb1 and ha proteins is presented in figures 8.110 and 8.112 . arthropod vectors. apparently, the main arthropod vector of dhov and bknv is hyalomma sp. ticks-in particular, h. marginatum. dhov has also been isolated from h. dromedarii, dermacentor marginatus, and ornithodoros lahorensis ticks. rare isolations of dhov and bknv from mosquitoes (anopheles hyrcanus, aedes caspius, and culex hortensis) suggest that they play some role in the circulation of these viruses. 9 vertebrate hosts. antibodies to dhov were found in 100% of camels, 19% of horses, and 2% of goats in the indian state of gujarat, where the virus was first isolated. antibodies to bknv were found in 1.0% of sheep and 1.3% of cattle in kyrgyzstan. 9 two strains of dhov were isolated from a hare (lepus europaeus) and a cormorant (phalacrocorax carbo) in natural foci of the virus. 4, 5 the bird, from which dhov was isolated on maly zhemchuzhnyi island, was ill with respiratory failure, inability to fly, and loss of coordination 4 (figure 8.114c) . human disease. several cases of disease caused by dhov have been registered. 11 the disease occurred with fever, encephalitis (40%), headache, and weakness. antibodies to dhov were found in 4à9% of the population in the volga river delta (in the south of russia) and in 0.8% in the south of portugal. 12 antibodies to bknv were found in the sera of 0.3% of the human population of kyrgyzstan. five cases of laboratory infection were identified. 11 the togaviridae family consists of two genera (alphavirus and rubivirus) of enveloped rna viruses. the virion of the togaviruses (70 nm) contains a core particle (40 nm) formed by a capsid protein and comprising a single-stranded, positive-sense genomic rna 11,400à11,800 nt long. the lipid bilayer contains the heterodimers of two surface glycoproteins e1 and e2, which form an icosahedral surface of the virion. the genomic rna has a cap structure at the 5 0 -and poly-a tail at the 3 0 -end, as well as two orfs encoding nonstructural and structural proteins. the nonstructural proteins are encoded by the 5 0 -orf (which occupies two-thirds of the genome), whereas the structural proteins are encoded by the subgenomic 3 0 -orf. 1 most viruses of the alphavirus genus are arboviruses and can replicate in either a vertebrate host and or an invertebrate vector. 2, 3 the rubivirus genus consists of one species-rubella virus-that is transmitted by aerosol and is the causative agent of disease known as rubella. 4,5 the genome of the alphaviruses is a singlestranded rna with positive polarity about 11,500 nt in length. the viral rna has a cap at the 5 0 -end and a poly-a tail at the 3 0 -end. a large part of the genome of the alphaviruses (about two-thirds, beginning from one-third into the genome and extending to the 5 0 -end) encodes nonstructural proteins that form the viral replicative complex nsp1, nsp2, nsp3, and nsp4). structural proteins (core, e3, e2, 6k, and e1) are translated from subgenomic rna (26s rna), which is formed in the process of replicating the virus and corresponds to the other one-third of the genome (figure 8.115 ). 1 the alphaviruses can infect a wide range of vertebrates. most of the alphaviruses are arboviruses and are associated with mosquitoes (genera culex, culiseta, aedes, coquillettidia, and haemogogus) and birds, the latter of which can transfer viruses during migration. 2à4 other vertebrate hosts of the alphaviruses are ruminants, reptiles, amphibians, and fish. 5, 6 the alphaviruses are divided into 10 antigenic complexes. among the alphaviruses are dangerous pathogens of humans or animals, such as eastern equine encephalitis virus (eeev), western equine encephalitis virus (weev), sindbis virus (sinv), chikungunya virus (chikv), and others. 7 history. chikv (family togaviridae, genus alphavirus, semliki forest group) is the etiological agent of a fever that is mortally dangerous to humans. this disease is accompanied by joint and muscle pains (right up to complete immobilization of the patient) and a two-wave course of the fever, together with a macu-laràpapular rash emergency (usually during the second wave). 1 the etymology of the name "chikungunya" is {chee-kungunyalac, which, in the makonde local language, means "doubled up," owing to the severe joint pains. chikv was originally isolated by r.w. ross from the serum of a patient with fever during the decoding of an epidemic outbreak in tanzania in februaryàmarch 1956. 2à4 the close relation of chikv to mayaro virus (mayv), from the semliki forest group, was demonstrated in 1957 by serological methods. 5, 6 distribution. chikv was also isolated in cambodia in southeastern asia in 1963, 7 in hindustan in 1964, 8, 9 and in the eastern part of new guinea in 2012. 10 the basic area over which chikv is distributed (table 8. taxonomy. chikv belongs to the togaviridae family, alphavirus genus, semliki forest group. on the basis of comparative analysis of the e1 gene, chikv was classified into three genotypes: a (asian), cesa (centre, east, and south african), and wa (west african) 1,12à14 (table 8. vertebrate hosts. rodents, bats, and monkeys are the natural reservoir of chikv. 1,11à14,46 there is substantial evidence, that, in africa, wild primates play an important role in the natural transmission cycle, but it is not clear whether infection in primates is incidental to or necessary for the maintenance of the virus. in uganda, chikv was frequently isolated from aedes africanus mosquitoes, which preferto feed on monkeys in the forest canopy. 47 specific anti-chikv antibodies were found among chimpanzees (pan troglodytes) in equatorial and savanna forests in the democratic republic of the congo (kinshasa) 48 and in savannas in southern africa. antibodies were found over a wide area in vervet monkeys (cercopithecus aethiops) and baboons (pipio ursinus), and in both species the virus could circulate in the blood for two to three days at high concentrations without evidence of illness. 49 so, wild animals could play an important role as amplifying hosts. 49 chikv was isolated in dakar , senegal, from bats, which developed viremia after experimental infection. but in india, inoculation of the virus into two species of fruiteating bats was followed by low virulence. 50, 51 antibodies were found among donkeys, bats, and wild rodents in africa 52 and among domestic animals in asia. 49, 50 inoculation of african strains into cattle, sheep, goats, and horses failed to produce viremia. apart from chickens, adult fowl and several species of wild birds did not develop viremia after experimental infection. but experimental infection of vervet monkeys and baboons led to high viremia (up to 8 log 10 pfu/ml) during six days, which is sufficient for the infection of mosquitoes. 53 arthropod vectors. chikv is transmitted by bloodsucking mosquitoes. the main vectors for this virus during epidemics are aedes aegypti and ae. albopictus in urban regions and mosquitoes from the aedes, culex, and coquillettidia genera in rural landscapes. 1,11à14,46 chikv has been multiply isolated from ae. africanus, ae. luteocephalus, ae. furciferàtaylori, cx. fatigans, and coq. fuscopenatta, all of which could preserve the virus and realize virus circulation in natural foci. 1, 54, 55 epidemiology. a high level of viremia in humans (up to 8 log 10 pfu/ml) makes it possible for mosquitoes to transmit chikv from human to human 1 -a plausible reason that large epidemic outbreaks have been known in big cities of southern and southeastern asia since the 1960s. 11,13,56à58 beginning in the middle of the 1980s, epidemiological processes linked to chikv have intensified (table 8 .63), although this fact could be explained by improvements in laboratory diagnostics: previously, chikungunya fever was often confused with dengue. in any event, chikvprovoked lethality has increased, in some cases up to 4.5%). 1, 59 increases in the frequency of imported chikungunya fever cases seen at the beginning of the twenty-first century (table 8 .63) are most dangerous, especially when the possibility of chikv penetration into local mosquito populations is taken into account. since 2006, imported cases of chikungunya fever have become more frequent in europe (italy, 15, 38, 60, 61 spain, 39 france, 35, 44, 62 belgium, 35 switzerland, 35 germany, 35 the czech republic, 35 norway 35 ); the americas (canada, 13 the united states, 35, 63 brazil 44 ); eastern asia (hong kong, 36 south korea, 40 japan 37,45 ); and australia. 33 outbreaks in brazilian cities emerged with infections from aedes aegypti, whereas in rural regions aedes albopictus was the vector, introduced from southeastern asia, 44 including japan. 64 imported cases of chikungunya fever in russia. a 59-year-old patient arrived in russia september 22, 2013 , and suddenly fell ill, with a body temperature of 38.7 c. antipyretic drugs were not effective. early in the morning on september 24, 2013 , the patient was delivered to a moscow infection hospital with a diagnosis of "fever with unknown etiology." the fever had mid-level severity, and the patient complained of shivering, headache, and asthenia. hyperemia of the conjunctivae, papularàhemorrhagic rash on the abdomen, and cruses were found. a medical radiolograph (figure 8 .116) of the lungs of the patient revealed decreased clarity at the back of the lung field and diffuse reticular pneumosclerosis in the right lower lobe pyramid, as well as local changes with expressed peribronchial and perivascular alterations. a round shadow was detected near (i.e., peribronchially to) the intermediate bronchus. the roots were intensified. the heart was enlarged at the left. thus, the medical radiography portrait was consistent with rightside pneumonia with lymphadenopathy. several peculiarities of the case were the bareness of clinical symptoms (pneumonia was diagnosed only via medical radiography), a rapid progression of changes in the lungs, and the absence of inflammation markers in the peripheral blood. three days later, positive dynamics were detected: the basal parts of the right lung were restored to their previous level of clarity, although the shadow indicating a hypertrophic lymph node and right root broadening remained. bioprobes (blood swabs and nasopharyngeal swabs) were delivered to the d.i. ivanovsky institute of virology. the absence of influenza a and b viruses was established by rt-pcr. the strain chikv/leiv-moscow/1/2013 was isolated with the use of intracerebrally inoculated newborn mice and was identified with the help of a completegenome (genbank id: kf872195) nextgeneration sequence approach. phylogenetic analysis (figure 8 .117, table 8 .64) revealed that the chikv/leiv-moscow/1/2013 strain belonged to an asian genotype. this strain was deposited into the russian state collection of viruses (deposition certificate n 1239 with a priority of november 11, 2013). 65 serological methods revealed eight cases of imported chikungunya fever that had previously been described in russia: 66 from indonesia, singapore, india, the island of réunion, and the maldives islands. the chikv/leiv-moscow/ 1/2013 strain was found to belong to the a-genotype, whereas most of the cases imported into europe belong to the cesa genotype, reflecting the "bridge" role of russia between europe and asia. the modern-day intensification of both international links and transport flows among countries increases the probability of imported cases of infection emerging. the penetration of aedes aegypti and aedes albopictus to the russian black sea coast 1,67,68 suggests the emergence of seasonal outbreaks in the dynamically developing greater sochi region as well. history. getah virus (getv) was originally isolated in western malaysia from culex gelidus and cx. tritaeniorhynchus mosquitoes. 1à3 this virus is widespread in southeastern asia and in australia. 3à5 the first isolation of getv in northern eurasia was carried out by m.p. the genome of getv is 11,598 nt long. the strains of getv, circulating in different geographical regions of northeastern and southeastern asia, have a high level of similarity. 8à11 a pairwise comparison of complete genome sequences revealed that isolates from malaysia, south korea, china, mongolia, japan, and russia have 96à98% nt identities, suggesting that the rate of getv evolution is low. phylogenetic analysis of the e2 gene ( figure 8.118) is not conducive to dividing the getv strains into distinct clusters. analyses of numerous strains isolated in japan showed that genetic differences were determined by the time of isolation more than the place of isolation. 8 an analysis of 21 strains of getv isolated in different regions of russia revealed their high degree of similarity, but still, they could be divided into three groups on the basis of minimal differences. the first group comprises strains from tundra and for-estàtundra in the magadan region and the sakhaàyakutia republic in the north of asia. the second group encompasses strains from leaf-bearing forests of khabarovsk krai. the third group consists of isolates from forestàsteppe and steppe landscape belts of khabarovsk krai, the republic of buryatia, and mongolia. 10, 12 distribution. according to our data, 6,10,12à22 getv is distributed over eastern siberia and north pacific physicogeographical lands (figure 8.119) . the most intensive virus circulation was revealed in the steppe landscape belt of mongolia, as well as in the mixed forests of khabarovsk krai and in the northern taiga of the magadan region and the sakhaàyakutia republic. getv circulation intensity is significantly lower in tundra and forestàtundra landscapes, a phenomenon that could be explained by the temperature there. getv is the only member of the alphavirus genus whose distribution extends to the rough climatic conditions of the high latitudes of northern eurasia. 18, 19 getv has penetrated to the north of asia from the overwintering places of birds, which regularly migrate by the east asian flyway 17, 23 (figure 3.2) . the distribution of the virus in the north coincides with that of aedes mosquitoes, which are the effective vector of getv. getv and closely related viruses are known outside of northern eurasia in japan, various countries in southeastern asia, and australia. 1à3,5,24à29 human infection. the pathogenicity of getv to humans has not yet been described. nevertheless, the antigenically close rrv has been associated with large epidemic outbreaks of polyarthritis in australia and sarawak. 2, 4 vertebrate animal infection. symptomatic and subclinical infections of animals were reported in 1998 in japan, where there was a large outbreak involving 722 racehorses. 30, 31 among the clinical features seen were fever, rash on various parts of the body, and edema on the hind legs. virus isolates were more similar to the prototypical malaysian strain than to the japanese sagiyama strain. getv has been implicated in illness and abortion or stillbirths in pigs. 32,33 disease among horses was described in india. 34 infection in cattle is usually subclinical. 3 arthropod vectors. getv has been isolated from culex gelidus, cx. tritaeniorhynchus (malaysia, cambodia, china), cx. bitaeniorhynchus, anopheles amictus (australia), cx. vishnui (philippines); the sagiyama subtype of getv was isolated from cx. tritaeniorhynchus and aedes vexans, as well as from pigs with fever, in japan. 27, 35 although their natural transmission cycle is not known in details, mosquitoes acquire getv mainly while feeding on domestic mammals and fowl. there may also be a jungle cycle involving wild vertebrates. 5 the bebaru subtype was isolated from culex lophoceratomyia and aedes spp. mosquitoes collected in mangrove swamp forests of western malaysia. 32 the main vectors in russia (i.e., in northern eurasia) are aedes nigripes, ae. communis, ae. impiger, ae. punctor, and ae. excrucians. 18 4, 13 kfv was first noted in the summer of 1981 in the central and southwestern parts of fennoscandia, including russia, finland, sweden, and southern norway (figure 8 .120). 14 the prototypical strain leiv-65a of kyzv was first isolated from culex modestus mosquitoes collected in a colony of ardeidae birds (herons) in kyzylagach reservation, located on the coast of kyzylagach bay in the caspian sea (39 10 0 n, 48 58 0 e; figure 8 .120). 15 taxonomy. on the basis of a comparison of a partial sequence of the e2 gene, isolates of sinv can be divided into five genotypes (figure 8 .121). 9 genotype i includes viruses from europe and africa, genotype ii isolates from australia and oceania, and genotype iii viruses from india and the philippines. together with the chinese strain sinv xj-160, kyzv was assigned to genotype iv. genotype v consists of only the strain m78 from new zealand. the strains of genotype i form two subclusters, one of which comprises sinvs from northern europe and sub-saharan africa and the second of which consists of strains from the mediterranean region (southern europe, northern africa, and the middle east). 9 the genetic distance between the viruses of the different genotypes of sinv (e.g., between the european and australian isolates) is not more than 23% nt (table 8 .65). at the same time, sinvs isolated in the same geographic region are characterized by a high degree of similarity (figure 8.122) . thus, sinv strains isolated in russia, germany, sweden(ockv), and finland have about 99% similarity (table 8 .65). 3, 5, 6, 11 babanki virus, which is from cameroon, has 98% similarity to the european strains of sinv. despite the high degree of similarity among the different genotypes of sinv, known cases of human disease are caused only by strains of the europeanàafrican subcluster of genotype i (karelian fever, a disease of ockelbo, a disease of babanki). kyzv has a high similarity (99%) to the chinese isolate sinv xj-160, isolated from anopheles sp. mosquitoes in the xinjiang uighur autonomous region in the northwest of china. 16 the divergence of kyzv and xj-160 from the european isolates of sinv is 18% nt and 7% aa of the entire genome sequence (table 8 .65). the geographic isolation of kyzv and xj-160 and their genetic divergence from the european and australian isolates suggest that kyzv is a variant of sinv that is typical to central asia. distribution. sinv has been isolated in many regions of southern europe, the middle east, africa, southeastern asia, the philippines, and australia. 2, 17, 18 the african continent is almost all endemic for sinv: strains are known from egypt, the republic of south africa, uganda, the central african republic, sudan, nigeria, and zimbabwe. as for asia, there are strains from turkey, india, malaysia, and the philippines. in australia, sinv strains were multiply isolated in the north of the continent. in europe, sinv has been isolated in sicily (italy) and slovenia. on the territory of the former ussr, sinv strains were multiply isolated in belarus, ukraine, azerbaijan, tajikistan, and western siberia (in the areas around the central region of the ob river valley). 17à19 . vertebrate hosts. the main vertebrate hosts of sinv are different species of birds, predominantly of the orders passeriformes, pelecaniformes, ciconiiformes, and anseriformes. sinv infection in birds can chronic, allowing them to transfer the virus during their seasonal migration. 17à20 migratory birds play an important role in the wide distribution of this virus. sinv has been known to persist for as much as two months after experimental infection. sinv strains have been multiply isolated from aquatic and semiaquatic birds in the delta of the nile river in egypt, from the white wagtail (motacilla alba) and the common hill myna (gracula religiosa) in india, and from the reed warbler (acrocephalus scirpuceus) in the western part of slovakia. in zimbabwe, sinv has been isolated from insectivorous bats of the rhinolophidae and hipposideridae families. 2 occasionally, sinv has been isolated from rodents and amphibians. on the territory of the former soviet union, sinv was originally isolated from a yellow herons (ardeola ralloides) caught out of a bird colony in the southeastern part of azerbaijan in 1968. serological methods have revealed sinv circulation in the astrakhan region among aquatic and semiaquatic birds, especially those of the orders pelecaniformes (18%), ciconiiformes (15%), and anseriformes (11%). neutralizing antibodies to sinv were found in coots (fulica atra) (16.7%) from natural foci of the middle belt of the volga river delta. in the kuban river delta in krasnodar krai, specific anti-sinv antibodies were found among eight species of aquatic and semiaquatic birds, most frequently mallards (anas platyrhynchos) and purple herons (ardea purpurea). in belarus, anti-sinv antibodies were detected in 4% of birds in the summer and in 0.4% in the fall. 21 antibodies to sinv have been detected among farm animals (table 8. cattle (17.5%) and horses (15.0%) in the middle belt of the volga river delta. arthropod vectors. sinv is closely associated with ornithophilic mosquitoes. in egypt, this virus was isolated from culex univittatus, cx. antennatus, and anopheles pharoensis; in uganda, from coquillettidia spp.; in sarawak, (malaysia), from cx. bitaeniorhynchus; in australia, from cx. annulirostris, aedes normanensis, and ae. vigilax; in india, from coq. fuscopennata; in sudan, from cx. quinquefasciatus; and in europe, from cx. pipiens, cx. torrentium, culiseta morsitans, coq. richiardii, ochlerotatus communis, oc. excrucians, ae. cinereus, and an. hyrcanus. 22, 23 according to our data, in the volga river delta sinv is transferred by culex pipiens in anthropogenic biocenoses and by anopheles hyrcanus and coquillettidia richiardii in natural ones. in the natural foci of the middle belt of the volga delta, 1 strain can be isolated from approximately 3,800 an. hyrcanus or 3,300 coq. richiardii mosquitoes; in the low belt of the delta the ratio is 1 in about in a power less, and in anthropogenic biocenoses it is 1 strain per 1,500 cx. pipiens mosquitoes. sinv strains from gamasidae ticks (ornithonyssus bacoti) in india and from ixodidae ticks (hyalomma marginatum) in sicily (italy) are known. 2 productive experimental infections were described in the argasidae ticks ornithodoros savignyi and argas persicus (although infected ticks did not transmit the virus during feeding). 23 most likely, ticks do not play an important role in sinv circulation or as a reservoir for this virus. human pathology. sinv causes acute fever in humans but has a favorable outcome. antibodies to sinv are widely detected in human sera (table 8 .66), although in eastern siberia and the far east cross-reactions with getv (another member of the semliki forest serogroup) can take place. the start of the 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in uzbekistan and turkmenia genetic characterization of caspiy virus (casv) (bunyaviridae, nairovirus), isolated from seagull larus argentatus (laridae vigors, 1825) and ticks ornithodoros capensis neumann in eastern and western cost of caspian sea structure of crimean-congo hemorrhagic fever virus nucleoprotein: superhelical homo-oligomers and the role of caspase-3 cleavage influenza virus pathogenicity is determined by caspase cleavage motifs located in the viral proteins ovarian tumor domain-containing viral proteases evade ubiquitin-and isg15-dependent innate immune responses the high genetic variation of viruses of the genus nairovirus reflects the diversity of their predominant tick hosts immunofluorescence studies on the antigenic interrelationships of the hughes virus group (genus nairovirus) and identification of a new strain ticks (ixodoidea) on birds migrating from africa to preliminary data about isolation of three novel arboviruses in caucasus and central asia chim virus, 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of alphaviruses and flaviviruses-experimental infections key: cord-009664-kb9fnbgy authors: nan title: oral presentations date: 2014-12-24 journal: clin microbiol infect doi: 10.1111/j.1469-0691.2009.02857.x sha: doc_id: 9664 cord_uid: kb9fnbgy nan [ primary immunodeficiency diseases are a heterogeneous group of disorders, caused by inherited defects in the immune system, and characterised by wide spectrum of clinical manifestations, particularly an increased susceptibility to infections and a predisposition to autoimmune diseases and malignancies. recurrent infections or infection with unusual organisms are the most commonly presentation of primary immunodeficiency diseases. although recurrent respiratory tract infections and gastrointestinal manifestations are the most common features of these diseases, especially in predominantly antibody deficiencies and combined immunodeficiencies, other organs can be involved as well. recurrent cutaneous abscesses with unusual organisms or deep abscesses may represent infections with an association with immunodeficiencies, particularly in phagocytes defects. meningococcal infections could have an association with complement deficiencies. meanwhile other bacterial infections, mainly streptococcus pneumoniae and staphylococcus aureus, as well as infections with viruses, fungi and parasites are also common in several primary immunodeficiency diseases. autoimmune diseases such as idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, systemic lupus erythematosus, juvenile arthritis, sclerosing cholangitis, and vasculitis are common in primary immunodeficiency diseases. whilst some syndromic immunodeficiencies (e.g., wiskott aldrich syndrome, di george syndrome) have a strong association with autoimmunity, there are a group of disorders (e.g., alps, apeced, ipex) that the autoimmune manifestations are typically the first and most significant findings. malignancies are also common in some primary immunodeficiency diseases (e.g., cvid, alps, xlp, and dna repair defects). other manifestations such as dysmorphic features, associated anomalies, skeletal dysplasia, and oculocutaneous hypopigmentation can be unique characteristics of some cases with primary immunodeficiency diseases. the clinical manifestations of these diseases are often helpful in guiding the appropriate evaluation of the patients. prompt and precise diagnostic laboratory evaluation should be performed in the patients with such features, whereas early diagnosis and successful management of these patients prevent irreparable organ system damage and improve the prognosis. immunodeficiency specialists from all over europe have composed a multistage diagnostic protocol that is based on their expert opinion, in order to increase the awareness of pid among doctors working in different fields. the protocol starts from the clinical presentation of the patient; immunological skills are not needed for its use. a list of relevant symptoms and signs from the history and physical examination that should alert any physician to potential pid is given. these are grouped together to form eight typical clinical presentations of pid: recurrent ent and airway infections; failure to thrive from early infancy; recurrent pyogenic infections; unusual infections or unusually severe course of infections; recurrent infections with the same type of pathogen; autoimmune or chronic inflammatory disease, or lymphoproliferation; characteristic combinations of clinical features in eponymous syndromes; and angioneurotic edema. these presentations lead the user towards different algorithms, which in fact represent the traditional division into antibody, complement, lymphocyte, and phagocyte deficiencies, respectively. the algorithms each are comprised of several steps. this multistage design allows cost-effective screening for pid within the large pool of potential cases in all hospitals in the early phases, while more expensive tests are reserved for definitive classification in collaboration with an immunologist at a later stage. g. schmid°(geneva, ch) in 1986, articles suggesting that male circumcision (mc) decreased the risk of hiv infection appeared. over the next 15 years, studies of two epidemiologic types − ecologic and observational − increasingly supported this contention. ecologic studies showed strong correlations between prevalences of mc and hiv, e.g., tribes with low prevalences of mc had high prevalences of hiv infection. observational cross-sectional studies showed that uncircumcised men had higher rates of hiv than circumcised men. observational cohort studies confirmed these weaker study design findings. a systematic review of observational studies in 2000 found a relative risk (rr) of 0.42 (95% ci, 0.34−0.54), a 58% protective effect. in 2005 and 2007, results from three randomised controlled trials, all from sub-saharan africa, were reported. results were consistent, and the pooled rr of 0.42 (95% ci, 0.31−0.57) was identical to that of the observational studies. the protective effect in the three trials, found at about 21−24 months' follow-up, has been extended in one trial to a protective effect of 64% at 42 months of follow-up. who and unaids have strongly endorsed mc as an effective hiv prevention strategy in generalised hiv epidemics where mc is uncommon. what about europe? mc is uncommon with an adult male prevalence of <20%. hiv incidence is low enough that mc for hiv prevention purposes is unlikely to have much impact. no public health authority recommends routine neonatal circumcision. increasingly, however, data are showing benefits of mc in addition to hiv prevention. lessened risk of urinary tract infection in infants (rr 0.13, 95% ci 0.08−0.20) and lifetime avoidance of phimosis and associated conditions occur when mc is performed neonatally. other benefits occur in males circumcised at any age. mc protects against acquiring sexually transmitted infections characterised by genital ulcers-syphilis, chancroid and herpes-and possibly trichomoniasis. circumcised men may be less likely to acquire hpv and are more likely to clear the infection. through the protective effect against hpv, mc halves risk of penile cancer (rr 0.52, 95% ci 0.33−0.82) and partners of circumcised men are at lessened risk of cervical cancer. other issues must be considered in making public health decisions about mc. cultural objections may occur, but mc in the developing world is readily accepted in non-circumcising societies. studies of sexual pleasure and function have found no relationship to circumcision status. mc may be advised for subgroups, even if not for the entire population. and, surgical risk and cost must be considered. while many sub-saharan african countries are scaling up mc services to prevent hiv infection, public health agencies in many industrialised countries are reconsidering mc policies-the outcomes of both efforts are being followed with interest. acute otitis media (aom) is generally considered a bacterial infection that is treated with antibiotics. however, despite extensive use of broadspectrum antibiotics for this condition, the clinical response to the treatment is often poor. this fact, together with vast clinical experience connecting aom with viral respiratory infections, has prompted research into the role of viruses in aom. to date, ample evidence from studies ranging from animal experiments to large clinical trials supports a crucial role for respiratory viruses in the aetiology and pathogenesis of aom. in most cases, viral infection of the upper respiratory mucosa initiates the whole cascade of events that finally leads to the development of aom as a complication. the pathogenesis of aom involves a complex interplay between viruses, bacteria, and the host's inflammatory response. recent studies indicate that with sensitive techniques viruses can be found in the middle-ear fluid in most children with aom, either alone or together with bacteria. viruses appear to enhance the inflammatory process in the middle ear, and they may profoundly impair the resolution of otitis media. it is important to understand, however, that our increasing knowledge of the importance of viruses in the etiopathogenesis of aom does not diminish the central role of bacteria in aom. therefore, while viruses may explain many of the problems encountered in treating aom, the ultimate decision on whether or not to treat aom with antibiotics cannot be based solely on the degree of viral involvement in aom. the non-judicious use of antibiotics has lead to an epidemic in antimicrobial resistance. acute otitis media (aom) is the most common indication for use of antibiotics in children in the united states (us). despite available evidence that supports a wait and see approach, most us physicians immediately prescribe antibiotics for the treatment of aom. the american academy of pediatrics published a guideline in 2004 that addressed the diagnosis and treatment of aom. this guideline recommends the use of observation as a potential strategy for the treatment of aom. the key components of this published guideline will be discussed, as well as the evidence and rationale that supports the use of observation as an initial strategy to treat aom. otitis media (om) is the most common bacterial infection in children aged <5 years for which antibiotic treatment is prescribed worldwide. although most of the time this entity resolves spontaneously it is associated with morbidity, family dysfunction, antibiotic use and burden on the medical system. efforts to reduce the burden of om by vaccination have not been extremely rewarding, but some progress has been made. the first obvious step would be to reduce viral infections leading secondarily to om. in the modern era, the only viral vaccine with proven effect on aom is the influenza virus vaccine. both the inactivated and the live virus showed some effect, but since influenza virus has only a limited season yearly the effect on the overall om rate is far from being remarkable. haemophilus influenzae (hi) b vaccine did not reduce om since most hi causing om are nontypable (nthi) and not hib. the newly developed pneumococcal conjugate vaccines (pcvs) have all been shown to reduce >50% of the om caused by the serotypes included in the vaccines, but some replacement with serotypes not included in the vaccines and non pneumococcal organisms was demonstrated to reduce the overall effect of pneumococcal vaccines. the effect of pcv on the reduction of recurrent om, om with effusion, the need for ventilation tubes and frequent visits for aom has been suggested, and the real impact is still being studied. aiming with pcv at those with established recurrent om has proved disappointing. pcvs can reduce om caused by antibiotic-resistant s. pneumoniae but the continued overuse of antibiotics is responsible for the increase in antibiotic resistance in non-vaccine serotypes. a newly developed pcv with an outer membrane protein for hi (pnpd) is suggested to reduce also om caused by hi, but confirmation studies are needed. the expansion of the 7 serotypes included in the current licensed pcv to 10 or more serotypes may add to the prevention of om in the near future. in the next decade, om will continue to be an important disease in children. however, we can expect it to be modified in terms of bacteriologic aetiologies, antibiotic resistance and hopefully short and long term consequences. v. korten°(istanbul, tr) infectious consequences of an earthquake mainly involve several types of communicable diseases and crush related infections. water-borne and food-borne illnesses often result from the disruption of the public water and sewage systems and contamination of water supply. overcrowding, poor hygiene and sanitation in temporary shelters also may be factors. the type of infectious diseases are associated with the epidemiology of communicable diseases in the area where the earthquake occurred. the most common outbreaks associated with earthquakes are gastroenteritis, infectious hepatitis and pulmonary infections. in unvaccinated populations, there are reports of increased measles. tetanus can be seen in populations where vaccination coverage levels are low. the risk for diarrhoeal disease outbreaks following earthquakes is higher in developing countries than in industrialised countries. an outbreak of acute watery diarrhoea involved >750 cases occurred in a camp after the 2005 earthquake in pakistan. acute respiratory infections, hepatitis e clusters and measles (>400 clinical cases in the 6 months) also occurred among the displaced victims after the same earthquake. contamination of drinking water led to an outbreak of rotavirus after the 2005 earthquake in kashmir, india. an unusual outbreak of coccidiomycosis associated with exposure to increased levels of airborne dust occurred after the 1994 southern california earthquake. persons who have been trapped by rubble for several hours or days may develop compartment syndromes requiring fasciotomy or amputation. infectious complications were common in renal victims of the1999 marmara earthquake in turkey and were associated with increased mortality when complicated by sepsis. of 639 renal victims, 223 (34.9%) had infectious complications, mainly sepsis and wound infections. most of the infections were nosocomial in origin and caused by gram-negative aerobic bacteria and staphylococcus spp. multivariate analysis of the risk-factors for nosocomial infections revealed a significant association with fasciotomy and length of hospital stay in a back up university hospital. the most frequent pathogens isolated from pus and/or wounds culture in 2008 wenchuan earthquake survivors were s. aureus, e. coli, a. baumannii, e. cloacae, and p. aeruginosa. disaster-preparedness plans, focused on trauma and mass casualty management and also on health needs of the surviving affected populations may decrease the health impact of earthquakes. s16 infections in the disaster setting: famine. experience from darfour, sudan clinic malnutrition is a known risk factor for id worldwide. subsaharan africa and india is at higher risk due to vegetarian habits on absolute absence of animal meat proteins, resulting to depletion of micronutritients (zinc, iron, selenium), responsible for recovery of postmalarial anaemia. in addition, depletion of proteins results to immunoglobulinaemia and to delayed response to many bacterial pathogens causing id in topics (pneumococci, salmonella, etc.) . third problem is absence of vitamins dissolved in oil and fat, resulting to delayed phagocytic activity. therefore proteinocaloric malnutrition results to significant adverse outcome in hiv, tb (diarrhoea, pneumonia), the major killers of children under five. st. elizabeth university tropical programme runs 4 antimalnutrition centres: 1 in sudan, darfour and 2 in kenya amaong upcountry refugees from major conflict areas (sudan − turrana border) and 1 in uganda trying to rehabilitate malnourished children under 5 and helping them to combat disease, responsible for 12.5 million deaths in children mean 5 a year − malaria (1.2 mil), tb (1.1 mil), hiv (2.0 mil), pneumonia (7.5 mil) and diarrhoea (0.5 mil. children deaths approximately a year). h. giamarellou°(athens, gr) for the last six years greece has faced a large number of infections, mainly in the intensive care units (icu), due to carbapenemsresistant klebsiella pneumoniae. the proportion of imipenem-resistant k. pneumoniae has increased from less than 1% in 2001, to 23% in isolates from hospital wards and to 53% in isolates from icus in 2008. likewise, in 2002, these strains were identified in only three hospitals, whereas now they are isolated in at least 32 of the 40 hospitals participating in the greek surveillance system. until 2007 this situation was due to the spread of the blavim-1 cassette among the rapidly evolving multiresistant plasmids and multiresistant or even panresistant strains of mainly k. pneumoniae and also other enterobacterial species. however, the fact that most strains display mic values below or near the clsi resistance breakpoint create diagnostic and therapeutic problems, and possibly obstruct the assessment of the real incidence of these strains. as of 2007, the emergence of kpc-producing k. pneumoniae has been noted in icus of some greek hospitals and has now spread to most hospitals throughout the country creating a countywide outbreak in 2008. in attikon university hospital we recently described the icu outbreak of kpc-producing k. pneumoniae. twenty-nine patients (admitted from february to december 2008) were colonised mainly in gi tract. fifteen patients were male (52%) and the median apache ii was 19. patients had already long hospital stays preceding icu admission with a median of 25 (17−40) days. in twenty-two of these patients (76%) kpc-producing k. pneumoniae colonisation was definitely icuacquired while in 7 (24%) acquisition in other wards or other hospitals was hypothesized. five of these patients are still hospitalised in the icu and, of the remaining 24, 11 died (icu mortality 46%). ten of the 29 colonised patients were clinically infected. fifteen infections were documented, mostly bsi (11/15), followed by vap (2/15) and ssi (2/15). only 1 patient died from this infection (1/15, 6.7%). an evidence-based consensus on the therapeutic strategy for these infections has been reached by keelpno and the greek ministry of health which proposed the use of high dose meropenem (6−8 g/day) combined with an active aminoglycoside or colistin for strains with an mic 4 mg/ml whereas for strains with a higher mic the use of carbapenems is contraindicated and active alternatives (monotherapy with tigecycline, colistin, or an aminoglycoside or aztreonam-based combinations) could be used. antibiotic stewardship is of great importance in such a dismal situation but stringent adherence to infection control measures is probably of even greater importance for the effective containment of these pandrugresistant strains. the presentation of clostridium difficile infection (cdi) varies from mild diarrhoea to a potentially fatal pseudomembranous colitis. the recent emergence of types 027 and 078 of c. difficile has been associated with increased virulence. c. difficile takes advantage of disruption of the normal intestinal flora as caused by antibiotic therapy. the antibiotical class and the antimicrobial resistance pattern of c. difficile influence the development of disease. in the netherlands, significantly more patients with cdi due to type 027 used fluoroquinolones (or, 2.88; 95% ci, 1.01−8.20) compared with those who were infected with other pcr ribotypes. similar as type 027 cdi, patients infected with type 078 also more frequently received fluoroquinolones therapy (or, 2.17; . the risk to develop cdi due to type 027 was particularly high in persons receiving a combination of cephalosporin and fluoroquinolone (or 57.5, ). this association was also strongly dependent on the duration of therapy. the use of clindamycin was found as a protective factor. however, the recent detection of clindamycin-resistant c. difficile type 027 strains in other european countries is an important and worrying development. since the association of cdi with fluoroquinolones has only been investigated at patient level, a study was performed to investigate the relationship between cdi incidence and the preceding use of different antibiotic classes at hospital level in the netherlands. comparisons were made between hospitals where type 027 caused an epidemic, hospitals where only isolated cases of type 027 were observed and hospitals where no outbreak of cdi or type 027 were encountered. in the pre-epidemic period, the total use antibiotics was comparable between affected and unaffected hospitals. higher use of secondgeneration cephalosporins, macrolides and all other studied antibiotics were independently associated with a small increase in cdi incidence, but the effect was too small to predict which hospitals might be more prone to 027-associated outbreaks. despite the fact that the netherlands is known by its restrictive and conservative use of antibiotics, outbreaks of cdi due to new emerging types have been recognized. this is probably associated with the use of antibiotics at patient level and hospital department level rather than the use of antibiotics at the level of the healthcare institute. m. peiffer, j. bulitta, h.a. haeberle, m. kinzig-schippers, m. rodamer, v. jakob, b. nohé, f. sörgel, w.a. krueger°(trier, de; albany, us; tubingen, nuremberg, constance, de) piperacillin-tazobactam (pip-tazo) is a broad spectrum antibiotic, used for treatment of severe infections such as ventilator-associated pneumonia (vap). the effectiveness of betalactams is best predicted by the duration of free drug concentrations above the minimal inhibitory concentration (t > mic) of infecting pathogens [1] . animal experiments suggest that more than 50% of t > mic should be reached. continuous infusion (ci) of pip-tazo may enhance the therapeutic performance, but there is little data on pharmacokinetic/-dynamic (pk/pd) parameters, when ci is used in critically ill patients. objectives: the aim of our study was to determine concentrations of pip-tazo in plasma and broncho-alveolar epithelial lining fluid (elf) at steady state during ci. based on these results, the penetration ratio (plasma/elf) and pk/pd parameters for pip-tazo are derived. methods: after approval by the ethics committee, 16 mechanically ventilated critically ill patients were enrolled during treatment in 3 intensive care units. each patient received a loading dose of 4 g/0.5 g of pip-tazo, followed by ci of 12 g/1.5 g over 24 h. at steady state (67.8 + 39.5 h after loading dose), a total of 30 blood samples were drawn and bronchoalveolar lavage (bal) was simultaneously performed in 8 cases (1 sample discarded for technical reasons). samples were stored at −80ºc until analysis by liquid chromatography coupled with mass-spectrometry (lc-ms). elf-concentrations were calculated from bal-samples using the relation of ureaplasma:ureabal as dilution factor. results: plasma concentrations of pip and tazo (n = 30 in 16 pts.) amounted to 15.38+8.89 mg/ml, and 1.31+0.95 mg/ml, respectively. elflevels (n = 7) were 56.63+27.24 mg/ml, and 5.95+3.74 mg/ml. elf-levels were 368+236%, and 587+584% of corresponding plasma levels (n = 7) for pip and tazo, respectively. the ratio pip:tazo was 11.74:1 in plasma, and 9.52:1 in elf. conclusions: using advanced analytical techniques, elf concentrations were higher compared to traditional bolus administration [2] . ci yielded steady state plasma concentrations in excess of mics of susceptible bacteria (<8 mg/ml, according to eucast) in 76.6% of measurements, respectively, but elf levels exceeded 8 mg/ml in all cases. taken together, our data provide further arguments for ci being the preferred mode of administration for pip-tazo in critically ill patients with suspected vap. [ objectives: staphylococcus aureus is a potential pathogenic microorganism and a causative agent of~25% of infections in intensive care patients. an optimal empiric choice for the treatment of these infections will result in a reduction in morbidity and mortality. therefore, it is essential to provide the clinician with resistance data of the bacterial population to be treated. to optimise the empiric choice and to monitor the emergence of microbial resistance, a national surveillance program of the swab was started in the netherlands in 1996.this study describes the results of the resistance development of s. aureus from icu's of 14 hospitals all over the netherlands over a ten year period. methods: in the first 6 months of each year, the participating hospitals collected clinical isolates from among others blood and respiratory samples. in total 943 isolates were collected: 250 from 3 hospitals in the north, 187 from 2 in the east, 229 from five in the west and 280 from four in the south. the antimicrobial susceptibility was determined as a micro broth dilution method according to the clsi guidelines. results: an increase in resistance to ciprofloxacin was observed from 4% until 2002 to 14% from in 2005, which dropped again to 7% in 2006. the resistance to moxifloxacin was rather constant over time, i.e. 2%, only in 2003 8% resistance was found. resistance to clarithromycin increased to 10% in 2003, but decreased in 2006 to 6% the level before 2003. resistance to penicillin, clindamycin and tetracycline fluctuated over time at~75%, 4−8% and 2−10% respectively. during the study period seven methicillin resistant s. aureus were isolated, no resistance to vancomycin, teicoplanin and linezolid was observed. resistance to gentamicin and rifampicin was sporadicly found. regional differences were observed for ciprofloxacin, being the highest in the western and southern part and tetracycline being the lowest in the northern part. conclusion: during the 10 year study period only an increase in resistance to ciprofloxacin was observed. the data presented justify the empiric choice of flucloxacillin, (with rifampicin or gentamicin depending on the indication) in case of an infection in icu patients probably caused by s. aureus. j.j. lu°, p.r. hsueh, s.y. lee (taichung, taipei, tw) objectives: to investigate the prevalence of visa in hospitalised patients with mrsa infections or colonisations at a teaching hospital in taiwan and to evaluate the possible clonal spread of visa in the hospital. methods: from september 2001 to august 2002, 1500 consecutive mrsa isolates were collected from various clinical specimens of 637 patients hospitalised at a teaching hospital in taiwan. minimum inhibitory concentrations (mics) of vancomycin for all mrsa isolates were determined by the broth microdilution method in accordance with clsi guidelines. molecular characteristics and antimicrobial susceptibilities of visa isolates were investigated and pulsed-field gel electrophoresis was used to evaluate the clonality of the isolates. results: among the 1500 mrsa isolates, 43 (2.9%) were visa. of the 43 visa isolates, 35 had vancomycin mics of 4 microgram/ml and 8 had vancomycin mics of 8 microgram/ml. all isolates were inhibited by tigecycline at 0.5 microgram/ml, linezolid at 1 microgram/ml, and ceftobiprole at 2 microgram/ml. five (11.6%) isolates had reduced susceptibility to daptomycin (mics of 1−2 microgram/ml). six of the 43 visa isolates had decreased susceptibility to autolysis in 0.05% triton x-100. the 43 visa isolates were recovered from 21 patients; 13 of these patients had received glycopeptide treatment prior to the isolation of visa. five (23.8%) patients died despite vancomycin therapy. all 43 visa isolates carried sccmec type iii and agr group i but were negative for pvl gene (luks-lukf). none of the enterococcal van genes were detected in the 43 visa isolates. results of pfge analysis revealed that one major clone of visa isolates (90.5%, clone a exhibiting sccmec type iii, agr group i, and absence of pvl gene) had disseminated in the hospital. conclusion: this retrospective study demonstrated that clonal dissemination of visa had occurred in the hospital. rapid and correct detection of visa and proper use of antibiotics are the most effective approaches for preventing its emergence and spread. x. zheng°, c. qi, a. o'leary, m. arrieta, s. shulman (chicago, us) objectives: vancomycin remains one of the major options for treating methicillin-resistant s. aureus (mrsa) related infections. some but not all studies have shown an increase in prevalence of mrsa isolates with elevated vancomycin mic values among recent clinical isolates, so called "mic creep". although still within the susceptible range, higher mics may be associated with increased chance of treatment failure. because of the conflicting reports and lack of published data from paediatric patients, we sought to assess possible mic change over time and to compare results generated by using different methodologies including etest, agar dilution, and broth microdilution (microscan) methods. methods: we studied 318 mrsa isolates predominantly community acquired including all blood and normally sterile site isolates collected in our large children's hospital in 2000/2001, 2003, 2005, and 2007 molecular bacteriology o41 genome sequence of a virulent, methicillin-sensitive staphylococcus aureus clinical isolate that encodes the panton-valentine leukocidin toxin l. faraj, l.a.s. snyder, n.j. loman, d.p. turner, m.j. pallen, d. ala'aldeen, r. james°(nottingham, birmingham, uk) objective: to determine the genome sequence of a virulent meticillinsensitive staphylococcus aureus (mssa) clinical isolate sanot01. methods: roche 454 sequencing determined the genome sequence of the clinical isolate at 12 times coverage. newbler sequence assembly (roche) generated 10 scaffolds that were annotated using gendb and compared with other s. aureus genome sequences. results: an 11-year-old asian girl presented with fever and a 1-week history of knee pain following a trivial fall. an mr scan revealed a large subperiosteal abscess around the upper tibia secondary to metaphyseal osteomyelitis. a pvl-positive, mssa was isolated from blood cultures and pus. the child deteriorated, required repeated debridement and developed septic shock. further investigation revealed aortic valve endocarditis with an aortic root abscess. whole genome sequencing revealed that sanot01 is the first sequence of an st30 s. aureus isolate to be determined. sanot01 is agr type iii and carries three coding regions that are not found in any other s. aureus genome sequences. amongst the unique genes present in these regions is a dihydrofolate reductase gene (dfrg) which is present in addition to the usual dfrb gene. downstream of the orfx gene, a 6.5 kb remnant of sccmec type ivc was found. this sequence has only previously been found in the mrsa252 genome sequence where it is located between the orfx and sccmec type ii sequences. mrsa252 is unique in sharing 14 genome regions with s. aureus strain rf122, a causative agent of contagious bovine mastitis. all but one of these 14 genome regions are also present in sanot01. conclusions: comparison of the genome sequence of sanot01 and the closely related mrsa252 ha-mrsa (emrsa-16) isolate reveals new insights in the evolution of both ca-mrsa and ha-mrsa isolates and the link to s. aureus rf122. pvl-encoding mssa strains can be significant pathogens but are not currently under mandatory surveillance in uk. as the cost of whole genome sequencing falls further it will become feasible to use this technology to monitor the evolution of both mssa and mrsa in healthcare settings and reveal clinically relevant information that will help to improve patient outcomes. objectives: ca-mrsa often produce panton-valentine leukocidin (pvl), a leukocidin encoded by two co-transcribed genes located on lysogenised phages. five pvl-encoding phages have been described in s. aureus: phipvl, phi108pvl, phislt, phisa2mw and phisa2958. single nucleotide polymorphisms (snps) in the pvl genes tend to vary with lineage and may have structural and functional implications. we examined a selection of pvl-positive ca-mrsa reported in our hospital to determine whether sequence variation and the pvl-encoding phage vary with lineage. methods: twenty-two pvl-positive isolates were chosen to reflect mlst clonal complexes identified in our hospital: cc1, 5, 8, 59, 80, 88 and 154 . isolates were characterised by antimicrobial resistance profile, sccmec and spa type, pulsed-field gel electrophoresis (pfge) profile and multilocus sequence typing (mlst); an oligonuleotide array (clondiag arraytube) was used to detect a range of toxin and antimicrobial resistance genes. primers were designed to amplify and sequence the luksf-pv genes. the pvl-encoding phage was characterised using a recently described pcr-based assay (ma et al. j clin microbiol 2008; 40:3246−58) . results: snps were identified at seven positions in the luksf-pv genes and the snp profile varied with lineage. three of the snps were coding mutations, which may have structural and functional implications. cc1 and cc80 isolates were both found to carry phisa2mw. the pvlencoding phage was not definitively identified in the other lineages, although the cc59 isolates carried a phisa2958-like phage and the cc8, cc80 and cc154 isolates carried elongated head-type phages. one of the cc1 isolates had an unexpected snp pattern compared with other cc1 isolates; this isolate also carried a novel or variant phage. conclusion: pvl gene sequence and the pvl-encoding phage vary with lineage in pvl-positive ca-mrsa isolates. this suggests that certain lineages are susceptible to infection or lysogeny with certain phage types. although ca-mrsa commonly carry pvl genes, some strains do not; it is possible that some pvl-negative types are resistant to infection with pvl-encoding phage, perhaps via restriction modification systems. crucially, our findings suggest the pvl genes have co-evolved with their phage and are not freely transmitted between different phages. further work is required to characterise the pvl-encoding phage in other isolates and to investigate whether the pvl sequence variants result in biological differences. objectives: community-associated mrsa (ca-mrsa) of many different mlst clonal complexes (ccs) can harbour lysogenised bacteriophage dna (prophage) encoding panton-valentine leukocidin (pvl). five pvl phages (phipvl, phislt, phisa2mw, phi108pvl, and phisa2958) have been reported to date. we sought to determine the distribution of chromosomally integrated copies of these lysogenised pvl-phages amongst dominant clones of pvl mrsa in england and wales. methods: seventy isolates of previously characterised pvl-mrsa were analysed by pcrs developed by ma et. al, (jcm, 2008) , to identify and discriminate between the five known pvl phages. to maximise any underlying diversity, representatives of each cc were selected based upon their spa, staphylococcal cassette chromosome mec (sccmec), toxin gene and pulsed-field gel electrophoresis (pfge) profiles. these included isolates of internationally disseminated pvl-mrsa lineages ccs 8, 30 and 80 which resemble the usa300, south west pacific (swp) and european clones, respectively. in addition we analysed pvl-mrsa from ccs 1, 5, 22, 59, 88 and st93. results: all seven cc80 isolates, which included representatives of the european clone, possessed an elongated-head-type phage and were positive by the pcr specific for the phisa2mw phage. one of the cc30 isolates possessed a phi108pvl phage, four swp representatives had elongated head type phages, whilst the remaining four cc30 isolates harboured an icosahedral-head-type phage. one cc30 was positive for both head shapes. the 12 cc8 (including representatives of usa300), eight cc1, six cc88 isolates and the st93 isolate were all positive for elongated-head-type phage. nine cc5 isolates were non-typeable for phage head shape and specific phage pcrs. three of four cc59 isolates, harboured a phisa2958-like phage of an unknown head type and the other cc59 isolate was non-typeable. all 14 cc22 isolates possessed an icosahedral-head-type phage, 13 were positive for the phipvl phage type and one possessed phi108pvl type. we have determined the pvl phages present in a diverse panel of distinct pvl-mrsa clones and found considerable inter-lineage variation in the pvl prophage present. there was also evidence of intra lineage variation in some major ccs such as ccs 22, 30 and 59. together with variation in mlst cc and sccmec, these data suggest pvl-mrsa have evolved on multiple occasions, sometimes within the same lineage. o44 transcriptional profiling of klebsiella pneumoniae genes controlled by the transcription factor, rama objectives: rama is an arac/xyls family transcriptional activator where over expression is associated with a multidrug resistance phenotype. in both multidrug resistant klebsiella and salmonella isolates, the rama gene has been associated with increase in expression of the acrab efflux pump. in salmonella it has been shown that a deletion of the rama locus prevents the emergence of multidrug resistant mutants. therefore in order to understand the role of this key regulator in the emergence and development of antibiotic resistance, transcriptomic analyses of its regulon were undertaken in k. pneumoniae. methods: rna was extracted from a combination of isogenic mutants and clinical isolates using the qiagen or ribopure kits. rna integrity was assessed using nanodrop and agilent nanochip systems. the rna was transcribed into double stranded cdna prior to labelling with cy3. the cdna was hybridised to the nimblegen expression array platform designed from the k. pneumoniae mgh 78578 genome. results: approximately 50 genes were found to be affected by rama expression, of which twenty (involved in metabolism, physiology, transcription, drug efflux, protection responses and the cell envelope) were confirmed by rt-pcr. the rama protein appears to affect drug efflux operons not previously shown to be associated with multidrug resistance and or affected by similar proteins such as mara. comparative transcriptome analyses of different k. pneumoniae clinical isolates overexpressing rama showed that variations exist in the levels of expression of the drug efflux genes. of note genes shown to be directly regulated by rama have a marbox-like sequence within the promoter sequences. conclusion: in this study, the transcriptome of the regulatory protein, rama, was determined in the pathogen k. pneumoniae. drug efflux proteins not previously associated with rama overexpression were found to be directly affected. the rama regulon overlaps with the mara and soxs regulons in e. coli and salmonella but is directly associated with regulating the expression of a subset of genes via a marbox sequence. interestingly, variations in the levels of the expression of the regulon genes were found in the different rama overexpressing strains. m. eshoo°, c. crowder, h. li, h. matthews, s. meng, s. sefers, r. sampath, c. stratton, d. ecker, y.w. tang (carlsbad, nashville, us) objectives: the potential for fatal outcome from tick-borne human infections such as ehrlichiosis emphasizes the need for rapid diagnosis. we developed and validated an ibis t5000 assay (ibis biosciences, inc., carlsbad, ca) that can detect and identify a wide range of tick-borne pathogens from clinical samples. methods: a multi-locus assay was used that employs 16 broadrange pcr primer pairs targeting all known bacterial tick-borne pathogen families. electrospray ionisation mass spectrometry of the pcr amplicons was used to determine their base composition. these base composition signatures were subsequently used to identify the organisms found in the samples. the assay was developed using field collected ticks and a wide range of clinical sample types and has been shown to be sensitive to the stochastic limits of pcr. results: whole blood (198) , cerebrospinal fluid (20) and plasma (1) samples, which were originally submitted for ehrlichia species detection by a colorimetric microtiter plate pcr (pcr-eia), were collected consecutively from january 5 to august 1, 2008 at vanderbilt university hospital. among the total 219 specimens, pcr-eia detected 40 ehrlichia species with a positive rate of 18.3%. the ibis system detected ehrlichia in 38 of the 40 pcr-eia-positive samples and 1 in 179 of the pcr-eia-negative specimens, giving sensitivity and specificity of 95.0% and 99.4%, respectively. the ibis system further characterised the 38 ehrlichia-dual positive specimens to the species level (e. cheffeensis, 35; e. ewingii, 3) with a 100% agreement to that identified by pcr-eia using additional species-specific probes. in addition we demonstrated the detection of borrelia burgdorferi from the blood and skin of a patient with lyme disease. conclusions: we demonstrate broad-range detection of tick-borne pathogens in a single assay using skin, whole blood, plasma, skin and csf. in addition to ehrlichia, the ibis system detected 4 rickettsia rickettsii positive specimens, which were confirmed by serology and clinical findings. the ibis t5000 system, which can be completed within five hours from specimen processing to result reporting, provides rapid and accurate detection and identification of a broad range of pathogens causing tick-borne human infections. r. sampath°, l. blyn, r. ranken, c. massire, t. hall, m. eshoo, r. lovari, h. matthews, d. toleno, r. housley, s. hofstadler, d. ecker (carlsbad, us) objective: to investigate the use of a novel platform-based approach for rapid characterisation of hai organisms. pathogens that cause healthcare-associated infections (hais) pose an ongoing and increasing challenge to hospitals, both in the clinical treatment and in the prevention of the cross-transmission of these problematic pathogens. here we describe the utility of a pcr electrospray ionization mass spectrometry (pcr/esi-ms) detection platform as an innovative, rapid approach for detection and complete characterisation of important hai pathogens. methods: we have developed pcr/esi-ms based methods to rapidly identify and characterise mrsa, vre, c. difficile (nap-1 strain), p. aeruginosa and a. baumannii. each target organism can be analyzed using an independent 8-well assay that can be run on the same platform and can provide species and strain id, virulence factors, antibiotic resistance and genotyping as appropriate. validation studies were performed using 100-300 retrospective, well-characterised clinical isolates for each organism. this was followed by a prospective study for one of the 5 organisms, mrsa, that included screening of 557 clinical specimens (nares swab) from patients who were admitted to a medical unit with a high prevalence of mrsa clinical infections. results: for each of the five hai organisms, pcr/esi-ms species identifications were compared to gold standard testing results from the clinical microbiology laboratory and showed 100% concordance. for s. aureus, p. aeruginosa and a. baumannii, molecular genotyping by pcr/esi-ms was compared to pulse field gel electrophoresis (pfge) clusters and showed >95% concordance. characterisation of virulence and/or drug resistance was performed for mrsa, vre and c. difficile and showed 90−95% correct detection compared to existing testing methods. analysis of clinical specimens for mrsa showed that of the 557 swabs, 95 (15%) contained mrsa, either singly or as a dual infection with cons, 33 (5%) were mssa and 358 (58%) contained meca+ coagulase negative staphylococcus (mr-cons). comparison to gold standard analysis showed 100% sensitivity for mrsa detection with 96.8% specificity, 84% ppv and 100%npv. the pcr/esi-ms technology is a high throughput assay system useful for infection control and for epidemiological studies. it is capable of simultaneous identification of hai organisms while detecting presence of key phenotypic markers and genotypic strain characterisation. m. reijans°, j. ossel, j. keijdener, g. simons (maastricht, nl) objective: molecular diagnostics play an increasingly important role in the detection of infectious agents in cerebrospinal fluids. however, the growing list of targets and the relatively small sample volumes are challenges that demand an improved molecular diagnostic approach. the meningofinder is a multifinder assay allowing the simultaneous detection of 7 viruses and 1 internal control in 1 reaction. until now, the analysis of multifinder assays was based on size-fractionation, identifying each multifinder probe due to its specific length. here we present an alternative approach allowing realtime detection of eight meningofinder probes in a single tube. the realtime detection enables a faster analysis, less handling and lowers the risk of contamination. method: the meningofinder assay is a multifinder assay which detects herpes simplex virus 1 and 2 (hsv1−2), human parechovirus (hpev), cytomegalovirus (cmv), epstein-barr virus (ebv), enterovirus (ev) and varicella-zoster virus (vzv) plus an internal control in a single reaction. each meningofinder probe can be distinguished based upon the specific length of each probe by size-fractionation using gel or capillary electrophoresis. we developed an alternative detection method using fluorescently labelled probes which allow specific identification of 8 multifinder probes in a realtime pcr machine. results: a large number of qcmd samples (n = 44), several enterovirus types (n = 27) and characterised clinical samples (n = 66) were analyzed using the meningofinder. all meningofinder reactions were analyzed by capillary electrophoresis and by fluorescently labelled probes in a realtime pcr machine. the results of the meningofinder showed a very good correlation with the expected results (>95%). furthermore, the results of both meningofinder analyses showed a high degree of correlation. the realtime detection of the meningofinder probes decreases the analysis time and post pcr handling dramatically. we developed a new assay for the realtime detection of 8 meningofinder probes. the realtime analysis showed a very good correlation with the conventional capillary electrophoresis analysis. in addition, the realtime detection reduced contamination risk and patient results became available more quickly. the combination of multifinder technology combined with realtime detection shows great potential in fast and easy multiparameter screening of clinical samples for infectious pathogens. in-house naats were applied to nucleic acid extracts obtained by own in-house methodology in each centre. results: sensitivities for the detection of the respiratory viruses were 40% for commercial mx naat, 86% for in-house mw naat, and 90% for mono in-house naat. the viral load was low each time false-negative results were obtained. false positive results were obtained by all methods used, resulting in specificities ranging from 88%-97%. for the atypical bacteria, the 2 multiplex naats failed to detect low l. pneumophila positive samples and low m. pneumoniae positive sample resulting in sensitivities of 25% and 75% compared to 100% in the inhouse mono naats. the commercial mx naat also failed to detect strong positive samples. no false positive results were obtained for the atypical bacteria. revisiting phage therapy against problematic pathogens s61 how the past feeds the future: from d'herelle to modern phagotherapy the increasing antibiotic resistance problem boosts the interest in alternative treatments for infections. a prominent example for this is the so-called phagotherapy. it makes use of bacterial viruses − bacteriophages − as drugs against bacterial agents. these bacteriophages are isolated from nature, characterised and then tested against the bacterial strains that are targeted. in theory, this approach has several advantages. for instance, bacteriophages infect, as a rule, their bacterial prey very specifically. therefore, they do not harm the commensal bacteria of the patient. additionally, if a bacterial strain becomes resistant against a certain bacteriophage strain, evolution will provide for new and active bacteriophage strains. in practice, phagotherapy has been used for a long time. already one of the two discoverers of bacteriophages, félix d'herelle, was an ardent advocate of this method. in fact, he was the first to use bacteriophages against infections − 1919 against bacterial diarrhoea (shigella spp.). after that, phagotherapy has been used to quite some extent in europe, the us and other parts of the world until penicillin entered the market in the 1940 s. in some parts of the former soviet union and the eastern bloc, the method has been utilised until today. now, several companies and university researchers are developing bacteriophages for therapeutical purposes again. historical documents related to phagotherapy and oral history reveal a fascinating past. bacteriophages have been employed against a wide variety of bacterial diseases in a time in which there were virtually no other anti-infectives. for example, in india, millions of cholera patients were treated with bacteriophages in the 1930 s. anti-cholera phages were also poured into drinking wells as prophylactics. bacterial viruses have also been utilised by the german and soviet armies in the second world war. the history of phagotherapy makes for more than an exciting story, however. analysis of the old literature helps identify important factors for success and failure. this is especially relevant for a field which holds promise but which has had limited funds at its disposal in the past few years − and which, therefore, has been making rather slow progress. additionally, examination of the strategy used for phagotherapy in the soviet union and poland also contributes to a better application of this method today. the discovery of bacteriophages, particularly their ability to replicate and lyse pathogenic bacteria may have been among the most important milestones in the history of biomedical sciences. in the pre-antibiotic era of the early 20th century, phage therapy was becoming a powerful weapon against infectious diseases of bacterial aetiology. unfortunately, phage treatment and research was largely forgotten in the western world as antibiotics became widely available. nowadays, the rapid propagation of multi-drug resistant bacterial strains is leading to renewed interest in phage therapy. in contrast to its decline in the west, phage therapy remained a standard part of the healthcare systems in eastern europe and the ussr during the second half of the 20th century. phage preparations were used for diagnostic, therapeutic and prophylactic purposes to combat various bacterial infections. the eliava institute of bacteriophages, microbiology and virology (tbilisi, georgia) is perhaps the most famous institution in the world focused on the study of bacteriophages, particularly the isolation and selection of phages active against various bacterial pathogens. phages have been isolated against bacterial strains received from all over the former ussr and socialist east european countries; consequently, a huge collection of phages and pathogenic bacterial strains has been constructed at the institute. thousands of people were treated with individual phages and phage mixtures during the soviet era. the preparations developed in tbilisi have been studied through extensive preclinical and clinical trials. however, little of this information has ever been published and even when details are available, the trial reports do not meet internationally approved regulations and standards. bacteriophages have a number of advantages in comparison to antibiotics. phage therapy as an alternative approach for treatment of infections has become an evident and promising remedy. today, many people from various parts of the world express their willingness to take phage treatment against different infections, including those that are caused by antibiotic-resistant bacterial pathogens. the eliava institute has elaborated new, phage-based products and technological schemes for their production. strong collaboration with the medical community in the design of clinical trials according to international standards is absolutely critical to supporting the broader implementation of phage therapy. an australian male aged 57 years died from an intracerebral haemorrhage ten days after he returned from a trip to rural yugoslavia. his kidneys and liver were donated to three female recipients aged 44 years (kidney), 63 years (kidney), and 64 years (liver). four to five weeks after the organ donation, all three recipients died. all had febrile illnesses with altered mental status. subsequent testing of post-mortem tissues from the recipients identified a novel arenavirus, which was related to lymphocyctic choriomeningitis virus (lcmv). this viral detection process involved the use of high-throughput sequencing techniques to identify novel microbial rna sequences. confirmatory testing was performed using the techniques of reverse transcriptasepolymerase chain reaction, immunohistochemical analysis for arenavirus antigens, and immunofluorescent testing for igg and igm antibodies. the clinical features in these four patients as well as other similar problems with transplant-related illness from classic lcmv will be discussed, as well as details of the laboratory identification of this new virus, and implications for organ transplantation protocols in future. successful management of invasive fungal infections depends on timely and correct treatment. over the last decades a number of new tests have become available which have improved the diagnostic options. in contrast to the scenario for bacterial infections, acquired resistance in fungi is rare and thus species identification is a valuable tool guiding choice of treatment. therefore, microscopy & culture is still a corner stone in diagnosis, but culture and identification are time consuming (app. 1−5 and 1−3 days, respectively). the sensitivity and speed of microscopy have been improved by the use of fluorescent brighteners such as calcofluor white or blankophor. but only with the recent development of pna probes specific for a number of the candida spp. has species identification become possible directly from a positive blood culture before subculture on agar media. chromogenic agars allow a presumptive identification of several candida spp. and facilitate the recognition of yeast isolates in samples containing several yeasts or yeast and bacteria in combination. the use of such plates has been shown to lead to a better identification of mixed cultures in a recent nordic eqa scheme including more than 50 laboratories. rapid species identification of the most important candida spp. is possible in the routine laboratory using easy commercially available kits. thus, a species identification of c. albicans, c. dubliniensis and c. krusei can be obtained within minutes using latex agglutination kits (bichro-dubli, krusei-color; fumouze diagnostics) and c. glabrata can be rapidly identified due to its high amounts of preformed intracellular trehalase enzyme (glabrata rtt; fumouze diagnostics). finally, pna probes and fluorescence microscopy can also be used for a same day identification of a range of the clinically relevant candida spp. (advandx). susceptibility testing is possible using etest and the results are comparable with those obtained by reference methodologies in head to head comparisons. however, recent data from eqa distributions suggest that detection of isolates with acquired resistance causes many laboratories difficulties. this illustrates that a critical number of isolates should be tested per technician per week and quality control strains should be included on a regular basis. in conclusion, a number of new diagnostic tests have become available over the last decade and the diagnostic laboratories are encouraged to take advantage of these new options. 19th eccmid, oral presentations since the introduction of newer antifungals with different in vitro spectra, the aetiology of invasive fungal infections (ifi) has become a major diagnostic issue as a prerequisite for a guided antifungal therapy. while molecular methods, such as pcr and sequencing for the diagnosis of ifi have been evaluated from specimens such as blood and bronchoalveolar lavage fluid for some years, they have been less studied for biopsies. characteristics inherent to these molecular methods, e.g. sensitivity, specificity and short turnaround time makes them promising as adjuncts to conventional diagnostic tests, e.g. culture and histopathology from organ biopsies. studies using tissue from animal models of mould infections suggest that pcr might be more sensitive than culture and allows for a better species identification than histopathology. however, most of these studies used assays detecting only a small range of agents or even single organisms. while this may increase the sensitivity of the assays and reduces the likelihood of contaminations it limits the usefulness in the clinical setting, given the broad range of potential fungal pathogens. studies using fresh clinical samples suggest that the detection and identification of a wide range of fungi is possible using broad range assays in combination with sequencing or by combining more specific pcr assays. further studies are needed to optimise dna extraction, define the best molecular targets and the best method for amplicon detection. the prevention of contaminations due to ubiquitous fungi and unspecific amplifications are a major problem, especially when using broad range assays. in contrast, fish probes may potentially be more specific than pcr due to the visualisation of fungal elements in tissue. in contrast to pcr, they appear to work well with formalin fixed specimens. species identification might be more challenging than by pcr and sequencing. direct comparisons between fish and pcr are needed to characterise the pros and cons of each method in determining the aetiology of ifi. molecular tissue diagnosis has the potential to evolve into a useful method to describe the aetiology of ifi even in culture negative samples. results might be obtained fast enough to guide the antifungal therapy in patients with ifi progressive to empiric antifungal therapy. in these patients, the risk associated with invasive tissue sampling might be outweighed by potential benefits of a guided antifungal therapy. the two groups of carbapenemases (serine carbapenemases and metallobeta-lactamases (mbls)) can be encoded by genes that can be carried on plasmids. the serine carbapenemases are distinctly either class a or oxa (class d); the latter being mainly associated with acinetobacter spp. the dominant mbl subgroups, vim and imp have genes that are reportedly carried on plasmids and chromosomes. recent evidence has shown that the majority of blavim-2, even those initially reported, are indeed plasmid mediated and probably accounts for their rapid dissemination. blavim-1 genes have been recently shown to be carried on incn and incw plasmids. the "brazilian" mbl gene, blaspm-1, is exclusively chromosomally encoded. the mbls sim-1 and aim-1 are both chromosomally encoded whereas gim-1 is encoded from a plasmid of approx. 48 kb. the recently described blakmh-1 gene is also carried on a plasmid (200 kb). hitherto, only two mbl-positive plasmid sequences are available thus far -those carrying blaimp-8 and blavim-7. the former carries other resistance genes and are approx. 302 kb (inchi2), whereas the latter is a small plasmid (24 kb) and shows similarities with incp plasmids. oxa carbapenemase genes have been shown to be both plasmid and chromosomally mediated. thus far, the blaoxa-23 and blaoxa-24/40 clusters can be both plasmid and chromosomal and have mainly been found in acinetobacter spp. the blaoxa-48 and blaoxa-58 clusters have been found in k. pneumoniae and acinetobacter spp., respectively, and both are plasmid mediated. blaoxa-48 and blaoxa-58 have been shown to be carried on 70 kb and 28-100 kb plasmids, respectively. a blaoxa-58 plasmid has been recently sequenced and shown to carry two different replicases. the class a carbapenemase genes, blakpc, blaimi-2 and blages are all carried on plasmids. blakpc is found mainly in k. pneumoniae and carried on plasmids that vary in size 12−95 kb and mostly possessing the origin of replication incn. however, kpc-2 has recently described in a pseudomonas as being chromosomally mediated. blaimi-2 is exclusive to the usa and carried on a 66 kb plasmid although blaimi-1 is chromosomal. the blages genes have been found in p. aeruginosa and enterobacteriaceae of which ges-2, 4, 5 and 6 have been shown to be plasmid mediated although little else in known. this lecture will provide a synopsis, discuss the evolution of resistance due to plasmids and briefly predict what we may face in the 21c with respect to carbapenemase resistance. nosocomial infections caused by multidrug-resistant pathogens, especially gram-negative bacilli, have become a serious clinical concern in every healthcare setting worldwide. as well as carpapenemhydrolysing metallo-b-lactamases, ctx-m-type b-lactamases, and qunolone-resistance genetic determinants such as qnr, aac(6 )-ib-cr, and qepa, plasmid-mediated novel molecular mechanisms such as rmta, rmtb, rmtc, rmtd, arma, and npma responsible for pan-resistance to aminoglycosides have recently been identified in pseudomonas aeruginosa, acinetobacter spp., serratia marcescens, esherichia coli, klebsiella pneumoniae, proteus mirabilis etc. since 2003, and these enzymes have indeed methylation activity of 1405g or 1408a at the a-site of the bacterial 16s rrna as found in aminoglycoside-producing actinomycetes. these plasmid-mediated 16s rrna methylases are speculated to be originated from some nonpathogenic environmental microbes that produce aminoglycosides or some similar compounds, so it is quite natural that several new enzymes would be further identified hereafter in both clinical and livestock farming environments. rmtb and arma have widely spread in asia, europe, america and australia via various pathogenic gram-negative bacilli, we should pay special attention to the further spread of such hazardous microbes. in my talk, i would like to give an outline of newly identified molecular mechanisms that confer pan-resistance to aminoglycosides in pathogenic microbes isolated from both human and veterinary environments. [ acquired resistance to quinolones mainly results from chromosomal mutations responsible for modification(s) of dna gyrase and topoisomerase iv, and for a decrease of drug accumulation into bacteria due to decreased permeability and/or overexpression of efflux systems. plasmid-mediated quinolone resistance (pmqr) was first reported in 1998 from the usa, and two other mechanisms have been identified to date. the first pmqr determinants, qnr proteins, belong to the family of pentapeptide repeat proteins. five determinants have been identified: qnra, qnrb, qnrc, qnrd, and qnrs with 6, 20, 1, 1, and 3 different variants, respectively. they may act by binding directly to both dna gyrase and topoisomerase iv leading to protect them from quinolone inhibition. they confer resistance to nalidixic acid and reduced susceptibility to fluoroquinolones (fqs), but may facilitate recovery of mutants with higher level of resistance. the overall prevalence of qnra, qnrb, and qnrs determinants generally ranges from 1 to 5%, and they have been identified worldwide mostly in esbl-producing enterobacterial isolates. the origin of the qnra and qnrs genes were identified as shewanella algae and vibrio splendidus, respectively. the second type of pmqr determinant, aac(6 )-ib-cr, is a variant of the aminoglycoside acetyltransferase aac(6 )-ib which confers resistance to kanamycin, tobramycin and amikacin. this variant possesses two substitutions (trp102arg and asp179tyr) that are sufficient to acetylation of ciprofloxacin and norfloxacin with a 2-to-4-fold mic increase. the overall prevalence of aac(6 )-ib-cr may range from 0.4 to up to 34%, and it has been reported mainly in escherichia coli and klebsiella pneumoniae. the third type of pmqr determinant, qepa, has been identified in two e. coli clinical isolates from japan and belgium. the qepa gene encodes a 14-transmembrane-segment putative efflux pump belonging to the major facilitator superfamily. this protein confers decreased susceptibility to hydrophilic fqs (e.g. norfloxacin, ciprofloxacin and enrofloxacin) with an 8-to-32-fold mic increase. the two epidemiological surveys for qepa may indicate its low prevalence (<1%). the natural reservoir of qepa remains unknown but might be an actinomycetal species. discovering of three main mechanisms of pmqr within the last ten years is peculiar. it may reflect the emergence of novel mechanisms of resistance but also a deeper investigation of resistance mechanisms in clinical isolates. emerging infections: can we cope with them? a. kühn°, c. schulze, h. ranisch, p. kutzer, h. nattermann, r. grunow (berlin, frankfurt-oder, de) objective: little is known about the prevalence of francisella tularensis in humans and animals in germany. interestingly, the pathogen emerged recently when several marmosets (callithrix jacchus) died from tularaemia and a group of hunters became infected in the areas of western germany. to find out more about the distribution of the pathogen also in eastern germany we investigated the seroprevalence of tularaemia under foxes (vulpes vulpes) and raccoon dogs (nyctereutes procyonoides) in the area of brandenburg (around berlin). methods: sera of animals (n = 351 and n = 32, respectively) from the years 2007 and 2008 were tested for f. tularensis − lps antibodies in an indirect elisa and suspicious samples were confirmed by western blot for lps ladder recognition using protein g − pod conjugate. furthermore we investigated the serum samples by a competitive elisa using a peroxidase-conjugated anti − lps monoclonal antibody. results: from the serum collection, we tested 31 (8.8%) foxes and 3 raccoon dogs (9.4%) positive for specific f. tularensis antibodies. the geographical distribution showed hot spots in the area of the investigated region. our results indicate for a higher seroprevalence in wildlife for tularaemia in eastern regions of germany than assumed. since the reported human cases for the last decade seem to be underestimated, the real prevalence of the pathogen is unknown. the high number of tularaemia antibody positive foxes and raccoon dogs indicates that this zoonose is present in wildlife in eastern germany. however, the impact of transmission of zoonotic pathogens from wildlife to domestic animals and humans is not yet well studied. in conclusion, the obtained data will contribute for creating of up-to-date strategy for more efficient control of the two rickettsial zoonoses. objective: helicobacter pylori is established as the primary cause of gastritis and peptic ulceration in humans. in a minority of patients with upper gastrointestinal symptoms long tightly coiled spiral bacteria, clearly distinct from h. pylori, and provisionally named as "h. heilmannii", can be observed in gastric biopsies. our objective was to isolate and identify the spiral organism, resembling "h. heilmannii" from the gastric mucosa of a finnish patient presenting with severe dyspeptic symptoms. methods: we used two different selective media for the isolation of the bacteria from gastric biopsy samples before and after treatment of the patient with a 7-day course with lansoprazole, tetracycline and metronidazole. the isolates were characterised by testing for urease and catalase activity, light and electron microscopy, and sequencing the partial 16s rrna and ureab genes. single enzyme aflp was used to analyse the genetic diversity among the isolates. results: growth of long spiral organisms was obtained from 7 out of 8 antrum and all 8 corpus biopsies before and all three antrum biopsies after treatment of the patient. the partial 16s rrna gene sequence showed high sequence similarities with other gastric helicobacter species. the partial ureab gene showed high sequence similarity with h. bizzozeronii and was clearly distinct from other gastric helicobacter species. aflp indicated that the isolates belonged to the same clone however some minor genetic diversity was observed among the isolates. results: b. pseudomallei was primarily found in close proximity to streams and in grass-rich areas but was also correlated with environmentally disturbed soil such as caused by the presence of animals, farming or irrigation. prediction maps are currently being verified by sampling predicted b. pseudomallei "hot-" and "cold-spots". see in figure a prediction map for rural darwin with red areas indicating high probability for presence of b. pseudomallei. this study contributes to the elucidation of the environmental distribution of b. pseudomallei in endemic tropical australia and to the clarification of environmental factors influencing its occurrence. it also raises concerns that b. pseudomallei are spreading due to changes in land management. o82 concurrent multi-serotypic dengue infections in various body fluids w. kulwichit°, s. krajiw, d. chansinghakul, g. suwanpimolkul, o. prommalikit, p. suandork, j. pupaibool, k. arunyingmongkol, c. pancharoen, u. thisyakorn (bangkok, th) objectives: dengue virus infection is one of the rapidly-spreading emerging diseases worldwide. the virus is divided into 4 distinct serotypes with limited cross-protective immunity; therefore, one can be reinfected with different serotypes. while each episode is usually caused by a single serotype, an individual can occasionally be infected by concurrent multiple ones. our group has previously detected dengue virus from urine and oral specimens of some patients. in this study, we sought to determine the characteristics of multi-serotype infections when analysing beyond the patients' blood compartments. methods: during 2003 during -2007 and adult patients suspected of dengue infections were enrolled. plasma, peripheral blood mononuclear cells (pbmc), urine pellets, buccal brushes, and saliva were collected during and after the febrile episode. only specimens from patients with both positive dengue serology and pan-dengue-specific rt-pcr were included. serotype-specific rt-pcr was then performed on the aforementioned various specimens of each patient. results: 95 patients met the above criteria. serotyping was successful in 85 patients. den-4 was the most common serotype, accounting for half of the cases. 20 of these 85 (23.5%) demonstrated multiserotypic infections when combining data from all specimen types in each individual. serotyping using single, conventional serum/plasma specimens, however, would detect only half of the cases. the phenomenon of concurrent multi-serotypic infections was present in all examined specimen types, including urine pellets, buccal brushes, and saliva. the most frequent combinations were den-1 + den-4 and den-2 + den-4 (5 cases each). two patients were simultaneously infected by serotypes 1, 2, and 4 and one by serotypes 1, 3, and 4. there was no demonstrable significant difference in clinical severity between single-and multi-serotypic infections. conclusion: in a dengue-hyperendemic country with simultaneous circulation of all four serotypes, the phenomenon of concurrent multiserotypic infections are more common than previously demonstrated by traditional serotyping on single serum/plasma specimens. this may be explained by the sensitivity limitation of the detection method or by biological behaviour of the virus. our findings have an implication for potentially more accurate epidemiologic studies in the future, and for further exploratory investigations regarding dengue virus in various secretions and excretions. o83 emerging concepts about the evolutionary history of hantaviruses h.j. kang, s.n. bennett, l. sumibcay, s. arai, a.g. hope, j.a. cook, j.w. song, r. yanagihara°(honolulu, albuquerque, us; tokyo, jp; seoul, kr) objective: recent discovery of genetically distinct hantaviruses in shrews (family soricidae), captured in widely separated geographic regions, challenges the conventional view that rodents are the principal and progenitor reservoir hosts of hantaviruses, and raises the possibility that other soricomorphs, notably moles (family talpidae), harbour hantaviruses. methods: using oligonucleotide primers based on conserved genomic regions of rodent-and soricid-borne hantaviruses, rna extracts from tissues of the japanese shrew mole (urotrichus talpoides), american shrew mole (neurotrichus gibbsii) and european common mole (talpa europaea) were analyzed for hantavirus sequences by rt-pcr. newfound s-, m-and l-segment sequences were aligned using clustal w and were analyzed phylogenetically by the maximum-likelihood and markov chain monte carlo tree-sampling methods, with the gtr+i+g model of evolution. results: novel hantavirus genomes, designated asama virus (asav), oxbow virus (oxbv) and nova virus (nvav), were detected in tissues of urotrichus talpoides, neurotrichus gibbsii and talpa europaea, respectively. sequence and phylogenetic analyses indicated that asav and oxbv were related to hantaviruses harboured by soricine shrews in eurasia and north america, respectively. by contrast, phylogenetic analyses of full-length s-and l-segment sequences showed that nvav formed a unique clade, clearly distinct and evolutionarily distant from all other hantaviruses. despite the high degree of sequence divergence at the nucleotide and amino acid levels, the secondary structures of the nucleocapsid proteins, as well as the l-segment motifs, of the moleassociated hantaviruses were well conserved. conclusions: while cross-species transmission has influenced the course of hantavirus evolution, such host-switching events alone do not satisfactorily explain the co-existence and distribution of genetically distinct hantaviruses among species in two taxonomic orders of small mammals spanning four continents. when viewed within the context of molecular phylogeny and zoogeography, the close association between distinct hantavirus clades and specific subfamilies of rodents, shrews and moles is likely the result of alternating and variable periodic codivergence at certain taxonomic levels through evolutionary time. thus, the primeval hantavirus might have arisen from an insect-borne virus, with ancestral soricomorphs, rather than rodents, serving as the original mammalian hosts. from south-eastern france m. kaba, b. davoust, j.l. marié, m. barthet, m. henry, c. tamalet, j.m. rolain, d. raoult, p. colson°(marseille, toulon, fr) objectives: autochthonous hepatitis e is currently considered as an emerging disease in industrialised countries and several studies suggest that hepatitis e is a zoonosis, especially in pigs, boars and deer. we aimed to study whether hepatitis e virus (hev) is commonly present in domestic pigs in southern france, and to determine the relationship between hev sequences detected from pigs and those described in human hepatitis e cases. methods: serum and stools samples were collected from 207 three or six-month-old pigs from different regions of southern france. 107 sixmonth-old pigs were from a slaughterhouse, and 100 three-month-old pigs were from a pig farm. swine igg anti-hev antibodies testing was performed using a commercial elisa kit for clinical diagnosis with minor modifications. swine hev rna detection was conducted by realtime pcr and amplification/sequencing assays using in house protocols targeting the 5 orf2 region of the hev genome. results: 40% of pigs were seropositive, and 65% of three-monthold pigs were hev rna-positive, whereas none of the six-monthold pigs were hev rna-positive. hev rna was significantly more frequently detected from stools than from serum (65% versus 22%; p < 0.001). phylogenetic analysis showed that swine hev sequences belong to genotype 3f or 3e and formed two clusters within which sequences showed high nucleotide homology (>97%). these clusters were correlated with the geographical origin of pigs as well as with their repartition into pens and buildings in the pig farm where samples were collected. swine hev sequences from the present study were genetically close to hev sequences found from humans or swine in europe, although no strong phylogenetic link could be observed neither with these latter sequences nor with those from human hepatitis e cases diagnosed in the laboratory. conclusion: our data indicate that three-month-old farm pigs from southern france might represent a potential source of contamination to humans, and they underscore the great potential of hev to cause epizootic infections in populations of farm pigs. o85 clostridium difficile: changing epidemiology trends, 2000 -2007 objectives: clostridium difficile infection (cdi) has become a growing concern world-wide with an increased reported incidence and an increase in the associated financial burden. our aim therefore was to review trends in cdi occurring from 2000-2007 inclusive. methods: all patients admitted to lothian university hospitals division (luhd) tested for c. difficile toxins a+b by eia were included. retrospective analysis of prospectively collected data was performed. the number of occupied bed days was provided by nhs-lothian statistics department. the most recent published costs associated with cdi were used to estimate potential costs to lothian nhs trust. results: 50,590 faecal samples were tested for c. difficile toxins from 2000-2007 inclusive; of these 7301 samples were positive. overall cdi was identified in 15.2 cases/10000 patient days and 5.8 cases/1000 inpatient hospital admissions. the incidence of identified cdi rose from 3.6cases/10000 patient days in 2000 to 14.8cases/10000 patient days in 2007. incidence also increased with age from 3.3cases/10000 patient days in the 0−20 years age group to 18.1cases/10000 patient days in the 61−80 years age group. renal medicine and intensive care had the highest incidences of identified cdi with greater than 57cases/10000 patient days each followed by infectious diseases and gastrointestinal medicine whose rates were 47.5 and 42.6 cases/10000 patient days respectively. medicine of the elderly in comparison had an incidence of 19.5cases/10000 patient days. of note 10% of all patients were transferred through a minimum of two specialties during the period in which they remained positive for c. difficile toxins. estimated costs over the study period for toxin testing alone were in the region of £126,500 and the minimal potential hospitalisation costs of patients with cdi was in the region of £20,000,000. conclusion: the incidence of patients identified with cdi has risen markedly and not surprisingly the incidence has also been noted to increase with age. medicine of the elderly however had a much lower incidence than several other specialties and therefore risk assessment of cdi development and containment should now also be targeted within other specialties. with 10% of identified cdi patients transferred through different specialties and the significant financial burden cdi imposes on healthcare institutions judicious application of infection control measures remains an important factor to prevent cdi spread. isolates of this strain were pvl negative, but positive for enterotoxin a (sea) and, in most cases, also for seb, sek and seq. a fifth strain was the "taiwan clone", st59/952-mrsa-v (wa mrsa-9 and -52) which also comprised two closely related sequence types. this strain carried a sccmec element of type v(t) or vii as well as pvl and, usually, seb, sek and seq. it was the most common cc59 strain in wa. the sixth strain differed from the "taiwan clone" in the presence of a sccmec type v element and in the absence of pvl. the differentiation of this clonal complex into various different strains indicates a rapid evolution and spread of sccmec elements, and the diagnostic microarray technology allows one to distinguish beyond mlst level and hence to accurately trace outbreaks and spread of these strains. a sample taker 12 has daily contact with poultry and is excluded from analysis. b sample taker 5 reported no contact with livestock elsewhere than in this study at that moment (spa-types of sample taker 5 and farm are not corresponding). c sample taker 6 tested mrsa-negative in following tests. d sample taker 9 was not tested again. complete data sets (samples taken before, directly after and 24 hours after a visit) were collected on 141 visits by 29 sample takers visiting 50 farms. on 28 farms mrsa was collected from pigs or stabledust (56%). these farms were visited 78 times by 23 different sample takers. one sample taker (#12) was positive for mrsa before visiting a farm, he was removed from the following analysis. fifteen of the 78 (19%) visits to mrsa-positive farms resulted in acquisition of mrsa and 11/23 (48%) sample takers acquired mrsa at least once after visiting a positive farm. of these 11 positive sample takers 2 acquired mrsa twice and 1 sample taker acquired mrsa three times after separate visits. of the 15 acquisitions of mrsa, 13 were negative after 24 hours. the spa-types of mrsa isolates found on the farms and sample takers were grossly comparable. on the 32 negative farms, none of the 60 visits resulted in mrsa acquisition. for further information see the table. discussion: mrsa-cc398 was acquired by 48% of the sample takers after occupational exposure in this study. however, in 11 of the 13 cases the strain was not recovered the next day, therefore acquisition was of short duration, posing a limited treat to human health. some persons seemed to be more vulnerable to acquire mrsa during their work. the sample size of this study was too small to draw final conclusions concerning this inter-personal variation. this requires a more extensive study. [ objectives: community-associated mrsa is an increasing problem and an association with food animal contact has been made in some regions. this has led to concerns about the potential role of food in mrsa transmission. the objective of this study was to evaluate the prevalence of mrsa colonisation of retail pork in canada. methods: pork chops, ground pork and pork shoulders were purchased at retail outlets in four canadian provinces in conjunction with the canadian integrated program for antimicrobial resistance surveillance. both direct inoculation of meat into enrichment broth and rinsing of meat in broth were performed for pork chops and shoulders, followed by inoculation onto chromogenic agar. ground pork was tested only using the direct method. mrsa isolates were typed by pfge and spa typing. real time pcr was used to detect panton-valentine leukocidin genes. results: mrsa was isolated from 31/402 (7.7%, 95% ci 5.5−10.7%) of samples. there was a significant difference between provinces (p < 0.001) but no difference between different products, with mrsa isolated from 23/296 (7.7%) pork chops, 7/94 (7.4%) ground pork and 1/12 (8.3%) pork shoulders (p = 0.99). 21/403 (5.2%) samples were positive using direct culture while mrsa was isolated from 15/355 (4.2%) of samples testing using the rinse method. nine samples were positive on direct culture but negative using the rinse method, while 10 others were positive only with the rinse method and only 5 were positive with both methods. seven samples (ground pork) that were positive on direct culture were not tested using the rinse method. 3 main clones were present. the most common (40% of isolates) was a group of 3 related spa types (t064, t008 and new related type) were classified as canadian epidemic mrsa-5 by pfge, an st8 human epidemic clone that has been associated with horses. pfge-non-typable spa t034 were not surprisingly common, accounting for 30% of isolates. the 3rd main group was 3 related spa types (t002, t045 and new type) that were cmrsa-2 (usa100), an st5 clone that is common in humans in canada, that also accounted for 30% of isolates. the clinical relevance of mrsa contamination of pork is currently unclear. it is possible that contact with contaminated food could be a mode of mrsa transmission in the community, although further study of the prevalence of contamination, amount of mrsa in contaminated samples, sources of contamination and implications on human health are required. o95 prevalence of the novel trimethoprim resistance gene dfrk among german staphylococcal isolates of the bft-germvet monitoring study k. kadlec°, s. schwarz (neustadt-mariensee, de) objectives: very recently a novel trimethoprim resistance gene, dfrk, was identified on a tet(l)-harbouring plasmid in a porcine mrsa isolate from the bft-germvet monitoring study. this study included in total 248 independent coagulase-positive and coagulase-variable staphylococci collected between 2004 and 2006 all over germany: 46 isolates from infections of the urinary-genital tract of pigs, 44 isolates from skin infections of pigs, 57 isolates from respiratory tract infections of dogs/cats, and 101 isolates from infections of skin/ear/mouth of dogs/cats. in this study, we investigated the prevalence and the plasmid location of the dfrk gene among these isolates. methods: pcr primers were designed and a pcr with subsequent restriction analysis of the pcr product was established to detect dfrk. isolates with positive results were tested for a plasmid location of dfrk by transfer experiments and dfrk-carrying plasmids were further analysed. the trimethoprim resistance gene dfrk was detected in another 10 isolates. all isolates were from pigs: 9 from skin infections and the remaining 1 from a urinary-genital tract infection. six staphylococcus hyicus subsp. hyicus isolates, 3 s. aureus isolates (2 mrsa and 1 mssa) and 1 s. pseudintermedius. all these isolates harboured plasmids. in 7 isolates (4 s. hyicus, 2 mrsa and the single s. pseudintermedius), the plasmid location of dfrk was confirmed by protoplast transformation with subsequent susceptibility testing and pcr analysis of the transformants. in all 7 cases, the plasmids harbouring dfrk also carried a tet(l) tetracycline resistance gene. the results of a combined pcr assay with primers from tet(l) and dfrk confirmed that the dfrk gene was always located immediately downstream of the tet(l) gene. further analysis of these dfrk-and tet(l)-harbouring plasmids showed that they varied in size between 6 and 40 kb and that similar sized plasmids differed in their ecorv and hindiii restriction patterns. the novel trimethoprim resistance gene dfrk occurred in 11 (12.2%) of the 90 porcine staphylococcal isolates from the bft-germvet study. in 8 (72.7%) of the 11 isolates, it was located on structurally diverse plasmids, however, always in close proximity to a tet(l) gene. the linkage of the dfrk and tet(l) genes allows the maintenance and coselection of such plasmids under selective pressure by either tetracyclines or trimethoprim, both of which are widely used in veterinary medicine. (table) . the isolates were resistant to ciprofloxacin, clindamycin, erythromycin, gentamicin but susceptible to vancomycin. only one se was methicillin-susceptible and two isolates were quinupristin/dalfopristin non-susceptible. all strains were clonally related and clustered into three subtypes (a, a1 and a2). cfr gene was detected in a linezolid non-susceptible strain (mic, 64 mg/l), which was recovered from a 57 y/o male who underwent liver transplantation. plasmid analysis identified six plasmid bands ranging from c.a. 1.5-to 154-kb in the cfrcarrying strain. hybridisation signals were observed from the 154-kb plasmid band as well as from a chromosomal band after i-ceui digestion. mutations at the 23s rrna, l4 or l22 were not detected. the cfr increased the linezolid mic value between 8-and 16-fold. this report highlights the ability of se to acquire linezolid resistances. the potential mobility of cfr combined with the clonal tendency for dissemination among staphylococcus spp., represent a serious threat to several potent gram-positive-active agents, including oxazolidinones. active surveillance combined with effective infection control and molecular studies seem prudent to minimise the spread of these resistance mechanisms. the objective is to get a glimpse of the potential impact of infectious diseases on music, as regards to the composer's or performing musician's own disease, living conditions or other relevant elements which might have affected the end result, the music we enjoy today. as music is an art of senses, full of drama, despair, realities of life − or just the opposite, blissful ignorance of those realities, full of romance, beauty, and delicacy − various forms of music was researched paying special attention to infections which potentially have played a significant role in the birth of that particular piece or performance. the entire research process was subjective, biased, and emotional, but done wholeheartedly. it aimed at to taking into account, not only the personal life of a composer or performing musician, but also the historical context in which the music was born. musical examples, served to the audience along with the essential background data, will show the extent to which infections have impacted music. regarding the aetiology of those infections, bacterial, viral and parasitic agents are well represented. in addition, many epochs in history have played their role. sometimes, the connections are surprising, even dramatic. if listened to with a tender ear, music quite often turns out to be affected also by infectious diseases. as physicians we should realise the strength with which some people are driven by this demonic, divine − but altogether beautiful force: music. the prevalence of antibiotic resistance has been increasing in asian countries in recent years. this problem has most likely arisen due to a combination of inadequate infection control practices particularly in hospital settings and the widespread misuse of antibiotics in hospital and community settings. factors that lead to antibiotic misuse include inappropriate antibiotic prescription due to a lack of clinical, microbiological and/or imaging data in many clinical settings in the asian region. a lack of separation of prescribing and dispensing by medical practitioners as practised in many countries in asia as well as the easy availability of over the counter medications also contribute to antibiotic misuse. optimal control of antibiotic use can only be achieved through a multipronged approach that includes better education of the public and medical practitioners on rational use of antibiotic, a review of the health system structure, as well as better control of over the counter sales of antibiotics. upgrading of microbiology and other laboratories and radiological facilities that will enhance the accuracy of clinical diagnosis is also urgently needed in most developing countries to keep pace with the complexities of managing patients in this new era to minimise the widespread practise of inappropriate antibiotic use. examination of the csf for microorganisms, wbc and differential counts, and concentrations of glucose and protein is the primary investigation to diagnose meningitis. however, this csf examination may not always be conclusive, and it can be difficult to distinguish bacterial from viral meningitis. therefore, improvement in diagnostic sensitivity and specificity of bacterial meningitis and development of rapid test for a bacterial aetiology are still needed. this presentation gives a review of the strength and weakness of several analyses and methods to reveal the microbiological agent (i.e. csf microscopy and culture, antigen or antibody detection, molecular methods to detect dna or rna) and the use of several mediators of the host immune response for diagnostic and prognostic purposes. bacterial meningitis is a medical emergency that requires a multidisciplinary approach. a diagnosis of bacterial meningitis is often considered, but the disease can be difficult to recognize. recommendations for antimicrobial therapy are changing as a result of the emergence of antimicrobial resistance. in this lecture, current concepts of the initial approach to the treatment of adults with bacterial meningitis will be summarised. the management of the critically ill patient with bacterial meningitis poses important dilemmas. controversial areas (i.e., prehospital admission antibiotics) will be reviewed and relevant literature will be discussed in the framework of current treatment guidelines, highlighting new developments in adjunctive dexamethasone therapy. acute bacterial meningitis (abm), especifically when caused by infection with streptococcus pneumoniae, still has an unacceptably poor prognosis with a mortality of 10−30%. bacterial infection of the meninges causes one of the most powerful inflammatory reactions known in medicine. yet 50 years ago, this inflammatory reaction was suggested to contribute substantially to brain damage. this concept underlies the use of anti-inflammatory agents as adjunctive therapy in abm. of all adjunctive treatments in abm, only corticosteroids have been properly evaluated in clinical trials. these trials recommend corticosteroids in patients with haemophilus influenzae type b and pneumococcal meningitis (pm). however, adjunctive corticosteroid therapy has several weaknesses such as a narrow treatment window and borderline effects on neurologic sequelae. thus, there is still the need for additional or alternate adjuvants in the therapy of abm. experimental studies using animal models (predominantly of pm) have provided insight into the pathogenic mechanisms underlying brain injury in abm. it is now clear that the autodestructive inflammatory reaction is initiated by the interaction of bacterial components with host pattern recognition receptors (prr) like toll-like receptors (tlr). prr signaling results in the activation of transcription factors like nf-kb which up-regulate the production of proinflammatory cytokines. cytokines like il-1b are also potent triggers of nf-kb activation and therefore can exaggerate the inflammatory reaction (via positive feedback loops). as a consequence, great numbers of neutrophils are recruited to the meninges. activated neutrophils release many potentially cytotoxic agents including oxidants and matrix metalloproteinases that can cause collateral damage to brain tissue. additionally to the inflammatory response, direct bacterial cytotoxicty has been identified as a contributor to tissue damage in abm. thus, experimental studies point at four different targets of adjunctive therapy, namely interference with (i) the induction of inflammation (e.g., tlr blockade), (ii) the exaggeration of inflammation (e.g., il-1 antagonism), and (iii+iv) the generation of cytotoxic factors (either of host or bacterial origin, e.g., scavenging of oxidants). this presentation will give an overview of the pathophysiology of abm (with special emphasis on pm) and highlight promising targets for adjunctive therapy in abm, as deduced from experimental studies. a clinician's approach to managing difficult infections s120 acute post-surgical prosthetic joint infection optimal management of prosthetic joint infections (pji) remains undefined. important issues such us when the implant can be retained (conservative strategy), optimal duration of antimicrobial therapy (at) or the role of rifampin are yet matter of controversy. in spite of a number of reports, literature appears confusing. among the limitations of the literature we must emphasize: 1) different criteria to classify pji; 2) different criteria to select for conservative strategy (cs); 3) no description of the initial population from which patients were selected for cs; 4) very different at (from 4 weeks to chronic suppressive therapy); 5) low numbers of patients or short follow-up; 6) absence of clinical trials. it is not so surprising that the rates of cs success have varied from 0 to almost 100%. the most useful classification to approach pji was proposed by tsukayama (1996) . in his series 25 out of 35 patients with early pji managed by a cs (debridement, exchange of polyethylen and implant retention) were cured after 4 weeks of at. the spanish group for the study of pji was constituted in 2003 within the spanish network for the study of infectious pathology (reipi), a public funded initiative. data from 139 consecutive cases of early pji attended in 10 hospitals were recorded in an online database. 117 cases managed with cs could be analysed (mean followup of 2 years). sixty-seven patients (57.3%) were cured after a mean of 81 days of at. in 35 (29.9%) the infection was not controlled (or relapsed) after a mean of 84 days of at, and the implant had to be removed. in other 15 patients (12.8%) the implant was not removed, but suppressive at was given because of suspected ongoing infection. results were significantly worse in one hospital. no other factors resulted statistically significant, but there was a trend of worse results for mrsa produced infections (p = 0.06). time from the symptoms appearance to debridement was shorter in successfully treated cases (median, 7 days) than in failures (median, 10 days); p = 0.08. good functional results were obtained in patients with successfully cs. in summary, a substantial proportion of early pji can be managed with cs strategy and a definite (non suppressive) at. it is difficult to identify patients at higher risk for failure, although mrsa aetiology and longer time until debridement seem to predict failures. different outcomes in some centres suggest that surgical technique could be an important factor for failure. more than 3 million cardiac pacing systems are implanted worldwide and the estimated rate of infections after implantation of permanent endocardial leads is 1% to 2%, but varies between 0.1 to 20%. pacemaker infections correspond to different clinical situations including localised infection in the device pocket, pacemaker leads to systemic infection associated with bacteraemia and lead-associated endocarditis. this latter represents 10 to 25% of all cases of pacemaker infections. the severity of pacemaker related infective endocarditis is sustained by a mortality range between 10 to 20%. risk factors related to infections of implanted pacemakers are correlated with fever before 24 h before implantation, temporary pacing before implantation and early re-interventions (haematoma, lead dislodgment). in contrast, an inverse correlation is observed between development of infection and antibiotic prophylaxis and implantation of a new system. data to guide therapy in patients with pacemaker infection are limited and the most appropriate management remains to be determined. according to different series, staphylococci accounted for 60 to >90% of the responsible organisms. coagulase-negative staphylococci (cns) are reported as predominant pathogens following by staphylocococcus aureus. the biofilm production, responsible for bacterial survival, and the emergence of methicillin-resistant in s. aureus and cns have complicated the management of pacemaker infections. this implies that empiric treatment of suspected pacemaker infection should coverage for staphylococci including methicillin-resistant strains. streptococci, corynebacterium spp, propionibacterium acnes, gram-negative bacilli and candida spp can cause occasional infections. the optimal therapy combines complete device extraction (percutaneous ablation or surgical removal during extracorporeal circulation) and prolonged course of antibiotics, in particular in case of multiresistant bacteria. leaving the device intact is associated with increased mortality and risk of relapsing or persistent infections. in absence of prospective studies, the duration of antibiotic treatment remains to be determined but 1 month has been shown not to be associated with an increased incidence of relapse. shortest course of treatment (2 weeks) has been proposed in case of vegetations strictly localised to leads without affecting cardiac valves. antibiotic therapy working alone should be reserved for highly selected patients. infection remains the most critical complication of ventriculoperitoneal shunt placement with an incidence of 2.2−39%. factors as the age of patient, aetiology of hydrocephalus, the type of shunt implanted, and the surgeon's experience are determined to be associated with increased risk of infection. children are more likely than adults to acquire shunt infection. the possible reasons are longer hospital stay, higher skin bacterial concentrations, immature immune systems, or more adherent strains of bacteria. staphylococci, as skin commensals, are the main causative organisms. nevertheless, in recent years a change in the epidemiology of microorganisms was observed with an increase of gram-negative bacteria. appropriate systemic antibiotics according to the antimicrobial susceptibility testing and surgical removal of the shunt with temporary external cerebrospinal fluid drainage and shunt replacement following the eradication of the infection are the cornerstone of the treatment of cerebrospinal fluid shunt infections. good compliance with infection control practices, inserion of the catheter under aseptic techniques and short-term perioperative antimicrobial prophylaxis in order to prevent the emergence of drug-resistant subpopulations are important steps in the prevention of shunt infections. o125 influenza in adults admitted to canadian hospitals: data from two seasons a. mcgeer, d. gravel, g. taylor°, c. weir, c. frenette, j. vayalumkal, a. wong, d. moore, s. michaud, b. amihod (toronto, ottawa, edmonton, montreal, saskatoon, sherbrooke, ca) objective: seasonal influenza (flu) remains a cause of substantial morbidity and mortality. antiviral treatment should be considered for all hospitalised patients with influenza. to better understand the epidemiology and burden of illness within the hospital sector in canada and the current use of antiviral therapy, we carried out a multihospital survey of virologically confirmed flu in hospitalised adults. methods: cnisp is a network of largely teaching hospitals across canada that collaborates to collect data on infections in hospitalised patients. during two consecutive years (2006/2007 and 2007/2008) hospitals within cnisp identified inpatients >16 years who had virologically confirmed flu. case patient charts were reviewed to capture demographic and clinical data and to determine whether flu was community (ca) or hospital acquired (ha). cases were reviewed at 30 days to determine outcomes. deaths at 30 days were reviewed to determine whether flu was a main or contributing cause. results: fifteen (06/07) and 11 (07/08) hospitals were recruited from the cnisp network. 532 virologically confirmed cases of flu were found, 182 in 06/07 (95% flu a) and 358 in 07/08 (56% flu a). mean patient age was 67 years, 52% were male. there was documentation of patient vaccination that season in 29%. incidence of ca flu was 11/10,000 admissions in 06/07 (range by hospital 2 − 23) and 27 in 07/08 (1 − 47). admitting diagnoses in ca cases were: pneumonia or influenza 48%, exacerbation of copd 20%, sepsis or fever not otherwise specified 9%, cardiac diagnoses 7%, other diagnoses 16%. 24% of cases were ha, range by hospital 3.9 − 5.4/100,000 patient days. 68% of patients were managed with droplet and contact isolation practices, an n-95 mask was used in 19%. 29% of ca cases but 75% of ha cases received antiviral therapy p < 0.01, almost entirely oseltamivir. 9% of cases were admitted to an icu; 30-day mortality was 8% with 2.6% attributed to influenza. conclusion: there is considerable season-season and hospital-hospital variation in flu in patients in canadian hospitals. hospitalised patients ca flu present with a wide spectrum of clinical diagnoses; nearly a quarter of all cases were ha. few ca cases but most ha cases were treated with antiviral drugs. attributable 30 day mortality was 2.6%. v. papastamopoulos, e. kakalou°, t. panagiotopoulos, j. baraboutis, m. samarkos, a. skoutelis (athens, gr) objectives: our study sought to describe influenza vaccination coverage among adults in greece for the season 2007/08. methods: we conducted a random-sampling, telephone based household survey among adult individuals in greece. for this purpose a sample of 1104 adults representative of the basic demographic, social and geographical characteristics of the overall greek population according to the latest national survey, was used. two target groups were determined for analysis: persons >65 years of age and persons with chronic conditions such as respiratory and heart conditions (other than hypertension), diabetes mellitus and other conditions. results: the influenza vaccination rate for the season 2007/08 among the adult population in greece was: 16% for the overall adult population (19.5% for men, 12.7% for women), 48.1% for people >65 years of age, 31% for persons with chronic illness (32.5% for persons with respiratory illness, 50.2 for persons with heart conditions, 35% for persons with diabetes mellitus). a high rate of 81% of the overall population reaching 88% among persons with chronic conditions report having had any type of contact with the national health system or a private physician within the last three years. among them only 20.1% had been recommended to get vaccinated. among the ones recommended any vaccination, 80.5% of persons with respiratory illness, 100% of persons with diabetes mellitus and 89.1% of persons with heart conditions had been recommended to get the influenza vaccine. conclusions: available data show unacceptably low levels of influenza vaccination coverage among vulnerable groups such as the population over 65 years of age and people living with chronic illness. influenza vaccination is the only preventive measure reducing influenza morbidity and mortality and its use has proven cost-effective among high risk groups. it is also the main vaccine recommended by physicians. however the overall rate of physicians recommendation of vaccination is very low. dynamic efforts are thus needed to design and implement strategies and policies that have demonstrated their rigorous effectiveness in enhancing influenza vaccination coverage rates. conclusions: nasopharyngeal sampling with flocked swabs is well tolerated and suitable to be used in an outpatient setting. implementation of real-time mono and multiplex naats results in a significant improvement of the rate in diagnosing lrti. hrv account for the majority of viral lrti in primary care followed by influenza and coronaviruses but also rsv and hmpv are prevalent in an adult population. in this study, 19 polyomaviruses were detected of which 10 were involved in a double infection. methods: observational analysis of a prospective cohort of 1041 nonseverely immunosuppressed adults with pp requiring hospitalisation (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) . of them, 556 were diagnosed by urinary antigen and/or 650 were diagnosed by culture. overall, 86% of pneumococcal strains were available for serotyping (quellung) and 58% for pfge (smal) and or mlst. the diagnosis of septic shock was based on a systolic blood pressure <90 mmhg and peripheral hypoperfusion with clinical or bacteriologic evidence of uncontrolled infection. results: a total of 114 (11%) patients with pp had septic shock at presentation. patients with shock were younger (61 vs 66 yrs; p = 0.003), were more frequently current smokers (45% vs 28%; p = 0.002), had received more commonly corticosteroid therapy (13% vs 6%; p = 0.015), and were more frequently classified into high-risk psi classes (81% vs 60%; p < 0.001) than those who did not have this complication. they were also less likely to have received prior influenza vaccine (31% vs 48%; p = 0.007) and had more frequently bacteraemia (41% vs 30%; p = 0.014). no significant differences were found in rates of penicillin-(2% vs 2%) and erythromycin-resistance (16% vs 12%). serotype 3 was more commonly associated with shock (40% vs 24%; p = 0.007), whereas serotype 1 was rarely associated with this complication (2% vs 9%; p = 0.041). no significant differences were found regarding genotypes: st2603 (26% vs 16%), netherlands-ser8-st53 (10% vs 3%), netherlands-ser3-st180 (10% vs 8%), spain-ser9v-st156 (10% vs 12%). patients with shock required more frequently mechanical ventilation (38% vs 4%; p < 0.001), and had longer los (19 vs 10 days; p < 0.001). early (10% vs 1%; p < 0.001) and overall case-fatality rates (25% vs 5%; p < 0.001) were higher in patients with shock. conclusions: pp presenting with septic shock is still associated with a poor outcome. it occurs mainly in current smokers, patients receiving corticosteroids, and in those infections caused by serotype 3. prior influenza vaccination and pp caused by serotype 1 are associated with a lower risk of shock. o131 high long-term mortality rate after initial recovery from severe community-acquired pneumonia background: despite the presence of antibiotics and vaccination strategies against pneumocci, community-acquired pneumonia (cap) is still a major cause for mortality in developed countries. however, it is unclear how an episode of cap influences long-term survival after initial recovery. therefore, we determined mortality up to 5 years after discharge in patients hospitalised because of an episode of severe cap in a non-intensive care setting. methods: in 5 hospitals in the netherlands, patients (pts) with severe cap (psi class iv and v without need for treatment in icu) were prospectively followed for 28 days and mortality up to 5 years after discharge was determined using the dutch municipal public records database. we used cox regression analysis to examine predictors for mortality. results: compared to strategy 2, strategy 1 resulted in slightly higher costs (chf 8,748 vs. 8,981) but fewer infections (.008 vs. 0.006) during patients' mean length-of-stay, producing an incremental costeffectiveness ratio (icer) of chf 83,303 per mrsa infection avoided. strategy 3 was dominated by strategies 1 and 2 (both more costly and less effective). sensitivity analyses suggest that prevalence of colonisation on admission is a stronger predictor of cost-effectiveness than the costs of infection or rapid screening, the probability of cross-transmission, or the incremental costs of isolation and contact precautions. increasing the relatively low on-admission prevalence at our centre by 20% lowers the icer to chf 60,973 per infection avoided. in contrast, increasing the cost of each infection, the cost of rapid screening, or the risk of cross-transmission by 20% only marginally affects the icer. conclusion: this analysis suggests that compared to risk factor identification and pre-emptive isolation, universal rapid screening upon surgical admission is not strongly cost-effective at our centre. however, local epidemiology plays an important role. in particular, settings with higher prevalence of colonisation on admission may find universal rapid screening more cost-effective. of note, no screening is undesirable, as costs and infections would be higher. results: admission and weekly screening coupled with patient isolation was found to dramatically reduce the number of mrsa acquisitions. the largest reductions were obtained with pcr technology, followed by chromogenic agar. the differences, however, were surprisingly small, and all screening technologies achieved reductions in mrsa acquisition of close to 80% compared with the no-intervention scenario. nonetheless, chromogenic and pcr-based systems were able to decrease the number of unisolated mrsa-bed-days by approximately 15 and 35% respectively. conclusions: the small differences in the ability of the screening technologies to reduce mrsa acquisition reflect both a relatively low estimated isolation efficacy and the observed highly skewed distribution of icu-stays, and may provide some important insights into the reasons for recent disappointing trial results. in particular, the skewed length of stay distribution means that most mrsa-bed days are accounted for by relatively long-stay patients for whom rapid detection will make the least difference. key sources of uncertainty were found to be isolation effectiveness and attributable mortality due to mrsa infections, both of which are difficult to accurately estimate with currently available data. the model results allow us to quantify the expected value of reducing these key uncertainties, and help to provide a rational basis for setting future research priorities. objectives: we have shown that there is substantial colonisation of mrsa among nursing home residents and staff with our recently conducted point prevalence study in 45 nursing homes which revealed an overall prevalence rate of 24% in residents and 7.6% in staff.1 the aim of this study was, therefore, to test the effectiveness of an intervention in nursing homes which sought to improve standards of infection control as a means of reducing mrsa prevalence. methods: a cluster randomised controlled trial (crct) involving 32 nursing homes, with each home representing the unit of analysis, was performed. the study ran for 12 months with data collected at baseline, 3, 6 and 12 months. nasal swabs were taken at baseline from consenting residents and staff in all homes prior to randomisation with an audit of infection control procedures also undertaken. following collection of these baseline data, nursing homes were allocated to the intervention or control arm (1:1). intervention home staff were trained in infection control, specifically hand hygiene, catheter care, barrier approaches such as use of gloves, aprons and masks, and decontamination of equipment and the environment with usual practice continuing in control homes. after each data collection timepoint, feedback was given to the intervention homes in terms of their performance and further education and training provided as required. the primary outcome was the prevalence of mrsa in intervention homes compared to control sites. results: preliminary analysis of the data has revealed no significant change in the prevalence of mrsa in the intervention and control homes, taking account of the clustering, over the one-year intervention period [risk ratio 0.83; 95% confidence intervals (ci) 0.53−1.29]. however, there was an improvement in infection control audit scores in the intervention homes, with a mean score in control homes at 12 months of 64.4% compared with 81.7% in the intervention sites; these scores were significantly different (paired t-test, p < 0.0001). the results suggest that infection control education and training as implemented in this study was not sufficient to affect mrsa prevalence. therefore, a more detailed education and training package either alone or in combination with mrsa decolonisation of staff and residents, may be required to reduce mrsa prevalence within this unique environment. [ objectives: in a response to the rapid global increase in the nosocomial prevalence of multi-resistant micro-organisms, infection control measures, such as patient isolation, are increasingly used. it is unknown how these measures influence the quality of life (qol) of patients during short-term isolation, and this was determined in a prospective matched cohort study. methods: all adult patients needing isolation in a single-patient room between 11/06 and 03/07 in the umc utrecht were eligible and included 24−48 hours after start of isolation (after giving informed consent and being able to fulfil study requirements). for each index patient we identified two control patients, admitted to the same wards at the same time, yet not subjected to any isolation measure. anxiety and depression and qol were assessed using the hospital anxiety and depression scale (hads) and visual analogue scale (eq-5d-vas) in all patients. opinions on and experiences with isolation were measured in isolated patients by means of a self-developed 'isolation evaluation questionnaire'. results: 42 isolated patients and 84 controls were included, with comparable baseline characteristics (age, sex, nationality, level of education, length of hospital stay and severity of underlying disease and co-morbidity (using the cumulative illness rating scale)). reasons for isolation were clostridium difficile-associated disease (n = 17, 40%), high risk for mrsa carriage (n = 12, 29%), or resistant gram-negative bacteria (n = 7, 17%). mean scores of questionnaires are presented in table 1. isin univariate analysis only duration of isolation of 48 hours (compared to 24 hours) was associated with a reduced quality of life (vas 57.7 compared to 68.7, p 0.02). on a visual analogue score of opposite terms isolation measures were rated with means of 87.5, 83.3 and 70.8 for safety, usefulness and quietness, respectively. conclusion: short-term isolation (up to 48 hours) is not associated with anxiousness or depression, but with positive feelings about safety, usefulness and quietness. index patients (n = 42), mean (sd) 4.7 (3.5) 5.3 (3.5) 9.9 (6.0) 62.3 (15.5) control patients (n = 84), mean (sd) 5.4 (3.7) 5.2 (3.6) 10.6 (6. objectives: there is a lack of data about the impact of healthcare associated infection (hai) on the experience of individual patients. this information is essential to empower health organisations to understand, prioritise, develop and implement solutions that will minimise risks to patients. this study explored comparable narratives from patients who had experienced a staphylococcus aureus blood stream infection with patients who had not. we conducted qualitative semi-structured interviews with eighteen adults who had previously been an in-patient in an acute teaching hospital in scotland. nine patients had had a laboratory diagnosed staphylococcus aureus blood stream infection and nine had no blood stream infection. all patients were interviewed for 20−40 minutes. the interviewer asked patients about their thoughts around hai, what concerns they had or still do, what measures they took to safeguard themselves from hai and how their experience impacted on their confidence of the nhs. probing questions were then asked depending on the responses given to the initial questions. all interviews were recorded, transcribed and analysed thematically. results: analysis of transcribed interviews is ongoing. preliminary analysis showed that all patients had positive and negative comments about infection prevention and control practice in the hospital. specific concerns included poor communication, poor cleanliness, awareness of patient boarding, lack of facilities, staff shortages and multi-tasking. some patients who had experienced bacteraemia said they had not been informed about the infection. those who had been informed were not given clear information about treatment or subsequent results. most patients were not specifically told what they or their family should do to safeguard them from infection and little or no written information about hai was provided. most patients are worried about hai on future admissions. the concerns of patients were not fundamentally different if they did or did not experience blood stream infection. the patient's reported experiences show that they have a broad awareness of systems issues that may increase risk of infection. consequently we need to involve patients in the design and evaluation of systems change and information that will improve patient experience. improving the safety and reliability of the system will have direct benefits for all patients in the hospital, not just the ones at risk of hai. analysis of surgical specialties separately revealed a significant reduction of mortality in cardiothoracic surgery who had been treated with mup-chx (2.3% (5/218) vs. 6.5% (11/170), p = 0.040, figure) . in other surgical specialties no significant difference was found. conclusion: peri-operative application of mup-chx in nasal carriers of s. aureus undergoing cardiothoracic surgery results in a threefold reduction of mortality after one year. o142 a lot done, more to do − a survey of teaching about healthcare-associated infections in uk and irish medical schools h. humphreys°, d. o'brien, j. richards, k. walton, g. phillips (dublin, ie; norwich, newcastle-upon-tyne, dundee, uk) objectives: patient safety and the prevention of healthcare-associated infections (hcai) are increasingly important health issues. medical doctors have traditionally been poor in complying with preventative measures to minimise hcai such as hand hygiene compliance. we surveyed medical schools in the uk and ireland to assess what is being taught and assessed in this area. methods: a questionnaire was drafted, piloted and then subsequently forwarded to the heads of medical schools as well as to known contact professionals with an interest in hcai in 38 medical schools. the questionnaire surveyed topics covered in the curricula, the modalities used to assess knowledge and practice, the usefulness of various teaching methods and materials, e.g. lectures, and what education resources were available. results: replies were received from 31 (82%) medical schools; two supplied data on their undergraduate and postgraduate courses. only 18 (60%) covered hcai as a quality and safety issue but over 90% covered prevalence, recognised risk factors, transmission, and preventative measures. 24 (80%) medical schools assessed competence in undertaking aseptic techniques and the disposal of sharps and mcqs were the most common (87%) means of assessment. case scenarios, resource materials and clinical skills stations were used in educating students in 26 (87%), 22 (73%) and 22 (73%) medicals schools respectively. 25 (83%) medical schools would be willing to share educational resources on hcai with other medical schools. conclusions: medical schools in the uk and ireland include hcai in their curricula but its importance as a safety and quality issue needs to be further emphasized. there is potential for agreeing a core curriculum on hcai and for sharing teaching resources such as videos and e-learning material. objectives: noroviruses are most common cause of outbreaks of gastroenteritis in uk national health service hospitals, leading to ward closure costing as much as £115 million per annum. using a detailed data set on norovirus outbreaks from three hospital systems in the south west of england, we estimated (1) the relative importance of introduction of norovirus from the community and within the hospital and (2) the cost effectiveness of ward closure at different time points during an outbreak. methods: using regression models we examined the association between number of new outbreaks in a hospital and community levels of activity and number of outbreaks currently occurring in other wards within the hospital. we examined the effect of different ward types (admission, general and long stay units) and whether the ward was open or closed to new admissions on a given day. we then undertook as analysis of cost (-effectiveness) of unit closure by developing a dynamic transmission model taking into account that ward closure may reduce norovirus transmission within and between wards. the stochastic simulation model was based on the actual characteristics of an acute hospital and the norovirus transmission parameters quantified in the statistical analysis. we measured the costs and benefits of closing affected wards at 1, 3 and 5 days after the onset of symptoms in the first case. results: community level of norovirus infection had a significant effect on the occurrence of new outbreaks as did outbreaks in admission and general medical units. the cost of closing wards to new admissions varied between £0.5 million to £0.9 million depending on the assumed effectiveness of closure in curtailing transmission. cost of bed day loss − compared with staff illness -accounted for around 90% of the total cost of closure. although the total number of cases tends to fall with rapid ward closure (by around 50% compared with no closure), the actual cost of control is similar regardless of when the closure is performed. we have developed a modelling framework to assess the effectiveness and cost-effectiveness of strategies to control norovirus outbreaks in hospital settings. ward closure is effective at preventing cases but since closure itself is an expensive intervention, it may not always be cost-effective. . other prevalent ribotypes were 001 (25%) and 106 (36%). 76% of the 027 isolates originated from 5 hospitals located in 2 healthboard areas. the remaining 18 isolates of ribotype 027 originated from 11 hospitals across scotland. in vitro 96% of 027 isolates were resistant to clindamycin with a mic range of 8−24 mg/l, mic50 of 12 mg/l and mic90 of 16 mg/l. furthermore 100% of the 027isolates were highly resistant to erythromycin (mic50 256 mg/l, mic90 256 mg/l), and to levofloxacin and moxifloxacin (mic50 32 mg/l, mic90 32 mg/l for both), while 65% of these isolates were resistant to cefotaxime (mic50=64 mg/l, mic90=96 mg/l). all 027isolates were susceptible to metronidazole, vancomycin, meropenem and piperacillin-tazobactam. high frequencies of clindamycin, erythromycin, levofloxacin, moxifloxacin and cefotaxime resistance were also found among isolates of ribotype 001 (90−99%) and 106 (94-100%). conclusion: until 2008 c. difficile ribotype 027 was only reported infrequently in scotland. in 2008, reports of ribotype 027 became more frequent and clusters were detected in 5 hospitals. the majority (96%) of ribotype 027 isolates were resistant to clindamycin. three other european countries have previously reported clindamycin resistance in pcr ribotype 027, albeit with a higher mic90 of >256 mg/l. objectives: to analyze trends in mortality due to clostridium difficile enterocolitis and to describe the most affected groups in order to better understand current clostridium difficile changing epidemiology. methods: we reviewed mortality data from the flanders and brussels regions in belgium (about 7 million inhabitants). we selected those records in which icd-10 code a04.7 (enterocolitis due to clostridium difficile) appeared as underlying cause of death within the death certificate. age-and sex-specific mortality rates were calculated for the period 1998-2006. direct standardisation was performed using the european standard population and 95% confidence intervals were calculated. stata 10 ® and excel ® were used as statistical software. objectives: toxigenic clostridium difficile is an enteric pathogen typical in the hospital environment but also community-acquired cases have been reported. however, relatively few attempts have been made to clarify the role of soil or water as a source of c. difficile infection. in november-december 2007, the drinking water distribution system in the town of nokia, finland was massively contaminated with treated sewage effluent resulting in a large gastroenteritis outbreak. the aim of the present study was to evaluate if contaminated water in this outbreak was also a potential source of c. difficile infection. a sample from the contaminated tap water and a treated sewage effluent sample were collected as soon as possible after the massive faecal contamination of the drinking water distribution system had occurred. c. difficile was isolated from heat-treated water samples by filtrating of 100 ml, 10 ml and 1 ml volumes of water and placing the membranes on selective ccey agar plates, which were anaerobically incubated for 3 d. stool samples from the patients fallen ill during the epidemic were examined for enteric pathogens, including c. difficile. all potential c. difficile colonies were subcultured on ccfa agar plates and toxin-positive isolates were identified by pcr. pcr ribotyping was performed according to the protocol of the anaerobe reference unit in cardiff, uk, using the cardiff-ecdc culture collection as a set of reference strains. after gel electrophoresis, the band patterns were analyzed using the bionumerics software. results: altogether 22 c. difficile isolates were found in water samples. twelve isolates were toxin-positive; 5 isolates were from contaminated tap water and 7 isolates from treated sewage effluent, the latter being the contamination source. among the tap water and sewage effluent isolates, 4 and 5 distinct pcr ribotype profiles were identified, respectively. the 9 human faecal c. difficile isolates detected were divided into 4 distinct pcr ribotype profiles. none of the profiles were identical with that of the hypervirulent pcr ribotype 027. two isolates, one from tap water and another from a patient, had an indistinguishable pcr ribotype profile. conclusion: our observation implies that c. difficile contamination of a tap water distribution system had occurred. waterborne transmission of toxigenic c. difficile and subsequent c. difficile infection seems possible. objectives: an accurate and rapid method is needed for typing of toxigenic clostridium difficile. a commercial automated repetitive pcr system (rep-pcr; diversilab ® , biomérieux inc., st louis, usa) utilises amplification and subsequent automated electrophoretic separation of the repetitive extragenic palindromic sequences of c. difficile. our aim was to evaluate the performance of this rep-pcr method for genotyping of c. difficile isolates and to compare it to pcr ribotyping. in addition, the correlation between the rep-pcr and the virulence gene profiles of c. difficile strains was studied. methods: a total of 195 toxin-positive c. difficile isolates were studied. we included consecutive isolates from two laboratories in finland, containing also strains of the hypervirulent c. difficile ribotype 027. in addition, selected c. difficile strains with >18 bp deletions in their tcdc genes were analyzed. the dna was extracted and the rep-pcr performed according to the manufacturer's instructions. the amplification products of rep-pcr were detected and analyzed using the diversilab system. further analysis was performed with the web-based software accompanying the system. the usefulness of the library construction option of the diverslab system for isolate comparison was tested. the virulence genes (tcda, tcdb, cdta, cdtb and tcdc) were analyzed by conventional pcr and the whole gene sequencing of tcdc was performed from isolates with deletions >18 bp. pcr ribotyping was performed using the protocol of the anaerobe reference unit in cardiff, uk. the correlation between the rep-pcr profile and the ribotype was excellent. all major ribotype groups were clustered in their own rep-pcr groups. interestingly, subgroups could be found with rep-pcr within two most prevalent ribotypes 001 and 027. the automated rep-pcr proved to be reproducible; the results from separate dna isolations and pcr-runs/microfluid electrophoresis as well as the results performed by different individuals of laboratory personnel were comparable. the rep-pcr profiles and pcr ribotypes correlated also with the virulence gene profiles. conclusion: this automated rep-pcr represents an effective and reproducible method for the genetic characterisation of c. difficile strains in clinical laboratories with molecular biology facilities. the constructed c. difficile library allows comparing the relatedness of c. difficile strains and their fingerprints over time. objectives: clostridium difficile infection (cdi) is a serious diarrhoeal illness associated with high morbidity and mortality. currently available treatments (oral vancomycin or metronidazole) usually produce good resolution of diarrhoea but are associated with a 20% to 30% incidence of recurrence. opt-80, the first in a new class of macrocyclic antibiotics, is bactericidal via unique inhibition of rna polymerase. this phase 3, non-inferiority clinical trial was conducted in more than 100 sites in north america and compared the efficacy and safety of opt-80 and vancomycin in treating cdi. methods: eligible patients were adults with acute cdi symptoms and a positive stool toxin test. patients received oral opt-80 (200 mg twice daily) or oral vancomycin (125 mg 4 times daily) for 10 days. primary end point was clinical cure (resolution of symptoms and no further need for cdi therapy 2 days after stopping study drug). secondary end point was cdi recurrence (diarrhoea and positive stool toxin test within 4 weeks after treatment). global cure was defined as a clinical cure with no recurrence. results: 629 patients were enrolled and 87% were evaluable. in the per protocol (pp) population (n = 548), mean age was 61.3±17.1 years and 44.0% of patients were male. equivalent rates of clinical cure were observed with opt-80 (92%) and vancomycin (90%) in the pp analysis; similar outcomes were observed in a modified intent-to-treat (mitt) analysis. significantly fewer patients treated with opt-80 (13%) than vancomycin (24%) experienced recurrence in the pp analysis (p = 0.004) and in the mitt analysis (15% vs 25%; p = 0.005). significantly more opt-80-treated patients achieved global cure (78%) than vancomycintreated patients in the pp analysis (67%; p = 0.006) and in the mitt analysis (75% vs 64%; p = 0.006). opt-80 was well tolerated with an adverse event profile similar to that of vancomycin. in this study -the largest comparative trial of a new antimicrobial agent versus vancomycin for the treatment of cdi -clinical cure rates after treatment with opt-80 or vancomycin were equivalent. however, opt-80 was associated with a significantly lower recurrence rate and a higher global cure rate than vancomycin. opt-80 is an oral, non-absorbed agent that has a convenient (twice daily) dosing schedule and low risk of adverse events. opt-80 represents a potential new treatment option for cdi that is associated with a lower recurrence rate than currently available treatments. results: sequence analysis (sa) revealed that locus a is absent in type 078 and that some mismatches are present in the primer annealing sites for loci b, c and g. lowering the annealing temperature and increasing the magnesium chloride concentration for loci b, c and g resolved the low yield of pcr products. applying the mlva on 54 type 078 strains revealed that 42 (80%) strains, encompassing isolates from human (n = 42) and porcine (n = 11) origin, are genetically related with a summed tandem repeat differences (strd) 10). three clonal complexes (cc, defined by strd 2) were recognized; one cc contained both human (n = 4) and porcine (n = 3) strains. the optimised mlva identified 3 genetically related clusters and 6 cc among the 67 isolates from e and ni. ccs contain isolates from more than one hospital and indeed for several clusters isolates from both e and ni. 2 isolates obtained from ni 8 years earlier were part of one large cc. the optimised mlva can distinguish and/or group type 078 strains from distinct settings. type 078 strains from human and animal origin are genetically related. the clustering of some isolates from distinct settings is consistent with community sources for type 078. the last 2 observations suggest zoonotic transmission. objectives: this paper updates our assessment of the contribution that community-associated clostridium difficile infection (cdi), as reported to the english mandatory surveillance scheme since 2007, makes to both the acute and community sectors of the national health service (nhs) in england. methods: nhs acute trusts (hospital groups) in england are required to report all c. difficile toxin positive diarrhoeal specimens processed by their laboratories whether the patients were in hospital or the community at the time of onset of the illness or when the specimen was taken via a web enabled reporting system. positive specimens from the same patient within 28 days are not reported. reported cases in patients under 2 years of age were omitted from this analysis. enhanced surveillance data (including information on date of admission, patient location prior to testing, sex, age and patient category) on cdi have been collected through a web-enabled reporting system since april 2007. risk factor information is completed on a voluntary basis. results: more than 75,000 cases of cdi in patients aged >2 years were reported, 23% of these cases were taken in non-acute settings of which 74% were taken by a general practitioner. a further 17% of specimens were taken on presentation or <2 days of admission into an acute trust. approximately 32% of all cases had at least one risk factor field completed, >19,000 cases reported risk factor information on episode category; 23% of these cases were community associated and 77% were hospital acquired. the information reported suggests that only 3% of the community associated cases were from patients with continued infection or relapsed episodes of cdi, this is compared to 8% of the hospital acquired cases who had continued infection or relapsed episodes of cdi. conclusions: 23% of the c. difficile specimens reported by acute trusts were diagnosed in a community setting. published studies suggest that 12−15% of these might be expected to have been acquired during a hospital stay within the previous month (i.e. were community onset hospital acquired cases). future work is required to investigate whether there are differences in the epidemiology, risk factors e.g. antibiotic exposure and outcome of patients with community onset disease. o152 clostridium difficile-associated disease: a newly notifiable disease in ireland m. skally, f. roche, d. o'flanagan, p. mckeown, f. fitzpatrick°( dublin, ie) new cases of clostridium difficile-associated disease (cdad) became notifiable in ireland on 4th may 2008. the main objective of this new notification process was to provide a national overview of the epidemiology and burden of cdad. this paper review the first six months of preliminary data notified. methods: the interim case definitions for new and recurrent cdad cases proposed by the european society for clinical microbiology and infectious diseases (escmid) study group for c. difficile were employed. this report reviews the weekly events of cdad extracted from the computerised infectious disease reporting (cidr) system in january 2009. census of population 2006 figures were used as denominator data in the calculation of incidence rates. results presented represent 34 weeks of data submitted. results: there were 1581 new cdad cases notified on cidr between the 4th may 2008 and 27th december 2008, representing a crude incidence rate (cir) of 37.3 cases/100000 population (estimated annual cir is 57.0 cases/100,000). all cases were laboratory confirmed. there was a higher occurrence of cases in females. the male:female ratio for the period was 1:1.6. in 0.4% of cases the sex was unknown. 71.4% of cases were in the greater than 65 years age category. the preliminary data submitted on cidr indicate that 63.0% of cases were hospital inpatients and 8.9% of cases were either gp patients or outpatients. the origin of 28.1% of samples is unknown. there was large variation between the 8 public health regions (table 1) . the incidence of cdad in ireland is prominent in older age groups and in healthcare settings. what is more remarkable is the regional variation of cases reported. this varies from 9.1 per 100,000 in the north east to 52.4 per 100,000 in the west. the seasonal trend is indistinguishable at present due to late and batch notifications from institutions. o153 clostridium difficile-associated diarrhoea in immunosuppressed patients with cancer objective: to assess the epidemiology, clinical features and outcome of clostridium difficile (cd) associated diarrhoea in immunosuppressed patients with cancer. methods: review of all episodes of cd associated diarrhoea documented in adults with cancer and haematopoietic stem cell recipients (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) . microbiologic diagnosis included cd isolation from stool samples, direct detection of cd toxin, and testing for cytotoxin production by the isolated strain. we documented a significant increase of cd associated diarrhoea, from 0.34/1000 admissions in 2000 to 4.05/1000 admissions in 2008 (p < 0.01). there were 56 episodes in 54 patients. thirty-one patients were male (55%) with a mean age of 52 years (± 16). forty three (77%) patients had an haematological underlying disease and 13 had solid tumour; 41 (73%) had received previous chemotherapy, 14 (25%) were stem cell transplant recipients (3 presenting with gvhd) and 17 (30%) were neutropenic (<500). in the previous month 52 patients (93%) had received one or more antibiotics (cephalosporins 63.5%, glycopeptides 40%, carbapenems 38.5%, betalactam + betalactam inhibitors 29%, quinolones 19%). fever >38ºc (71%) and abdominal pain (44%) were the most frequent manifestations, and the diarrhoea was hemorrhagic in 8% of the cases. most patients (77%) were treated with metronidazole (median 11 days), and the antibiotic therapy was discontinued in 56%. in 5 patients who had recovered from neutropenia, the diarrhoea resolved just by discontinuing the antibiotic therapy. no patient developed toxic megacolon or needed surgery. three patients (5.5%) had relapses. overall mortality (<30 days) was 22% (12 patients). the incidence of cd associated diarrhoea in cancer patients has increased significantly in recent years. it is related with important morbidity and mortality. better strategies to improve its prevention and treatment are needed. s154 linking research to the clinic: how laboratory findings relate to management of invasive candida infections the role of the research laboratory in the management of invasive candida infections goes beyond routinely available tests for identification of candida species and susceptibility testing of antifungal agents. cutting-edge molecular epidemiology technologies have been used to type isolates of candida species based on their dna sequences. multilocus sequence typing schemes have been designed for c. albicans, c. dubliniensis, c. glabrata, c. krusei and c. tropicalis. multi-locus sequence typing can be used to investigate possible hospital outbreaks of infection (finding widely different strain types within a unit indicates no outbreak, although the converse is not true). for c. albicans, typing multiple isolates from the same patient has shown that people tend to harbour as commensals a mixture of closely related but different strain types, which may provide for selection of the most appropriate type for invasion of a particular tissue or in response to antifungal treatment. strains in c. albicans clade 1, the largest group of related strain types, have a higher proportion of isolates resistant to flucytosine than other clades, and they all share a common resistance mechanism. research on mechanisms of resistance of candida species to many types of antifungal has progressed to the point that some investigators are looking to design dna chips that could be used both for identification and for susceptibility testing of a candida isolate. much research effort goes into detailed study of host-fungus crosstalk in experimental candida infections. animal models of infection have been greatly refined and the latest research shows how early release of chemokines that attract neutrophils into infected tissues contributes to the immunopathology of candida infection. this rapid, innate immune response also emphasizes the need for antifungal intervention at the earliest possible stage to provide the best chance for successful treatment of a disseminated candida infection − a finding now supported by clinical data as well as experimental models. translation of the latest research advances into practical diagnostic tests and new therapeutic approaches for candida infections always takes a long time − typically years − and not all research results find clinical applications. however, the level of effort invested in basic candida research ensures support for steady progress in diagnosis and management. the echinocandins are semi-synthetic lipopeptides that are increasingly used for the prevention and treatment of invasive fungal infections. understanding the pharmacokinetic and pharmacodynamic (pk/pd) characteristics of these compounds is critical for their optimal clinical use. the echinocandins have potent in vitro activity against candida spp., although c. parapsilosis is less susceptible than other candida species. the molecular mechanisms of resistance in candida species, which relate to amino acid substitutions in 'hot spots' within the fks1 gene, are becoming well characterised. susceptibility breakpoints for all three clinically available compounds have been determined recently by the clinical laboratory standards institute, with a 'susceptible-only' breakpoint of >2 mg/l suggested. the pk/pd of the echinocandins have been determined in experimental models of disseminated candidiasis, and of both disseminated and pulmonary invasive aspergillosis. these studies suggest that the echinocandins: (1) display concentration-dependent antifungal killing (or effect); (2) are extensively distributed into peripheral tissues, where they exhibit prolonged mean residence times at the site of infection; (3) are fungicidal against candida spp. and induce dose-dependent morphological changes in aspergillus spp.; and (4) result in a diminished propensity for angioinvasion by aspergillus spp. recent evidence also suggests that the echinocandins have important immunomodulatory properties, which may contribute significantly to their observed antifungal effect. pk/pd modelling and laboratory animal-to-human bridging techniques have been used to identify safe and effective dosages for the echinocandins for relatively uncommon clinical syndromes such as neonatal haematogenous candida meningoencephalitis. these techniques are an efficient method of identifying effective regimens for humans that can be expedited for study in clinical trials. pk/pd modelling techniques can and should be used to address outstanding clinical queries in relation to these compounds, including optimal dosages, decision-support analysis for the setting of in vitro antifungal susceptibility breakpoints and the clinical relevance of inherent or acquired reduced antifungal susceptibility. s156 invasive candidiasis: which antifungal treatment for which patient? management of patients with invasive candidiasis represents a complex issue owing to the heterogeneity of patients in whom these infections occur. established risk factors for invasive candidiasis, which include total parenteral nutrition, multiple organ failure and candida colonisation, are common to many types of patients that are treated within the critical care setting. furthermore, the severity of the underlying condition in these patients necessitates swift antifungal treatment to ensure optimal outcomes. an additional factor for consideration when treating candida infections is the changing epidemiology of candida species; potentially fluconazole-resistant species such as c. glabrata and c. krusei are becoming more common, particularly in patients with prior fluconazole exposure. a range of antifungal agents is available with in vitro activity against candida species. however, not all of these agents are suitable options for the clinical management of invasive candidiasis because of the overall complexity of both infection and underlying condition. for example, the position of the polyenes, particularly amphotericin b deoxycholate, is becoming less tenable as the risk of renal complications is increasingly regarded as unacceptable in patients that are likely to have or be at risk of multiple organ failure. furthermore, because of the increasing prevalence of fluconazole-resistant species, recent guidelines no longer recommend the use of azoles as first-line treatment for invasive candidiasis except in special cases, focusing instead on the echinocandin agents. there is now a wealth of clinical data available for the echinocandins. micafungin, for example, has been assessed in invasive candidiasis in clinical trials that included a wide variety of underlying conditions and patterns of infection, including neutropenic patients and those with deep infections such as peritonitis. furthermore, micafungin is the most extensively evaluated of the echinocandins in paediatric patients, having been tested both in children up to the age of 16 years and in premature infants and neonates. optimal management of patients with invasive candidiasis depends on a strategy that takes into account the complex nature of the disease. judicious selection of antifungal treatment should be accompanied by consideration of non-drug-related factors that improve survival, such as careful assessment of intravenous catheters and their potential involvement in candida infections. patients with invasive candidiasis often have underlying conditions that are severe illnesses in themselves. these range from neutropenia during cancer chemotherapy to the multi-organ failure of intensive care unit patients. against this background of severe underlying illness, it can be difficult to appreciate the success or otherwise of treatment strategies for candida infections. in the last decade, major advances have been made in antifungal therapy with the introduction of 1. echinocandins; 2. extended-spectrum azoles; and 3. lipid formulations of amphotericin b. robust clinical studies for their successful use in candidaemia have been published. however, it is important to translate these studies into practical strategies for the care of individual patients. in this presentation, individual cases will be used to provide insights into the successes and failures of these antifungal classes for the management of invasive candidiasis. specific interest will be focused on the use of fluconazole versus the echinocandins. these micafungin-based cases will be supported by insights from the evidence-based literature combined with practical experiences at the bedside. the factors to be considered are: 1. spectrum of activity; 2. drug toxicity; 3. drug interactions; 4. drug resistance; 5. pharmacology; 6. diagnosis; 7. site of infection; 8. use of biomarkers/cultures in treatment strategies; and 9. costs. it is important to realise that large clinical trials exclude many patients with invasive candidiasis. therefore, with the use of individual cases, it is possible to provide further insights into the clinical use of these outstanding antifungal agents. patient management: the era of rapid diagnostic results (symposium organised by cepheid) s161 will community mrsa and clostridium difficile change infection control in hospitals? infections caused by methicillin-resistant staphylococcus aureus (mrsa), vancomycin-resistant enterococci, and clostridium difficile are inter-related in healthcare institutions. the emergence of epidemic mrsa and c. difficile strains has placed a greater burden on infection control systems in healthcare facilities, which often must increase surveillance and change disinfection strategies to halt the transmission of these pathogens in hospitals. ironically, the usa300 mrsa strain arose in the community but now is being transmitted frequently in healthcare settings, while the epidemic nap1/bi/027 c. difficile strain was originally a healthcare-associated pathogen, which now is causing considerable morbidity in community settings. to successfully slow the spread of these pathogens, infection control must work closely with both the laboratory and pharmacy services to ensure that these organisms are detected rapidly and that the selective pressure to maintain the organisms in the institution are reduced. clearly, bundles of interventions, rather than single approaches, are necessary to contain the spread of these organisms in hospitals. the continued influx of patients with communityacquired mrsa and c. difficile infections into healthcare institutions is a challenge for infection control practitioners that will clearly increase in the future. the food borne pathogen l. monocytogenes discovered by murray in 1926 is responsible for a severe infection with various clinical features (gastroenteritis, meningitis, meningoencephalitis and materno foetal infections) and a high mortality rate (30%). the disease is due to the ability of listeria to cross three host barriers during infection: the intestinal barrier, the placental barrier and the blood brain barrier. it is also due to listeria capacity to survive in macrophages and to enter into non phagocytic cells, such epithelial cells. recovery from infection and protection against reinfection are due to a t-cell response, explaining why listeria has since many years has become a model in immunology. nearly three decades of molecular biology and cell biology approaches coupled to genetic and post-genomic studies have promoted listeria among the best models in infection biology. in depth studies of the mechanism of entry into cells has help unraveling how listeria crosses the intestinal and placental barrier. unsuspected concepts in cell biology were discovered. post-genomic studies have recently allowed to unveil the listeria transcriptional landscape during switch from saprophytism to virulence. the talk will give an overview highlighting recent results in the frame work of well established data. the last several decades of research in medical mycology have offered great insights into fungal cell biology, epidemiology, phylogenetics and the cells and molecules involved in the pathogenesis of fungal disease. a legitimate question is to ask to what extent our extensive advances in comprehension of the biology of fungal pathogens have contributed to improvements in diagnosis and treatment. to what extent do patients benefit from translation of basic research into tools for clinical management? and the equally valid question: to what extent does biological science benefit from study of fungi that are opportunistic pathogens? the speaker will examine some of these questions from the perspective of long experience in the field and the curmudgeonly attitude that develops with age. objectives: the incidence of invasive meningococcal disease (imd) has been reported in the czech republic since 1943. in response to the emergence of a new hypervirulent clonal complex, cc11, nationwide enhanced surveillance of invasive meningococcal disease was implemented by the national reference laboratory for meningococcal infections (nrl) in 1993. the case definition is consistent with the ecdc guidelines. culture and pcr are used for confirmation of cases. notification is compulsory and is performed by local epidemiologists. strains of neisseria meningitidis isolated from imd cases are referred by the field laboratories to the nrl to be characterised by serogrouping, pora and feta sequencing (http://neisseria.org/nm/typing/) and multilocus sequence typing (mlst) (http://pubmlst.org/neisseria/). in the nrl, the epidemiological database is matched against that of strains to avoid duplicate reporting in the final enhanced surveillance database. results: despite the stable trend in imd incidence (0.8/100 000) since 2005, the case fatality rate was high (11.8%) in 2007. the disease was caused mainly by serogroup b meningococci (67.4%) in 2007, followed by serogroups c (20.9%) and y (9.3%). the most frequent clonal complexes were cc18, cc41/44 and cc32 (typical for serogroup b) and cc11 (typical for serogroup c). the highest age-specific morbidity rates were observed in the lowest age groups, i.e. 0−11 months and 1−4 years (11.4/100 000 and 4.5/100 000, respectively), and were associated with high prevalence of serogroup b. the case fatality rate was the highest in infants under 1 year of age (38.5%). the incidence of imd caused by serogroup c is currently low and there is no indication for mass vaccination with menc conjugate vaccine. menb vaccine is needed for infants, but the sero/subtype coverage by the currently developed porin-based vaccines is low for czech meningococcal isolates (maximum 56.8% for nine-valent meningococcal pora vaccine). methods:the vaccination programme incorporates dedicated vaccine clinic with a multi-disciplinary team including a nurse, data manager, a pharmacist specifically appointed to the unit. additional interventions to improve vaccine uptake and outcome have included use of sms texting to announce availability of influenza annually and improve adherence to completion of hepatitis b vaccination, educational programmes changes in guidelines e.g. varicella vaccination and creation of a vaccine passport. we reviewed vaccination clinic activity in the cohort of 1,700 hiv positive patients since introduction of a dedicated vaccine service. results:there has been a large increase in the uptake of vaccinations since introduction of this service. the varicella vaccination uptake increased from 8 (2007) to 43 (2008) due to targeted vaccine programme.(see graphic, legend reads left to right) conclusion: strategies implemented increased the uptake of recommended vaccinations in our hiv population. these included appointment of a dedicated health professional team, use of it supports, education of staff and patients and development of a vaccine passport. we developed the vaccine passport to help with patient education and awareness and it will serve as a record of vaccine administration for physicians off site. in the latter year, post guideline change, we have targeted our varicella non immune population. the next intervention planned is to assess all late entrants to our healthcare system to determine need for catch up vaccines, including mmr. results: column purified recombinant protein sspb1 was found to be a good antigen for both groups of animals used for immunisation. antibodies against the recombinant sspb1 tested by opsonophagocytosis were found to enhance phagocytosis of 4 gbs strains belonging to different serotypes at the average 5.5 times relatively to control. affect against gas strains was less pronounced (2.5 times) but still statistically significant. antibodies were also capable to interfere with adherence of gbs strains carrying sspb1 relatively to the strain without the protein. adherence of the strain with sspb1 towards different cell lines was dramatically higher which proves the function of the protein as adhesin. in passive protection test carried out with mice challenged with virulent gbs or gas strains introduced intranasaly were eliminated from the lungs of the animals 20 times faster in case of the usage of anti sspb1 serum relatively the control. in the experiments with active protection sspb1 immunised animals were found be significantly better protected against gbs and gas infection. (table 1) . similar results were obtained in the analysis of factors associated with 90-day mortality. conclusion: these data suggest that outcomes of both community-onset and nosocomial bloodstream infections due to s. aureus may be improved by an expert consultation service. the factors most critical for better outcomes and modifiable in time by id specialist consultation remain to be determined and may be explored as process of care quality indicators. objective: worldwide, the present tuberculosis epidemic is characterised by an alarming emergence in drug resistance. given the limited therapeutic options in mdr (and especially xdr) tuberculosis, there is a need to define the resistance levels and mechanisms present in clinical isolates categorised as drug resistant on the basis of critical concentration testing, so as to facilitate rapid therapeutic decisions. methods: we determined quantitative resistance levels of drug resistant isolates of mycobacterium tuberculosis sampled in switzerland over the past 3 years. resistance-conferring genetic alterations were identified by probe assays and pcr-mediated gene sequencing. results: rifampicin resistant isolates unanimously showed a high-level resistant phenotype (>50 mg/l) associated with mutations in rpob. in contrast, a significant fraction of clinical tb isolates categorised as isoniazid resistant on the basis of critical concentration testing showed a low-level resistant phenotype (mostly mutations in inha); heterogeneous phenotypic resistance levels were associated with mutations in katg. one third of streptomycin resistant clinical isolates had a low-level resistance phenotype (<10 mg/l). ethambutol resistance occurred mostly in mdr strains and was linked to alterations in embb, but resistance never exceeded 25 mg/l. our data indicate that some first line agents may be considered as therapeutic treatment option despite in vitro resistance at the critical concentration. diagnostic mycobacteriology would benefit from standardised measures of quantitative drug susceptibility testing in particular for those drugs were significant variations in phenotypic resistance levels are found in clinical isolates, e.g. isoniazid, ethambutol and streptomycin. introduction recent advances in the diagnostics of varicella zoster virus (vzv) infections have changed the perception of this virus as a cns pathogen. a real-time pcr method amplifying a 70 nt segment of the vzv gb region gave 0.5 log improved sensitivity over conventional pcr and was employed for routine diagnosis of vzv dna in samples of cerebrospinal fluid (csf). in addition, a new elisa method for detection of antibodies in the csf to glycoprotein e was developed, using a mammalian cell expression system for optimal glycosylation of the antigen. these methods were utilised for studies of vzv-induced cns infections. in a retrospective study, almost all patients had a reactivated vzv infection, but only 60% showed skin lesions. the following diagnoses were made: acute aseptic meningitis (aam), n = 34; encephalitis, n= 22; meningoencephalitis, n = 6; cranial nerve affections, n = 20; encephalopathy, n = 5; and cerebrovascular disease, n = 6. in 66 patients in whom vzv dna levels were determined, significantly higher viral loads were found in those with aam and encephalitis compared to patients with cranial nerve affection (including ramsay hunt syndrome). of the 50% (n = 50) who had a follow-up, 50% (n = 25) had neurological complications after 3 months. sixty-two percent had a ct/mri scan of the brain performed and 46% of these had pathological findings. vzv encephalitis showed a more broad disease spectrum as compared with herpes simplex encephalitis (hse), as will be presented. detection of intrathecal synthesis of vzv ge antibodies was positive in the vzv encephalitis patients, as well as in some of the hse patients, arguing for a previous suggested role for vzv as a co-pathogen at least in some cases of the latter disease. vzv vasculitis was a more common finding (6% of all cases) than expected from the literature of case reports. mr findings showed that middle and posterior cerebral arteries were targeted. surprisingly, despite substantial vzv dna loads in the csf of these patients, investigated serum samples were pcr negative. thus, vzv might be suggested to be neuronally transported to the arterial walls rather than haematogenously spread. conclusions: vzv is a serious and underestimated cause of cns infection. a substantial number of the patients presented with serious neurological symptoms and sequela, and pathological findings on ct/mri of the brain were abundant, especially in patients with encephalitis and vasculitis. pk/pd controversies for the clinician s190 pk/pd and azoles the triazoles have revolutionised the treatment of invasive and allergic fungal diseases. fluconazole, itraconazole, voriconazole and posaconazole are available for clinical use. isavuconazole and ravuconazole are in development. the triazoles have broad spectrum antifungal activity. the pharmacokinetics and pharmacodynamics (pk-pd) of the triazoles have been extensively investigated in murine models of disseminated candidiasis. the pd parameter that optimally links drug exposure with the observed antifungal effect is the ratio of the area under the concentration-time curve (auc) to mic (auc:mic). there is increasing information on the magnitude of the auc:mic that is required for optimal antifungal effect. pk-pd principles have been used to define in vitro susceptibility breakpoints. the triazoles are fungistatic against candida spp. their mode of action against aspergillus spp. is less well defined, although they clearly exhibit dose-dependant decrement in fungal burden in laboratory animal models of invasive pulmonary aspergillosis. the triazoles accumulate in tissues and this is important for an understanding of their antifungal effect. in humans, the triazoles are characterised by complicated pharmacokinetic properties. both itraconazole and voriconazole exhibit nonlinear pharmacokinetics. the triazoles all exhibit clinically relevant exposureresponse relationships. recent work from our laboratory suggests that itraconazole exhibits clinically relevant concentration-toxicity relationships. higher concentrations of voriconazole are associated with a progressively higher probability of hepatotoxicity, photopsia and central nervous system toxicity. because of the significant pharmacokinetic variability and clinically relevant drug exposure-response relationships, therapeutic drug monitoring (tdm) is frequently used. a strong argument can be made for the routine monitoring of itraconazole and voriconazole. there may also be grounds to consider monitoring posaconazole levels. tdm should be considered for all patients receiving triazoles who have refractory disease. furthermore, tdm should be considered when compliance, drug interactions and variable pharmacokinetics result in uncertainty about resultant drug exposures. an understanding of the pk-pd relationships of the triazoles has been instrumental in optimising their clinical efficacy. innate immunity s192 the inflammasomes: danger sensing complexes triggering innate immunity the nod-like receptors (nlr) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. several nlrs (nalps and ipaf) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including il-1beta. amongst the various inflammasomes, the nalp3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. the important role of the nalp3 inflammasome is emphasized by the identification of mutations in the nalp3 gene that are associated with a susceptibility to inflammatory disorders. these and other issues related to the inflammasome will be presented. it is now 20 years since charles janeway hypothesized the existence of clonally derived pattern recognition receptors and pointed to the importance of these in initial responses to bacterial and viral infections. janeway's hypothesis has been validated by the discovery of three groups of prrs. first, are the toll-like receptors which detect microbial lipids and non-self nucleic acids at the cell surface an in intracellular compartments. in addition cytoplasmic sensors of bacteria (nods) and of viral nucleic acids (rigs) have also been characterised. as well as being critical for responses to infections, these prrs also underlie a large burden of autoimmune and inflammatory disease in the human population and are thus important targets for therapy. in my talk i will describe the molecular mechanisms by which these conserved pathogen associated moecules are recognized by the tlrs with particular reference to lipo polysaccharide and single stranded viral rnas. i will also present new results which show how receptor activation is coupled to downstream signal transduction and in particular the role played by oligomeric signaling platforms assembled form adaptors and other signaling molecules involved in the pathway. i will discuss the potential for structural analysis to be used in the rational design of new drugs. this session proposes a critical review of the most salient recently published papers in the field with a special focus on control of multi drug-resistant organisms, prevention of infections in the intensive care unit, surgery etc. and highlights the need for validity/scope assessment. it emphasizes also the importance to prioritise information published in the abundant literature available so as to be able to summarise and understand the potential changes in clinical practice, and identify unresolved issues and areas of possible future clinical research. tourism is europe's face to the world. it is also a major source of revenue, employment and productivity. each year over 450 million arrivals are recorded into the continent, and of those, approximately 4 million are from latin america. returning travelers are even more numerous and more often associated with disease transmission into europe. within countries of the european continent, imported cases of environmental and zoonotic illnesses such as cholera, dengue, malaria, viral haemorrhagic fevers and west nile virus infections are a rare but established fact. diseases imported from latin america with the potential for autochthonous transmission (chikungunya, malaria, yellow fever) and or high infectivity (viral haemorrhagic fevers) will be described in detail and the possibility of european outbreaks from latin american countries will be discussed. cutaneous leishmaniasis (cl) is a worldwide disease, endemic in 88 countries, that has shown an increasing incidence over the last two decades. so far, pentavalent antimony compounds have been considered the treatment of choice, with rates of curing close to 85%. however, the high efficacy of these drugs is counteracted by their adverse events. recently, in vitro and in vivo studies have shown that no plays a key role in the eradication of the leishmania parasite objective: to determine whether a no donor patch (developed by electrospinning technique) is as effective as meglumine antimoniate in the treatment of cl while causing less adverse events methods: a double-blind, randomised, placebo-controlled clinical trial was conducted with 178 patients diagnosed with cl in santander, colombia, south-america. the patients were randomly assigned to two groups. during 20 days group 1 received simultaneously meglumine antimoniate and placebo of nitric oxide patches while group 2 received active nitric oxide patches and placebo of meglumine antimoniate. biochemical determinations (aspartate aminotransferase, alanine aminotransferase, creatinine and pancreatic amilase) were measured at he beginning and at the end of the treatment. a follow up was realised 21, 45 and 90 days after the beginning of the treatment results: the study included 69 (38.77%) women and 109 (61.23%) men. the average age in group 1 was 30.80±14.23 years; while in group 2 it was 27.88±13.79 years. clinical and demographic data were similar in the two groups. after the follow up period, the complete clinical healing of group 1 was 94.81% versus 37.14% for group 2 (p= 0.0001). treatment with no patches generated both, a lower frequency of non-serious adverse events (fever, anorexia, myalgia, arthralgia, headache), and a reduced variation in biochemistry determinations (asat 26 the treatment with no patches resulted in a lower percentage of complete clinical response compared with meglumine antimoniate. despite its inferior effectiveness, the safety, the lower frequency of adverse events, the facility of administration (topical) and the low cost of the patches justifies its evaluation in further poblational studies, especially in populations as the colombian ones, where the serious adverse events due to glucantime have increased dramatically. objectives: trichinellosis is a zoonotic disease which has never been reported in taiwan and is rarely linked to consumption of reptiles. we investigated the first documented outbreak of trichinellosis in taiwan consisting of 8 patients who became acutely ill after eating at the same restaurant in may 2008. we conducted a retrospective cohort study by interviewing the patients and persons who ate together with them. a case was defined as illness in an attendee who had fever (>38.0ºc) or myalgia 4 weeks after the festivals and was seropositive to trichinella antigen using an enzymelinked immunoassay and immunohistochemical staining. environmental study of the soft-shelled turtle farm was performed. results: of the 23 attendees, 8 persons met the case definition (attack rate = 35%). the most common presenting symptoms were myalgia (88%), fever (88%), and periorbital swelling (38%). all 8 patients sought medical care; five were hospitalised. of the 7 patients who underwent blood test, all had moderate eosinophilia. all 8 patients' serum samples were strongly reactive to trichinella excretory-secretory antigen. the only food item significantly associated with illness was the raw softshelled turtle meat (relative risk undefined; p = 0.005). traced back to the farm, histological examination of soft-shelled turtles was negative for trichinella species. the most likely cause of this outbreak was consumption of raw soft-shelled turtle served in the festivals. this investigation indicates taiwan is not free of trichinellosis. prevention and control programs of trichinellosis should be established. the public should be aware of the risk of acquiring trichinellosis from consumption of raw soft-shelled turtle. objective: to develop and evaluate a modified, rapid giemsa staining procedure for detection of malaria parasites in blood smears. disadvantage of the rapid commercially available staining methods is that they require highly experienced technicians for interpretation of results because the interpretation can be difficult. for this reason, many laboratories use the giemsa stain. shorter giemsa staining times have been reported previously, however, to our knowledge, the effect of 5 and 10 minute staining in different giemsa dilutions have not been evaluated. the stock solution of giemsa stain (merck, darmstadt, germany) was used in different dilutions (1:10 and 1:5) and incubated for different lengths of time (10 min and 5 min). the staining effect was compared to our standard giemsa stain (1:40, 45 min). sensitivity was determined by examining smears of p. falciparum from fresh and edta blood. the level of parasitaemia was followed in two patients admitted to our hospital with p. falciparum parasitaemia's of 21.5% and 28.8% (see table; patient a and b) by examination of blood smears taken at different time points after initiation of therapy. these samples were used to evaluate the different giemsa dilutions and staining times. smears were read by three independent observers (a clinical microbiologist, a laboratory technician specialised in parasitology, and a resident in clinical microbiology). in the table results of the three staining methods on blood from two patients from ghana with high parasitaemia's on admission and during follow-up are shown. all smears were equally easy to read and yielded parasite counts within internationally accepted ranges of variation (see united kingdom national external quality assessment service). conclusion: staining blood smears for detection of plasmodium falciparum parasites with a 1:5 dilution of giemsa stain for five minutes provides easy to read slides and results comparable to those obtained with the standard giemsa staining. advantage of the rapid method is the shorter turnaround time, disadvantage is the larger amount of stain used. objectives: diarrhoeal diseases are common in developed and developing countries and are major causes of morbidity and mortality worldwide. the need to differentially diagnose protozoan parasites versus other gastrointestinal (gi) aetiologies is well recognized. the most common gi protozoan parasites infecting humans worldwide are considered to be entamoeba histolytica, giardia lamblia, blastocystis hominis, dientamoeba fragilis and cryptosporidium spp. laboratory detection of these parasites is relying on microscopic analysis of stool samples and water concentrates, as well as enzyme immunoassay (eia) tests. utilising the microscopic examination usually results in underdetection of gi parasites, while usage of eia is often not cost-effective. methods: savyon diagnostics is currently engaged with developing an approach aiming to address the unmet needs and the current limitations in this field. this approach includes 3 major aspects: (1) the ability to detect a panel of all the above 5 organisms in one test kit, (2) the possibility to perform the diagnosis in two steps − first, simultaneous detection of these organisms without distinguishing between the different species for screening of large number of specimens, and second, distinctive detection of the specific aetiology in the positively-found specimens, and (3) the ability to apply eia diagnosis in formalin-preserved specimens for all the mentioned parasites. results: polyclonal antibodies were produced in-house based on native antigen extracts, recombinant antigens and synthetic peptides. the resulted inventory of antibodies enabled finding the optimal combination that provided the desired performance parameters for separate detection of each of the parasites in fresh, frozen or formalin preserved faeces specimens. the analytical limit of detection and the performance in characterised clinical specimens were comparable to microscopy or to reference eia, when available. the results show unique detection of e. histolytica in formalin-preserved specimens, which is comparable to detection in fresh specimens. furthermore, we demonstrate simultaneous detection of the parasites without compromising performance characteristics in fresh or preserved specimens. the presented work is a paradigm of an innovative approach, expected to advance the diagnosis of protozoan parasites in gi patients, thus, enabling appropriate and cost-effective diagnosis and treatment. objectives: systemic administration of certain facultative anaerob bacteria to mice bearing solid tumours leads to accumulation in tumours compared to normal target organs, like spleen and liver, and to retardation of tumour growth. salmonella enterica serovar typhimurium (s. typhimurium) as well as escherichia coli 1917 nissle (ecn) are such bacteria. preliminary experiments showed that such bacteria that exhibit the ability to form biofilms in vitro might also do so in tumours. in the present study this was systematically investigated. methods: biofilm formation of bacteria were detected on low-salt biofilm plates. additionally, salmonella-or e. coli-infected ct26tumours of balb/c mice that were left untreated or were treated with anti-gr1 to deplete neutrophilic granulocytes were removed two days post infection, fixed and prepared for electron microscope analysis. the expression of different genes which are probably involved in the biofilm formation were tested via real-time pcr. results: when examined after colonising tumours s. typhimurium sl7207 and sl1344 as well as ecn are almost exclusively found extracellular although they are able to invade the ct26 cells in vitro. interestingly, like in vitro all three bacteria form biofilms to various extend when residing in the tumours. this was followed in more detail for s. typhimurium sl7207. biofilms were not formed by sl7207 when neutrophils had been removed by antibodies. in addition, when arda a central switch for biofilm formation in the salmonellla had been deleted no biofilms could be found. importantly, now bacteria could be found intracellularly most likely in neutrophilic granulocytes. conclusion: the formation of biofilms by facultative anaerobic bacteria when residing in solid tumours is a novel and surprising finding. when neutrophils were removed, no biofilms are formed, while uptake into neutrophils is allowed when the ability of the bacteria to form biofilms was blocked. hence, it appears that the bacteria use biofilm formation as a defence system against the immune system of the host. objectives: rama is an arac/xyls family transcriptional activator found in klebsiella pneumoniae, salmonella spp. and enterobacter spp., the overexpression of which is associated with an mdr phenotype. recently a tetr-like gene that lies upstream of rama, known as ramr, has been identified as a repressor of rama. k. pneumoniae kp342 is a diazotrophic endophyte strain which has been reported to exhibit notable resistance to antibiotics. despite its mdr phenotype kp342 has been shown to exhibit attenuated pathogenicity in mouse models in comparison to clinical k. pneumoniae strains. the aims of this study were to: determine the levels of rama expression and establish its role in kp342's mdr phenotype; determine the effect of ramr complementation on rama expression and antibiotic susceptibility. methods: genome and sequence analysis performed in k. pneumoniae strain kp342 demonstrated a 96 bp deletion within the ramr gene. cloning and complementation with full size wild type ramr was performed in kp342 (hereby known as kp342/ramr). rt-pcr was used to assess levels of gene expression which were subsequently quantified using bio-rad quantity one software. mic testing was performed against chloramphenicol (cm), norfloxacin (nor) and tetracycline (tet) according to bsac guidelines. biofilm formation was measured using a modified protocol of o'toole and kolter. results: kp342 containing the mutated ramr gene (96 bp deletion) was shown to overexpress rama and the putative outer membrane protein roma. complementation of the ramr gene resulted in the repression of both rama and roma transcription by 3−4 fold. interestingly, the ramr complemented strain demonstrated increased biofilm formation (up to 9-fold increase) over a 72 hour period in both lb and m9 medium after static growth at 37ºc. mics of the tested antibiotics were reduced up to 16-fold in kp342/ramr compared to the ramr mutated kp342. conclusions: this result demonstrates that ramr acts as a repressor of both rama and putative outer membrane protein roma thereby increasing its susceptibility to antibiotics. however the restoration of a functional ramr in kp342 also increases biofilm formation significantly, suggesting that ramr plays a role in the regulation of biofilm formation genes and possibly bacterial virulence. rifampicin showed the highest activity on biofilm matrix and bacteria in sa and pa biofilms. results also indicated that biofilm viable mass was more susceptible to treatment than the biofilm matrix, which is mainly responsible for biofilm persistence. further research should specifically focus on compounds destroying matrix and which can be used as an adjunct to antibiotic therapy. [ objectives: staphylococcus epidermidis is a common cause of foreignbody infections (fbi) because of its ability to form biofilms. biofilms are very resistant to antibiotics. active and passive immunisation against biofilm-associated bacterial antigens may be an alternative. we studied the effect of immunisation against the lpxtg protein sesc in s. epidermidis biofilms in vitro and in vivo. we previously reported that sesc is present in all s. epidermidis strains tested. sesc is mainly expressed during the early and late fbi and at a higher level in sessile cells than in planktonic cells. methods: we used rabbit polyclonal anti-sesc-iggs (4 mg/ml) to study biofilm inhibition in vitro and in vivo in our rat model (50 mg igg per rat) on 1-day old biofilms. we also vaccinated rats twice with sesc according to standard protocols. serum samples taken at day 0 and 2 weeks after the 1st and 2nd immunisation were tested by elisa and showed an increase in anti-sesc antibody levels. s. epidermidis strains 10b and 1457 are biofilm forming strains and have been described before. for in vitro experiments, s. epidermidis 10b or 1457 were mixed with anti-sesc-iggs and incubated for 2 hours at 4ºc. subsequently 10 6 cells were added to each well. after 24 h at 37ºc biofilms were washed and stained with crystal violet and od595 was measured. for in vivo experiments, catheter fragments were pre-incubated with s. epidermidis 10b and implanted subcutaneously in each rat. after explantation, the average number of cfu was determined after 24 hrs. results: our data show that rabbit anti-sesc-iggs inhibit in vitro biofilm formation by s. epidermidis strains 10b and 1457 by 74% and 65%, respectively (n = 9). in the in vivo rat model, rabbit anti-sesc-iggs reduced the bacteria in a 1-day old biofilm 60-fold (n = 18). active immunisation with recombinant sesc led to a 10-fold reduction of cfu compared to control rats in 1 day-old biofilms (n = 10). after 3 days, the reduction in biofilm-associated bacteria in the immunised rats was 15-fold (n = 10) (fig 1.) . conclusion: sesc represents a promising target for prevention of s. epidermidis biofilm formation. the higher effect of passive immunisation compared with active immunisation is probably due to the subcutaneous injection of anti-sesc-iggs at the place of catheter insertion. objectives: staphylococcus epidermidis has emerged as a pathogen associated with infections of implanted medical devices impeding their long-term use. characteristics of s. epidermidis that allow persistence of infection are the ability of bacteria to adhere to surfaces in multilayered cell clusters, followed by the production of a mucoid substance more commonly known as slime, encoded by the ica operon. the adherent bacteria and slime are collectively known as biofilm. the coupled effects of specific chemical terminal surface groups and flow conditions on slime production and biofilm formation by s. epidermidis were investigated in correlation to the expression of two genes of the ica operon. methods: reference control strains (atcc35984, slime-positive and atcc12228, slime-negative), and two clinical strains isolated from different hospitalised patients, (one ica-positive/slime-positive and one ica-positive/slime-negative) were tested. bacteria grown in bhi medium were suspended in physiological saline at a concentration of~3×10 9 cells/ml. hydroxyl (oh)-terminated (hydrophilic) and methyl (ch3)terminated (hydrophobic) glass surfaces were used as substrates in a parallel plate flow chamber. bacterial adhesion was examined under two flow rates: 2 ml/min and 20 ml/min for two and four hours. total rna from both planktonic (p) and adherent (a) bacteria, after detachment with trypsin, was isolated by the trizol method. reverse transcription followed by relative real-time pcr (rrt-pcr) towards a 207 bp part of 23s rrna gene, allowed the detection of expression levels of icaa and icad. adherent bacteria were investigated with scanning electron and confocal laser microscopes. results: higher expression levels of both icaa and icad genes onto glass and especially methyl-terminated glass surfaces were calculated by rrt-pcr, under higher flow rate in two hours by the reference and the clinical slime-positive strains. these results correlate well with adherent bacterial cell counts and images taken by both microscopes. the icapositive slime-negative clinical strain showed lower expression levels of ica genes, less adherent ability and pia production on glass surfaces, as observed by microscopes. higher flow rate enhances the expression level of both ica genes, with a peak in two hours. hydrophobic biomaterial surfaces seem to play a crucial role to initial adherence, increasing ica gene expression and pia synthesis. consenting men and women with dfi (predefined by clinical signs and symptoms) caused by mrsa were potentially eligible including those associated with bacteraemia. patients with initial osteomyelitis were excluded. patients could receive l 600 mg bid either iv or po. primary end point were cure or improvement rates (c+i) and microbiologic eradication (me) at 60 days after the beginning of l. secondary end points were c+i on days 5 and 30 after the beginning of treatment and hospital discharge day, need of amputation, duration of therapy and mortality rates. all the adverse events were collected. results: 70 patients were enrolled. relation men:women was 2.1.the age of patients was 63.2±13 years and the average period from the diagnosis of diabetes was 16.5±9.7 years. associated bacteraemia was present in 27.1% of patients included. primary end points: c+i 60 days after the beginning of l was achieved in 91.4% of patients and me was obtained in 84.3% of patients. secondary end points: c+i on day 5, hospital discharge day and day 30 after the beginning of treatment and were; 70%; 84.3% and 88.6% respectively. only 8 patients needed a minor amputation. the primary and secondary end points in the subgroup of bacteraemic episodes were not statistically different of those previously described. the mean duration of therapy was 29.5±18.4 days. global mortality was 4.3%. only one episode of polineuropathy was reported. neither thrombocytopenia nor lactic acidosis was found. conclusions: l achieved excellent c+i even at first evaluation visit in documented dfi caused by mrsa. l also showed high me rates. although patients received prolonged periods of treatment, l was a safe drug. objectives: azithromycin microspheres formulation (azm) was developed to enable a higher dosage of 2 g to be administered as a single oral dose without decreasing the safety profile. this study compared azm with moxifloxacin (mox) aimed at confirming the efficacy and safety of azm in acute exacerbations of chronic bronchitis (aecb). methods: this prospective, multicentre, randomised, double-blind, double dummy study compared azm 2 g single dose with mox 400 mg once daily for 5 days, enrolled aecb patients 50 years old and above, with anthonisen type 1 exacerbations, and with at least 2 exacerbations of aecb in the past 12 months. subjects were to have a history of smoking of at least 20 pack-years and documented forced expiratory volume in 1 second (fev1) less than 80% of predicted. they were followed up for up to 9 months. results: a total of 396 patients were treated (198 in each of the treatment groups) the distribution of the age, and mean fev1 were similar for the 2 treatment groups. pathogens were isolated from 62.9% of the patients (61.1% of patients on azm and 62.9% of patients on mox). the clinical success (signs and symptoms related to the acute infection had returned to the subject's normal baseline level, or clinical improvement was such that no additional antibiotics were deemed necessary) rate for the per protocol population at test of cure (toc) at day 12−19 was 93.0% for azm and 94.2% for mox group (95% ci −5.8, 3.9). bacterial eradication rate (bacteriologic pre protocol population) at toc was 96.0% for azm group and 96.7% for mox group (95% ci −4.5, 3.3). although the study population had history of at least 2 exacerbation in the past 12 months, less than half of the subjects experienced a recurrence during the follow-up, and there was no statistically significant treatment difference in time taken to first occurrence of aecb. both treatments were well tolerated. the incidence of treatment related adverse events was low, being reported by 17% of subjects receiving azm and 12% of subjects receiving mox. most aes were mild or moderate in severity. the most common aes were gastrointestinal disorders, being reported by 14% of subjects receiving azm and 8% of subjects receiving mox. conclusions: a single oral dose of azm was as effective as a 5-day course of mox in the treatment of aecb and was well tolerated. objectives: optimal duration of gentamicin containing regimen for therapy of human brucellosis is not clearly determined. methods: this randomised clinical study was conducted to compare the efficacy of gentamicin 5 mg/day for 5 days plus doxycycline 100 mg twice daily for eight weeks (gd group) versus streptomycin 1gr im for 2 weeks plus the same dose of doxycycline for 45 days (sd group). all cases were followed for one year after cessation of therapy. efficacy of both regimens (failure of therapy or relapse) were compared. results: seventy-nine patients with the mean age of 35±14.5 years and 75 cases with the mean age of 36.7±13.9 years were treated with regimen of gd or sd, respectively. the clinical manifestations in these two treated groups were similar. failure of therapy was seen in one patient in gd group and in 2 cases in sd group ( objectives: to study the efficacy of telavancin (tlv), an investigational bactericidal lipoglycopeptide, for the treatment of complicated skin and soft tissue infections (cssti) caused by presumed or confirmed grampositive organisms. methods: atlas 1 and atlas 2 were methodologically identical, double-blind, randomised, multinational, phase 3 studies. adult men and women presenting with cssti including major abscess were randomised 1:1 to tlv 10 mg/kg intravenous (iv) q24 h or vancomycin (van) 1 g iv q12 h for 7 to 14 days. test-of-cure (toc) visit was conducted 7 to 14 days after end of study treatment. the all-treated population (at) included patients with confirmed diagnosis of cssti who received 1 dose of study medication. this analysis examined the baseline characteristics and cure rates at toc for patients with major abscess in the combined atlas at population. results: in the pooled at population of atlas, 772 patients presented with major abscess. more than 60% of these patients required hospitalisation. the baseline lesion surface area exceeded 5 cm 2 in 98% of the cases, while 65% of the patients presented with lesions exceeding 50 cm 2 (table 1) . elevated white blood cell counts were found in more than 40% of the cases (table 1) . nearly all patients required surgical drainage, with approximately 2/3 performed prior to the first dose of study medication. very few patients required a surgical procedure more than 4 days after the start of study medication. clinical cure rates at toc are presented in table 1 . overall, adverse events in the at population were similar between the treatment groups with regard to type and severity. conclusion: telavancin administered once daily was non-inferior to vancomycin for the treatment of major abscess. objectives: b. fragilis and related species, members of the normal bowel flora, are the most widely isolated anaerobic bacteria from different infections. to follow the development and spread of the resistance among these strains is difficult, as antibiotic susceptibility testing of clinically relevant anaerobes in different routine laboratories in europe is less and less frequently carried out due to the fact, that clinicians treat many presumed anaerobic infections empirically. to follow the changes in the antibiotic resistance of bacteroides strains three europe-wide studies were organised during the past twenty years. the evaluation of the results of these studies may show changes in the resistance to different antianaerobic drugs. only clinical isolates and no normal flora members of bacteroides strains belonging to different species were collected from different countries throughout europe during these studies. agar dilution method was used for the antibiotic susceptibility determination. actual breakpoints accepted by nccls (clsi) and eucast were used. molecular genetic investigations were carried out to detect resistance mechanisms. since the first study the chromosomally mediated beta-lactamase production and tetracyclin resistance is the most prevalent among bacteroides strains in europe. clindamycin resistance in bacteroides is mediated by a macrolide-lincomycin-streptogramin (mls) mechanism and its frequency differs in different countries in europe. resistance to beta-lactam-beta-lactamase inhibitor combinations was studied using amoxicillin-clavulanic acid and/or piperacillintazobactam. increase in resistance was observed to both combinations throughout the years. the same is true for cefoxitine and in the third study several hetero-resistant isolates were found. the occurrence and spread of resistance to imipenem and metronidazole among bacteroides strains merit special clinical importance. the presence of the cfia gene is much more prevalent than the expression of the imipenem resistance; however the spread of the cfia gene among species other than b. fragilis is still very rare. the molecular genetic methods looking for the resistance genes among strains with elevated mics against these antibiotics prove that resistance breakpoints should be reconsidered. the resistance to moxifloxacin shows great differences in different countries. the lowest resistance rate was observed in the case of tigecyclin. many factors may affect the response to treatment such as site of infection, surgical procedures, severity of the illness, patient status, presence of other pathogens (mixed infection), pk/pd parameters of the antibacterial drugs. thus, correlation between treatment failure and antibiotic resistance among anaerobes remains difficult to assess. the main discrepancies came from intra-abdominal infections and a worrisome disjunction between surgeon and microbiologist opinions emerged in the 1990's. but, patients in whom primary therapy failed had more resistant strains compared with patients in whom therapy succeeded. in contrast many failures may be due to the lack of isolation of anaerobes from clinical samples! during anaerobic bacteraemia, salonen et al. demonstrated that mortality increased dramatically from 17% for initially effective treatment to 55% when an ineffective treatment was started. facing new mechanisms of resistance and global increase resistance to many antibiotics among anaerobes may lead nowadays to a different answer. clindamycin vs. penicillin studies for the treatment of lung infections pointed out the failure due to b-lactamase production among gram-negative anaerobes. we found many reports of failure after clindamycin treatment in osteomyelitis, septic arthritis, brain abscess in presence of clindamycin-resistant anaerobes (bacteroides fragilis group and prevotella), probably because when resistance occurs, clindamycin mic's are high. similarly, the lack of coverage of an undetected resistant anaerobe allows the selection of an anaerobic strain resistant to the treatment chosen against the associated aerobes such as imipenemresistant eghertella lenta or metronidazole-resistant strains of prevotella or bacteroides fragilis. the later failures may give opportunity to set up a new metronidazole breakpoint for resistance (mic > 4 mg/l). the main problem is related to the difficulty to detect some heterogeneous resistant strains, that needs prolonged incubation period on agar medium. this kind of situation is probably the most suitable to correlate the bacterial antibiotic resistance with the failure of the antibiotic treatment. methicillin-resistant s. aureus isolates causing community-acquired infections (ca-mrsa) in children is a major problem in several areas around the world. ca-mrsa are associated with both skin and soft tissue infections and invasive infections. recurrent soft tissue infections and infections within the family caused by ca-mrsa isolates are common. ca-mrsa s. aureus isolates containing gene coding for pvl have been associated with serious staphylococcal pneumonia as well as osteomyelitis complicated by subperiosteal abscesses or venous thromboses. in addition to vancomycin, ca-mrsa generally are susceptible to clindamycin and trimethoprimsulfamethoxazole. treatment of superficial skin and soft tissue infections involves surgical drainage of abscesses followed by an oral agent such as tmp-smx or clindamycin. minocycline or doxycycline is a consideration for children >8 years old. empiric vancomycin is typically administered for more serious and invasive infections such as osteomyelitis, septic arthritis, serious head and neck infections or suspected staphylococcal pneumonia. clindamycin is efficacious in treating invasive ca-mrsa infections caused by susceptible organisms. linezolid or daptomycin is another option in selected circumstances. mri is the optimal imaging modality for assessing children with ca-mrsa osteomyelitis. aggressive surgical drainage of subperiosteal abscesses or sites of pyomyositis is recommended. venous thombosis is increasingly recognized as a complication of ca-mrsa osteomyelitis. anti-coagulation until the thrombus has resolved is recommended. the optimal approach to prevention of recurrent ca-mrsa infections is unclear but a strategy that includes emphasizing personal hygiene, plus/minus antimicrobial soaps, mupirocin to the nose or "bleach baths" is frequently suggested. s226 understanding the pathogenesis of group a streptococcal disease: the bedside-to-bench approach invasive group a streptococcal (gas) infection presents itself in a range of guises, most notoriously necrotising fasciitis and the streptococcal toxic shock syndrome. as a human pathogen, gas pathogenesis research should ideally be shaped by clinical questions arising from either epidemiological or case-based investigation of human disease. in the mid 1990 s, large epidemiological studies pointed to a central role for specific t cell-stimulating superantigens in the aetiology of streptococcal toxic shock. this sparked a series of clinical and laboratory investigations that demonstrated production of superantigens during infection which were indeed capable of triggering massive t cell activation in patients but were unlikely, alone, to account for all the features observed in toxic shock. genomic, clinical and laboratory-based investigations have identified novel and highly potent superantigens that appear to directly contribute to sepsis pathogenesis and, together, may constitute targets for adjunctive treatments in invasive disease. epidemiological, clinical, and laboratory studies have highlighted a role for blunt trauma in the aetiology of at least a quarter of cases of gas necrotising fasciitis. one of the most striking findings on examination of tissues from patients suffering with necrotising fasciitis is the failure of neutrophils to migrate to the focus of infection. investigation of patients with invasive gas infection led to the discovery that gas produces an enzyme that can cleave and inactivate human chemokines and study of patients with bacteraemia has highlighted a likely role for the causal enzyme spycep in disease pathogenesis; this bacterial surface enzyme has also shown promise as a potential vaccine antigen. notwithstanding a potential role for individual virulence factors in disease causation, clinical studies have demonstrated that gas bacteria may persist at the site of infection despite high concentrations of bactericidal antibiotics, and this has been borne out by experimental studies; the reasons behind such persistence are unclear but may include internalisation of gas by immune cells, formation of biofilm, and antibiotic penetration of necrotic tissues. the persistence of viable bacteria in such cases is not widely recognized and deserves focused consideration in the research laboratory. genome-wide analysis of microbial pathogens and molecular pathogenesis processes has become an area of considerable activity in the last 10 years. these studies have been made possible by several advances, including completion of the human genome sequence, publication of genome sequences for many human pathogens, development of microarray technology and high-throughput proteomics, and maturation of bioinformatics. despite these advances, relatively little effort has been expended in the bacterial pathogenesis arena to develop and use integrated research platforms in a systems biology approach to enhance our understanding of disease processes. we have exploited an integrated genome-wide research platform to gain new knowledge about how the human bacterial pathogen group a streptococcus causes disease. results of these studies have provided many new avenues for basic pathogenesis research and translational research focused on development of an efficacious human vaccine and novel therapeutics. new data stemming from use of a systems biology approach to provide new data about group a streptococcus pathogenesis will be presented. streptococcal toxic shock syndrome and necrotising fasciitis caused by group a streptococcus are rapidly progressive invasive diseases that are associated with significant morbidity and mortality, ranging from 30−80% despite prompt antibiotic therapy and surgical debridement. s. pyogenes is known to primarily cause disease by activating and modulating host immune responses. the exotoxins with superantigenic activities have been demonstrated to be crucial triggers of excessive inflammatory responses and consequently systemic toxicity, organ dysfunction, tissue necrosis and shock. another important virulence determinant is the m-protein, which is classically known for its antiphagocytic properties, and lately, was shown to trigger pro-inflammatory responses as well as induction of vascular leakage and shock. this likely represents important mechanisms contributing to the rapid development of shock and systemic toxicity in patients with severe invasive group a streptococcal infections. the understanding of these infections as hyperinflammatory diseases highlighted the potential of immunotherapy to improve outcome. one such strategy includes the administration of intravenous polyspecific immunoglobulin (ivig) as adjunctive therapy. the mechanistic actions of ivig in this setting are believed to include opsonisation of the bacteria, neutralisation of the superantigens and suppression of the pro-inflammatory responses. there is growing evidence to support the use of ivig in patients with streptococcal toxic shock syndrome. these studies include one observational cohort study based on canadian patients identified through active surveillance of invasive group a streptococcal infections, and one european multicentre placebo-controlled trial. however, the question remains whether ivig is efficacious also for the severe streptococcal deep tissue infections. an observational study of seven patients with severe streptococcal deep tissue infections suggested that the use of high-dose ivig in patients with severe gas soft tissue infections may allow an initial non-operative or minimally invasive approach, which can limit the need to perform immediate wide debridements and amputations in unstable patients. the fact that seven patients with severe group a streptococcal infections survived with this approach definitely warrants further studies to be conducted on the use of ivig in these severe infections. hepatitis o229 prevalence and outcome of pregnancy in chronic hepatitis c virus infection i. julkunen°, a. sariola, m. sillanpää, k. melen, p. koskela, p. finne, a.l. järvenpää, s. riikonen, h.m. surcel (helsinki, oulu, fi) objectives: in the western countries the incidence of hepatitis c virus (hcv) infection has steadily been increasing especially among young adults. it is thus likely that an increasing prevalence of hcv infection is also found in pregnant women. methods: to assess the frequency of hcv infection in the metropolitan area of helsinki selected anti-hcv antibody testing was carried out for pregnant women during the years 1991-1999. in addition, hcv prevalence was analysed in serum specimens collected from pregnant maters during the years of 1985-2005. results: altogether 145 mothers were identified among 44680 mothers. the frequency of anti-hcv positivity rose from 0.13% in 1991 to 0.43−0.53 in 1997-1999. in early 90's only 20% of mothers knew about their seropositivity, whereas by the end of the follow-up period almost 70% of mothers knew about their hcv infection already before the pregnancy. intravenous drug abuse was the major risk factor (71% of cases) for contracting the disease. in 90% of the mothers chronic hcv infection was well under control and in this population the mean serum alanine aminotransferase (alt) values decreased towards the end of the pregnancy. however, 10% of anti-hcv ab positive mothers developed intrahepatic cholestasis (odds ratio 16.4) as characterised by itching and elevated serum bile acid levels. the correspondig value in the control pregnancies was only 0.7%. anti-hcv ab positive mothers were younger, delivered earlier and gave birth to babies with smaller birth weight as compared to control deliveries. to have a more comprehensive view of the problem of hcv infection during pregnancy randomly selected serum specimens from the finnish maternity cohort were tested. 2000-5000 serum specimens were tested in selected cohorts (1985, 1990, 1995, 2000 and 2005) . in 1985 the nationwide prevalence was 0.19% and it steadily role to 0.50% in 2005. in the metropolitan area of helsinki the prevalence was higher being 0.68% and 0.70 in 1997 and 2002, respectively. conclusion: our study indicates that there is an increasing problem of hcv infection in pregnant women in finland. although most women cope well with their disease during pregnancy there is a subpopulation of mothers who develop cholestasis and their liver status should thus be followed-up carefully. testing of all mothers for serum anti-hcv antibodies is recommended. objectives: the viral genome of hepatitis c virus constitutes a 9.6kb single-stranded positive-sense rna which encodes altogether 11 viral proteins. in order to study the humoral immune responses against different hcv proteins in patients suffering from chronic hcv infection, we produced three structural (c, e1 and e2) and six nonstructural proteins (ns2, ns3, ns4a, ns4b, ns5a and ns5b) in sf9 insect cells by using the baculovirus expression system. the recombinant hcv proteins were purified and used in western blot analysis to determine antibody responses against individual hcv protein in 68 hcv rna and antibody positive human sera that were obtained from patients suffering from genotype 1, 2, 3 or 4 infection. results: these sera were also analysed with inno-lia score test for hcv antibodies against core, ns3, ns4ab and ns5a, and the results were similar to our western blot method. based on our western blot analyses we found that the major viral antigens were the core, ns4b, ns3 and ns5a proteins and they were recognized in 97%, 86%, 68% and 53% of patient sera, respectively. there were no major genotype specific differences in antibody responses to individual hcv proteins. a common feature within the studied sera was that all except two sera recognized the core protein in high titers, whereas none of the sera recognized ns2 protein and only three sera (from genotype 3) recognised ns5b. the data shows significant variation in the specificity in humoral immunity in chronic hcv patients. anti-hcv antibody pattern also remains very stable within one individual. alt and ast levels were tested in all subjects. the presence of hbv-dna was determined quantitatively in plasma samples of hd patients with anti-hbc alone (hbsag negative, anti-hbs negative and anti-hbc positive) by real-time pcr using the artus hbv rg pcr kit on the rotor-gene 3000 real-time thermal cycler. results: of 289 patients enrolled in this study, 18 subjects (6.2%, 95% ci, 3.5%-8.9%) had anti-hbc alone. hbv-dna was detectable in 9 of 18 hd patients (50%, 95% ci, 27%-73%) with anti-hbc alone. plasma hbv-dna load was less than 50 iu/ml in all of these patients. our study showed that detection of anti-hbc alone could reflect unrecognized occult hbv infection in hd patients. the majority of these infections are associated with low viral loads. were included in the study. all the subjects had never been exposed to antiretroviral therapy. genotypic resistance testing was performed at the time of diagnosis with a sequence-based assay (trugene hiv-1 genotyping test) targeted at the protease region (codons 1 to 99) and rt region (codon 40 to 247) of the hiv-l genome. results: 21 of 218 patients (9.63%) harboured a virus with at least one mutation associated with phenotypic resistance; 1/218 with mutations associated with resistance to nucleoside reverse-transcriptase inhibitors (nrtis), 17/218 to non-nucleoside reverse-transcriptase inhibitors (nnrtis) and 3/218 to protease inhibitors (pi). resistance to nrtis was associated with the key mutation m184v, while resistance to nnrtis was associated with y181c and k103n mutations. among mutations to pi, major resistance mutations l90m and d30n were found in three patients, whereas there was a high prevalence of accessory pi resistance mutations at positions 10, 20, 36 and 63. conclusion: our data estimate the prevalence of primary resistance and mutations patterns among naive hiv patients, underlining the importance of genotypic resistance testing in hiv patients before starting treatment, especially when nnrtis would be included in the initial antiretroviral therapy. objectives: few data are available on the genetic mechanisms of protease inhibitor (pi) resistance in non-b hiv-1, and pi resistanceassociated mutations (rams) are commonly observed in pi-naive patients with subtype a/e infection. this study aimed to compare pi-rams between pi-naive and -experienced patients. methods: genotypic resistance testing was conducted among a cohort of hiv-1 infected patients who had virologic failure. patients were categorised into 2 groups: pi-naive and pi-experienced. we focused on pi-rams previously described by ias-usa 2008. results: we studied 137 patients (mean age, 41.8 years; 64% male). median cd4 cell count and hiv-1 rna at virologic failure were 169 cells/cu.mm. and 14100 copies/ml, respectively. 85% of patients were infected with subtype a/e; the others had subtype b (12%), ab (2%), and c (1%). there were 75 patients in pi-naive group and 62 patients in pi-experienced group. the clinical characteristics between 2 groups were similar (p > 0.05) except for the duration of antiretroviral therapy which was shorter in pi-naive group (31.5 vs. 46.8 months, p = 0.028). percentage of patients who had primary pi-rams was 1% in pinaive and 19% in pi-experienced groups (p = 0.001). the most common primary pi-rams in the latter group were v82a (10%) and i54v (7%). percentage of patients with secondary pi-rams in the corresponding groups was 99% and 98%, respectively (p = 1.000). median number of secondary pi-rams was also similar between 2 groups (p = 0.244). the most common secondary pi-rams in both groups were m36i (91%), h69k (34%), l89m (30%), i13v (26%), l63p (25%), l10i we also defined a "silent score" (ss) and a "resistance score" (rs) as the number of synonymous mutations and of resistance mutations (in the second sequence in comparison with the first one) divided by number of days between the two tests, respectively. (12); pts with drms in non-b-st (%) were 7 (23.3), 6 (14), 5 (7) and 3 (4.2). a significant increase of non-b-st (p = 0.021) and a significant decrease in drms (p < 0.001) were observed. crf02_ag was the prevalent non-b st (44%). 35.3% of non-b st pts were italians. among b-st, drms predicted a reduced susceptibility to one drug class in 23, 17, 15 and 14 cases in the different periods; to two drug classes in 4, 6, 5 and 8; to three classes in 3, 2, 0 and 0. in non-b-st, a reduced susceptibility to one drug class was found in 6, 6, 4 and 0 cases; to two drug classes in 1, 0, 0 and 2; to three drug classes in 0, 0, 1 and 1, respectively. among pts with one or two classes of resistance, a decrease of percentage of protease inhibitors related drms, and a persistence of non nucleoside rt inhibitors involving drms, mainly 103n and 190a, were observed. methods: from hiv+ persons with a history of, or an acute episode of opc, oral fungal burden was evaluated bi-weekly and buccal mucosa tissue was collected bimonthly for a period of one year. tissue was evaluated for the presence of cd8+ t cells and e-cadherin by immunohistochemistry or flow cytometry. objectives: to define the secular trends in the epidemiology of candidaemia in queensland, australia (population, 4.1 million) over a 10-year period. methods: all episodes of candidaemia within queensland public hospitals from 1999-2008 were identified from laboratory information systems. data on species identification, antifungal susceptibility, demographics, and hospital ward of diagnosis, and denominator data (hospital admissions, accrued patient-days (pt-days) and fluconazole usage) were collected. results: over the 10-year period, 1137 unique episodes (100% case ascertainment) were identified from 42 healthcare facilities (8 tertiary, 2 paediatric, 11 secondary and 21 smaller hospitals). the median patient age was 56.4 years. the overall incidence-density was 0.45/10000 ptdays, highest in paediatric (1.28/10000 pt-days) and tertiary hospitals (0.62/10000 pt-days). over the 10 years, the incidence-density increased 3.2-fold in tertiary hospitals and 6.6-fold in secondary hospitals (both p < 0.0001 for trend), but not in paediatric or smaller hospitals. the incidence-density in icus (5.2/10000 pt-days) was 10-fold higher than in non-icu wards, but did not significantly increase over the study period. the relative proportion of episodes occurring in adult general medical/surgical (ie non-oncology/non-icu) wards significantly increased (p < 0.001), accounting for 62% of episodes at the end of the 10-year period, whereas that occurring in paediatric and adult oncology wards decreased (p < 0.001 and p = 0.07 respectively). overall, c. albicans accounted for 44%, c. parapsilosis 27% and c. glabrata 13%. although the incidence-density of all species increased over the study period, the relative proportion caused by c. albicans decreased (p = 0.007) and c. parapsilosis increased (p = 0.01). despite significantly increased fluconazole usage (from 19.7 to 30.6 ddd/1000 pt-days, p < 0.0001), the relative proportion caused by c. glabrata/c. krusei did not change (p = 0.5). the overall incidence of candidaemia has increased almost 400% in queensland public hospitals over the last 10 years. the relative proportion of episodes occurring among general medical/surgical patients and caused by c. parapsilosis has increased. candidaemia is an increasing problem the epidemiology of which continues to evolve. it is increasingly affecting patients outside traditional risk groups. conclusions: this surveillance study and pharmaco-economic modelling has proved immensely beneficial in setting up inhouse processing, improved tat, reduced costs of outsourcing and subsequent use of expensive antifungals. reduction in mortality has been noted but is not statistically significant. c. albicans was the commonest isolate; fluconazole resistance is minimal and associated mortality is lower than reported from europe. many pts received systemic prophylaxis (72%); itraconazole and fluconazole were used in 68 and 33 pts respectively. no differences emerged between empirical vs pre-emptive therapy and none of the drugs resulted to significantly influence outcome. in 66% of pts initial empirical/pre-emptive drug remained unchanged after ia diagnosis, while in 16% clinicians shifted to a combined treatment. conclusion: this study allows as to analyzed multiple factors as potentially influencing outcome. we confirmed that aml phase and neutropenia influence ia outcome. present data confirm the perception that during last years the application of a correct and timely diagnostic work-up and the availability of more efficacious and less toxic drugs (i.e. voriconazole, liposomal amphotericin b, caspofungin) have modified the course of ia. however none of the new drugs emerged as the most efficacious in our series. even combined treatment did not confer any advantage in survival analysis. (<3% each). the first line therapy was monotherapy with voriconazole (49%), caspofungin (14%), lipid formulations of amb (9%) or used antifungal drugs combination (20%). the mortality rate at day 90 was 41% when first line therapy included voriconazole compared to 60% when it did not (p < 0.001). conclusion: comprehensive collections of cases based on systematic reporting and description of cases using a dedicated network of hospitals in selected regions and stringent definition criteria applied by trained clinicians and microbiologists are useful to describe ia, to assess its burden and secular trends, and to identify potential changes in diagnostic and therapeutic procedures. this network will expand to other regions in the near future, and data will help assessing the impact of new management strategies such as prophylaxis with posaconazole, the impact of modification of new diagnostic criteria as recently proposed (clin infect dis, 2008), and identifying new populations at risk for ia. nosocomial aspergillosis represents a serious threat for severely immunocompromised patients and outbreaks have been attributed to airborne sources. the role of hospital-independent fungal spread sources e.g. the private homes or business suites are not known. we investigated the relationship between fungal exposure prior hospitalisation and the ensuing onset of invasive mould infections (imi) in patients at risk. patients admitted to the department of haematology and oncology or to the department of transplant surgery of the innsbruck medical university received a structured questionnaire regarding their fungal exposure prior hospitalisation. questions inquired heavy fungal exposures up to five days prior hospitalisation. 234 patients were enrolled in this study and 19% were smokers, 22% suffered from an airborne allergy, 62% lived in old buildings, 73% were ruralists, 82% and 92% were exposed to any outdoor or indoor fungus sources. poor housing conditions and other fungus exposures were associated with the onset of community-acquired imi only in patients with acute myelogenous leukaemia (p < 0.01). aml patients being more at risk for imi when smoking cigarettes (p < 0.05), living on the country site (p < 0.05), having two or more fungus exposures (p < 0.05) and suffering from allergy to dust, pollen and/or moulds (p < 0.05). a similar trend was for lung transplant recipients receiving extensive immunosuppressive agents to treat allograft rejection. overall, 88% of imi were community-acquired cases. hospital-independent fungal sources highlight risk-factors for imi in severe immunocompromised patients and the rate of communityacquired imi does increase. an analysis of an individual patient's risk factors for fungal infection and the type of fungus to which they are most susceptible, indicates the preventative strategies that are likely to be successful. to the icu-mhs with aspergillus spp detected in significant amounts in clinical samples. the underlying conditions of the patients were heart transplantation (n = 5), major heart surgery (n = 4), and other (n = 2). eight (72.7%) patients developed proven/probable ia (4 with lung infection, 2 with mediastinitis, 1 with disseminated ia, and 1 with prostate involvement). the mortality of patients with ia was 87.5%. the icu-mhs is divided into 3 areas, one of which is equipped with hepa filters. only 1 case of ia occurred in the protected area. we measured the fungal conidia levels in the air of each of the 3 areas (508 samples analyzed) monthly. a total of 172 strains of a. fumigatus (110 clinical strains from 10 patients and 62 environmental strains) were genotyped using microsatellites (de valk et al, jcm 2005) . the mean airborne conidia levels (6 months) before and after the outbreak were, respectively, 5.6 (0−15) cfu/m3 and 1.8 (0−10) cfu/m3. no cases of ia occurred during these periods. however, all cases of ia were linked to 4 peaks of abnormally high airborne conidia levels (65, 70, 200 and 500 cfu/m3). a. fumigatus was involved in 7 cases of ia; 1 patient was infected by non-fumigatus aspergillus (not further genotyped). in 4 patients (1 mediastinitis, 2 pulmonary ia and 1 colonisation), we demonstrated similar genotypes in the air and in clinical samples. patient 1 was located in the protected area and had a unique genotype. patient 2 had two different clusters of genotypes: one cluster was similar to that of patient 3 and the other was also found in patient 4 and in the air. the genotype present in patients 2 and 4 was also detected in the air during a 6-month period. conclusions: epidemiologic and molecular typing suggests that there is a causal relationship between aspergillus causing ia and those present in the air. our finding also supports the need for hepa filtration in icu-mhs. j. guinea is contracted by fis (cm05/00171). sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were calculated in reference to proven and probable cases of ia. reasons for performing bronchoscopy on patients were also recorded. the protocol received approval by the local ethic committee. results: from the 117 samples studied, 5 (4.3%) were classified as proven, 6 (5.1%) as probable, and 35 (29.9%) as possible cases of aspergillosis. twelve samples (10.3%) represented colonisation, and 59 bal samples were obtained during routine surveillance. pulmonary aspergillosis was the main clinical presentation of ia (63.6%). using roc analysis, the best cut-off for galactomannan testing in bal was defined as 1.5 (sensitivity 90.9%, specificity 90.6%, ppv 48% and npv 99.1%). median bal gm index for the group of patients with proven/probable aspergillosis and for 'negative cases' were 3.3 and 0.5, respectively (p < 0.001). overall mortality was 20% (n = 12). the odds for death for patients diagnosed with ia were 11.8, in comparison to patients who did not have this infection (95% ci 2.9−48.4). conclusion: gm testing in the bal added to the diagnosis of ia in lung transplant recipients. in order to avoid false-positive results, a higher test cut-off should be applied to bal samples, in comparison to sera. increasing the cut-off to 1.5 resulted in a very high npv, with an associated sensitivity of >90%. objectives: 1) determine the performance characteristics of the galactomannan (gm) assay in broncho-alveolar lavage (bal) in haematology-oncology patients; 2) evaluate the prognostic value of the gm assay in this particular population. methods: the platelia gm eia assay (bio-rad) was performed on all bal specimens obtained from haematology-oncology patients at our institution between march 2005 and april 2008, in addition to routine laboratory stains and cultures. all results were reported to physicians. we conducted chart reviews to classify cases as proven, probable, possible or without invasive pulmonary aspergillosis (ipa) according to the revised definitions of invasive fungal disease from the eortc/msg consensus group. for performance characteristics, proven and probable cases were considered as ipa; possible cases were considered as without ipa. the result of bal gm was not considered as a criterium to classify cases in order to avoid incorporation bias. in patients with >1 positive (gm index >0.5) specimen, only the first one was considered for the analysis. mortality was calculated at 60 days following the first bal procurement. data were analyzed with stata 8.0. results: there were 173 bal samples from 145 patients, including 101 haematopoietic stem cell transplant (hsct) recipients. we found 5 proven, 7 probable and 35 possible cases of ipa (total of 12 ipa cases; 6.9%). gm on bal was positive in 47 (27.2%) specimens. the sensitivity and specificity of the gm assay in bal were 100% and 78.3% respectively. positive predictive and negative predictive values were 25.5% and 100%, respectively. false-positive results were found in 21 patients without ipa and in 14 with possible ipa. an index value 0.5 was significantly associated with a 60-day mortality risk (12/39 patients with a positive gm died within 60 days after bal compared to 13/106 with a negative gm (or = 3.2, 95%ci 1.3−7.8; p = 0.01). this association was even stronger when restricted to hsc recipients (or =4.6, 95%ci 1.5−13.6; p = 0.006). the clinical utility of gm assay in bal mainly lies in its negative predictive value, identifying patients at low risk of ipa. this test also carries a prognostic value in predicting patients at higher risk of mortality. (see table below) . not significant differences have been found among pneumocystis colonisation and copd status evaluated by fev-1%. as well as no significant differences respect to age, sex or lymphocytes and leucocytes blood count were found. background: infliximab, a monoclonal antibody targeting tumour necrosis factor alpha (tnf-a), is indicated for the treatment of rheumatoid arthritis (ra) and other autoimmune diseases. however, its use has been associated with opportunistic infections, including pneumocystis jirovecii pneumonia (pcp). moreover, p. jirovecii has been observed colonising to humans with several disorders. objectives: to obtain information about p. jirovecii colonisation among patients with rheumatologic disease treated with infliximab. this information could be useful for assessing new strategies in the prevention of pcp in patients at risk. methods: 62 consecutive patients treated with infliximab for rheumatic disorders were included in the study. oropharyngeal washes (ow) samples were collected for p. jirovecii detection. clinical and demographic data were collected (sex, age, rheumatologic diagnosis, duration of infliximab use, concomitant use of other drugs for rheumatologic treatment, use of any other anti-tnf-a agent, use of anti-pc drugs in the last six months, smoking, and diagnosis of chronic pulmonary respiratory disease). p. jirovecii colonisation was identify in ow samples by pcr at mtlsu-rrna gene, with primers paz102-x and paz102-y. we adapted a method previously described to a real-time pcr setting, using a lightcycler 1.5 (roche, germany). individuals in whom the presence of p. jirovecii was detected at two independent assay in the absence of respiratory symptoms or radiological findings suggestive of pcp were considered to be colonised. results: clinical and demographic data for 62 patients treated with infliximab are presented in table 1 objectives: most research with human bocavirus, a recently found respiratory pathogen, has been done by molecular biology (polymerase chain reaction, pcr). the results have been ambiguous because the virus has often been found in co-infection with other viruses, and also in clinically healthy subjects. it has been proposed that, for bocavirus, antigen detection could better indicate the aetiology than qualitative nucleic acid detection. we have developed a rapid antigen detection test for the virus. the one-step test for bocavirus vp2 antigen is based on a separation-free two-photon excitation fluorometry (arcdia tpx assay technique). the assay protocol is simple; the swab sample is dissolved in sample buffer, and the solution is dispensed (20 ml) onto a 384-well microtitre plate (containing the reagents in dry form) for incubation and automated quantitative measurement. the immunoassay applies microspheres as solid-phase carriers of purified bocavirus-specific polyclonal antibodies. the virus antigens concentrate onto the solid-phase which is probed in real-time with fluorescently labelled antibody reagents. strong positive samples are reportable in 15 minutes, while low positive and negative samples are reported in 2 hours. the performance of the method was studied with recombinant human bocavirus-like particles (vp2), and purified respiratory pathogens (group a streptococci, streptococcus pneumoniae, and influenza a and b, respiratory syncytial, metapneumo, adeno, and parainfluenza 1−3 viruses). results: analytical detection sensitivity of the method (lowest limit of detection, 0-control + 3sds) was 3 ng/ml, dynamic concentration range was three orders of magnitude, and intra-assay imprecision was 5−10%. cross-reactions with the other respiratory pathogens were not found. the new method enables rapid detection of bocavirus antigens. the new test is very easy to perform in comparison to standard elisas. the analytical sensitivity of the method is expected to allow analysis of clinical samples. the sensitivity of the antigen detection test could be significantly increased by the use of monoclonal antibodies (10-100 fold). our future objectives include increasing the detection sensitivity, and analysis of clinical samples in order to study the correlation of antigen detection and the clinical aetiology. life-year for patients who survived. all analyses were performed using treeage software (2008). results: the overall mortality rates for empiric vancomycin (v) and semi-synthetic-penicillin (ssp) was 30% and 35%, respectively, as apposed to 24% for those receiving the rapid mrsa pcr testing. these mortality rates were similar in both the eu and us subsets. furthermore, the number needed to test in order to save one life was 20 and 11 for empiric v and ssp, respectively. using sensitivity analysis the prevalence of mrsa was varied from 5% to 80% and yielded an absolute mortality difference favouring the pcr testing group of 10% and 2%, respectively as compared to empiric v and 1% and 18% compared to empiric ssp. in eu the c/e for empiric v and ssp treated patients was €873 and €949, respectively as compared to €807 for rapid pcr testing. in the us the c/e for empiric v was $1,049 as compared to $971 for rapid pcr testing. using sensitivity analysis the prevalence of mrsa was varied from 5% to 80% and yielded favourable c/e in both the eu and us for rapid pcr testing regardless of the empiric treatment regimen. conclusion: rapid mrsa pcr testing using the xpert mrsa/sa blood culture pcr assay appears to improve mortality rates and is cost effective in the eu and us across a wide range of mrsa prevalence rates. background: rapid detection of gastro-intestinal carriage of glycopeptide-resistant enterococci (gre) from screening cultures is crucial for an efficient control of their spread. we assessed 4 media − 2 chromogenic, chromid, (biomérieux), and chromagar (chromagar microbiology), and 2 selective, vre selective (oxoid) and eccv (bd) − for their ability to detect gre using well-characterised isolates and stool samples from hospitalised patients at high risk of gre colonisation. methods: twenty-five isolates consisting of 13 gre. faecalis/faecium carrying various van genes and 12 non-vre at concentrations of 10 6 -10 1 cfu/ml and 10 6 cfu/ml, respectively, and 37 stool samples were randomised and spiral plated on all media and scored by 5 blinded investigators for characteristic colonies after 24 hrs incubation. standard confirmatory tests were done on 1 putative gre colony or on 1 characteristically coloured colony each for e. faecalis/faecium from the selective and chromogenic media, respectively. detection of van genes, and ddl or soda based speciation was done on pcr-sequencing. mean sensitivity (sen) and specificity (spec), and confidence intervals (cis) were estimated for each medium by a logistic regression model using a penalised likelihood approach based on the reader response for the stool samples and isolates, and additionally on confirmation test results for the stool samples, both at the aggregated (gre detected) and penalised level (correct species-colony colour correlation). results: chromagar showed the highest sen based on reader response at the aggregated and penalised level for both stool samples and isolates (table) . using confirmation test results at the aggregated level, sen for eccv was highest while the two chromogenic media showed a decrease in sen by at least 11% in comparison to the values obtained based on reader response. sens for the 2 chromogenic media were even lower (<70%) based on confirmation test results at the penalised level. eccv and chromid showed the highest specs with both reader response (stool samples) and confirmation test results at the aggregated level, and chromid also at the penalised level, with narrow cis indicating a high precision of this parameter estimate. for isolates, specs were highest for chromagar at both levels. conclusions: chromagar showed the best overall performance considering both sen and spec estimates. eccv performed well as a selective medium for gre detection from stool samples. objectives: metallo-beta-lactamases (mbls) expressed from pseudomonas are able to confer resistance to all beta-lactams with the exception of aztreonam. however, enterobacteriaceae possessing mbls exhibit moderate cephalosporin and low carbapenem mics and thus are often underestimated. herein, we describe data from new etest prototypes specifically designed to detect this problematic resistance mechanism. methods: 82 mbl-positive (vim or imp derivatives) enterobacteriaceae clinical isolates from 8 countries and 27 randomly selected enterobacteriaceae negative controls (including the atcc type strains) were tested against the 4 different etest mbl prototypes. beta-lactam substrates used were imipenem (ip), meropenem (mp), ceftazidime (tz) and cefotaxime (ct) with or without the inhibitors dipicolinic acid (dpa) and edta. the etest standard procedure for gram negative aerobes was used and a reduction of beta-lactam mic by equal to or greater than 3 dilutions by edta or dpa was interpreted as positive for mbl. presence of esbls was tested using the etest ct/ctl, tz/tzl and cefepime (pm)/pml strips. ampc production was detected using the etest cefoxitin (fx)/fxi and cefotetan (cn)/cni strips. of the 784 select specimens that were negative for gbs, 345 grew turquoise-blue colonies, but the majority that required further work to rule out gbs grew after 48 hours. two strains of gbs that were missed grew as white colonies on select, and even at 48 h, did not exhibit the characteristic turquoise-blue colour. conclusion: ssb enrichment followed by select subculture was extremely sensitive (99.2%) and superior to cna/ssb for detection of gbs from genital specimens. however, non-gbs organisms can produce turquoise-blue colonies on select and further work must be performed to rule out the presence of gbs. objectives: screening for chlamydia trachomatis (ct) specific antibodies is valuable in investigating recurrent cause of miscarriage, pelvic inflammatory disease and tubal damage following repeated episodes of pelvic inflammatory disease. immunofluorescence (if) is considered the gold standard for detection of ct antibodies. the present study aims to compare the performance of 4 other commercial tests for the detection of serum igg antibodies specific for ct: two ct igg pelisa both using major outer membrane protein (momp; ["momp-medac", ct-igg-pelisa; medac, wedel, germany and "momp-ruwag", ct pelisa; ruwag, bettlach, switzerland), one ct hsp-60 igg pelisa ("hsp60-medac", chsp60-igg-pelisa; medac, wedel, germany), and a new automated epifluorescence immunoassay ("inodiag", "must chlamydiae; inodiag, signes, france). methods: a total of 405 patients with (n = 251) and without (n = 154) miscarriages were tested by all 5 serological tests described above. sensitivity and specificity were calculated using if as gold standard. a second standard, defining true positive or negative samples as sera respectively positive and negative in all 4 others tests, was also used (see table) . objectives: participation in diagnostic microbiology internal and external quality control (qc) processes is good laboratory practice, an essential component of a quality management system and compulsory in some european countries. currently, there is no qc scheme for diagnostic oral microbiology. the aim of this study was to collate information on current qc needs, and processes undertaken in diagnostic oral microbiology laboratories. method: an on-line questionnaire was devised to ascertain interest in participating in an oral microbiology qc scheme and sent to oral microbiology diagnostic laboratories. the laboratories were identified from participants attending the european oral microbiology workshop in helsinki, 2008. following this, a pilot round of qc samples was distributed to all interested laboratories. results: we identified 12 individuals that worked in diagnostic oral microbiology laboratories and received 7 (58%) positive responses. of these 7 laboratories (representing 6 european countries) 71% did not participate in either internal or external qc. each laboratory processed on average a total of 4135 samples annually. 86% of participants were in favour of a european-wide oral microbiology qc scheme. the preferred frequency for receiving external qc specimen was once in 3−4 months. the most preferred specimen types were periodontal pocket and oral pus specimens (both 29%), followed by oral mucosal swabs and caries activity tests. all participating laboratories were willing to share and harmonise their specimen processing and interpretation standard operating procedures. the pilot round specimen was a periodontal pocket sample. six laboratories reported their findings in the specified time. the predominant pathogens (aggregatibacter actinomycetemcomitans, porphyromonas gingivalis) were identified by 5 of 6 laboratories. in addition to conventional culture, one laboratory used pcr. 5 laboratories performed antibacterial sensitivity testing primarily by disc diffusion. conclusions: this is the first attempt to a standardised europeanwide approach to diagnostic oral microbiology. the findings from this feasibility study have indicated that a qc scheme for oral microbiology is of interest and have raised a number a pointers for subsequent rounds of specimens. further work to improve the quality, to standardise the methodology and the interpretation of diagnostic oral microbiology at the european level is on-going. objectives: since severe sepsis with acute organ dysfunction can be fatal within hours, it is customary to start empirical broad-spectrum antimicrobial therapy in all patients hospitalised for a suspicion of systemic inflammatory response syndrome. however, increased use of broad-spectrum antimicrobials over the years has contributed to the emergence of drug resistant strains of bacteria. especially, drug resistance among gram-positive bacteria, the leading cause of sepsis, is now a serious problem. the objective of this preliminary study was to develop a method for distinguishing between gram− and gram+ bacterial infection. methods: in this prospective study, leukocyte and neutrophil counts, crp, esr, and quantitative flow cytometric analysis of neutrophil complement receptors 1 (cr1/cd35) and 3 (cr3/cd11b), were obtained from 289 hospitalised febrile patients, of which 89 had bacterial and 38 viral infection. the patient data were compared to 60 healthy controls. results: it was noticed that in gram− infection (n = 21) the average amount of cd11b on neutrophils was significantly higher than in gram+ infection (n = 22). on the contrary, serum crp level was significantly higher in gram+ than in gram− infection. other measured parameters did not differ significantly between gram+ and gram− infections. we derived a crp/cd11b ratio dividing the serum crp value by amount of cd11b on neutrophils. in thirteen (76%) out of 17 patients with gram+ sepsis had crp/cd11b ratio cutoff value of 3.1 (figure 1 ). of these 13 patients, 9 (70%) were diagnosed with streptococcus pneumoniae, 2 with staphylococcus aureus, 1 with enterococcus faecalis, and 1 with both streptococcus intermedius and streptococcus oralis. corresponding percentages in patients with local gram+ infection, gram− infection, clinical pneumonia, other clinical infection, and viral infection were 20%, 14%, 30%, 15%, and 0%, respectively. conclusion: the detection of gram+ sepsis is possible after combination of neutrophil cd11b data and serum crp level. crp/cd11b ratio viral infections of the central nervous system s61 displayed 76% sensitivity and 80% specificity for detection of gram+ sepsis. the proposed crp/cd11b ratio test could, for its part, assist physicians to decide appropriate antibiotic treatment in patients with severe bacterial infection. a bacterial biofilm is a structured consortium of bacteria cells surrounded by a self-produced polymer matrix. biofilms may be monospecies or polyspecies biofilms. biofilm growing bacteria give rise to chronic infections, which persist in spite of therapy and in spite of the host's immune-and inflammatory responses. biofilm infections are characterised by persisting pathology and immune response (in contrast to colonisation). bacterial biofilms use both biofilm specific (b) and conventional (planktonic) resistance mechanisms (p) when they are exposed to antibiotics. the following resistance mechanisms have been described in bacterial biofilms: 1. stationary phase physiology (b), low oxygen tension (b) and slow growth (b) especially inside biofilms whereas the surface of biofilms is more similar to planktonic growth. 2. penetration barriers (b), binding to the polymer matrix (b). 3. mutations, hypermutators (b, p). 4. chromosomal betalactamase is upregulated (b, p). 5. antibiotic tolerance/adaptive resistance (b). 6. efflux pumps (b, p). 7. alginate production (b). 8. high cell density and quorum sensing (b, p). 9. pbp 3 − sos response ? (b). the knowledge of these resistance mechanisms can, however, be used to design new therapeutica approaches especially as regards quorum sensing inhibitors. we consider two factors that contribute to treatment failure in the absence of inherited resistance, the density of the population being treated and the physiological state of the bacteria. we also explore how these factors might contribute to the evolution of inherited resistance during the course of treatment. we conclude with a computer-and chemostat-assisted consideration of the potential clinical implication of these density and physiology effects and make suggestions for treatment protocols to deal with them. using in vitro cultures of staphylococcus aureus atcc25923 or the clinical isolate ps80 and antibiotics of six different classes we determined the functional relationship between the inoculum density and the efficacy of the antibiotics. as measured by the rates and extent of kill and/or the minimum inhibitory concentration (mic), the efficacy of all of these antibiotics declined with increases in the density of bacteria, albeit to different extents. for daptomycin and vancomycin, much of this density effect can be attributed to bacteria-associated declines in the effective concentration of the antibiotic in the medium. for gentamicin, vancomycin, ciprofloxacin and oxacillin, our bioassays failed to reveal significant reductions in their effective concentration in the medium. the effects of the physiological state of s. aureus on the efficacy of these antibiotics were examined for bacteria from cultures in "stationary phase" for different times and from chemostats run at different generation times. these experiments are currently under way but by the time of the symposium we will have the full (and true) story. it is, however, clear that the efficacy of all of these antibiotics declines with the time in stationary phase (its "age"). and, even slowly dividing cultures from chemostats are more susceptible to antibiotic-mediated killing that early stationary phase batch cultures. the efficacy in killing non-growing bacteria varies among the bactericidal antibiotics examined. to ascertain the potential clinical implications of these density and physiological effects, we use both computer and in vitro simulations of antibiotic treatment. the results of these simulations provide compelling support for the proposition that antibiotic treatment regimes, including those designed to prevent the ascent of resistance, should take into account the anticipated density and physiological state of the target population of susceptible bacteria. there have been an increasing number of neurotrophic viral infections playing an important role in the world over the last decade. the list includes west nile virus, nipah and hendra virus (both paramyxoviruses), as well as chikungunya virus which suddenly emerged. furthermore, the relation between jc virus in progressive multifocal leukoencephalopathy (pml) in patients with multiple sclerosis treated with a new immunosuppressive drug, has triggered our attention. the development and implementation of molecular based amplification method has assisted us to detect these viruses more efficiently. these technologies have been used now routinely in a large number of laboratories to enable the detection of more commonly known neurotrophic viruses, like hsv, vzv and the neurotrophic picornaviruses like enterovirus and parechovirus. the pitfalls of these molecular methods have been generally solved by implementing regular quality control testing schemes, like organised by qcmd (quality control of molecular diagnostics) and the introduction of internal controls during the whole diagnostic process. finally, with the ability to quantify the amount of nucleic acid present in csf, more information on the pathogenesis of these viral infections, as well as significant tool to monitor the antiviral effect of treatment options for these viruses, has become available. to as a rare disease in europe restricted to some endemic foci. however, current data suggest that the incidence of ae has significantly increased, and the disease is spreading to the north, west, and east. ae has become an emerging disease in the baltic countries. thus, human infections with e. multilocularis have arrived in the "centre" of europe. ae is a lifethreatening disease, and is characterised by a tumour-like lesion in the liver. the larva can infiltrate the surrounding tissues and metastasize to distant organs. in an attempt to classify the large variety of anatomical findings in ae, the pnm-classification system was developed and serves as a benchmark for standardised evaluation of diagnostic and therapeutic measures. modern imaging techniques, such as ultrasound, ct or mri and pet/ct contributed not only to a much better description of the lesions, but also to a judgment upon the activity of the metacestode. the differential diagnosis of ae varies from haemangioma-like lesion of the liver or cancer. the diagnostic skills are limited, and are the reason for frequent misdiagnosis in geographic areas where ae is rather unknown. continuous treatment with benzimidazoles is the backbone of a lifelong management of ae. however, radical resection is the procedure of choice and should always be strived for. ae is still a rare disease in europe, but where it occurs, it is often diagnosed too late. patients are misdiagnosed for months and years, before receiving the correct treatment. at that late stage the disease has progressed, and radical cure of the liver lesion(s) is not anymore possible. recent reports provided hints for an accelerated larval growth of echinococcus spp. in the immunodeficient host. a careful monitoring of patients receiving immune-modifying drugs is warranted. the modern clinical management and long-term parasitostatic treatment with benzimidazoles are highly effective. thus, a higher alertness for the "tumours from the centre" would increase the prognosis of this hepatic disease resembling liver cancer. the percutaneous treatment of liver hydatid cysts were considered to be contraindicated due to two main potential risks: anaphylactic shock and abdominal dissemination of the disease. since the first case percutaneously treated was published, several series of successful percutaneous treatment of the liver and the other abdominal organs, peritoneum, thorax, soft tissue and orbital cavity hydatid cysts have appeared in the literature. percutaneous treatment of hydatid liver disease is an effective and safe procedure with its unique advantages (e.g., shorter hospital stay, low complication rate). today, the percutaneous approach has an important role in treatment of hydatid cysts not only in the liver but also in the other organs and tissue. therefore it must be first treatment option whenever it is indicated. in europe, dirofilaria immitis and dirofilaria repens are responsible of autochthonous filariases in dogs. adults of d. immitis kills the dogs with an heart location and d. repens is often found in subcutaneous nodules in dogs and cats. the microfilariae are present in the blood of these animals. dirofilariasis is due to the transmission of microfilariae by some mosquito bites (aedes, culex, anopheles, mansonia, psorophora and taeniorhynchus). usually non pathogenic to humans, these parasites are particularly present around the mediterranean basin. d. immitis is very rare in humans in europe, sometimes found in a pulmonary nodule and the heart location is not described. d. repens is more frequent and emerging in humans. usually, only one larva develops, producing an immature adult worm inside a subcutaneous nodule. ultrasound examination may suggest the parasitic origin of the lesion before an extraction and a parasitological diagnosis of the worm. more often, a fortuitous diagnosis is made on histological examination. very rarely, an adult worm may mature and produce systemic diffusion of microfilariae. dirofilariasis due to d. repens can present problems in diagnosis and treatment. an ocular and subconjunctival location of the worm and a subcutaneous nodule enclosing an immature adult are the commonest clinical forms. exceptional pulmonary locations are described. the subcutaneous locations described are: skull, cheek, breast, inguinal area, buttocks, arms and legs. cases of testicular location with painful symptoms have been observed. blood hypereosinophilia was exceptionally observed in human. it is treated surgically, by excision, without chemotherapy. while the majority of esbls, isolated in clinically-relevant gram negative bacteria (gnb) (mostly enterobacteriaceae, p. aeruginosa, a. baumannii) are tem-, shv-or ctx-m-types, a few others have been reported (sfo, bes, bel, tla, ges, bel, per, veb-types, and some oxa-esbls). laboratory detection of esbl-producers is important to avoid clinical failure due to inappropriate antimicrobial therapy and to prevent nosocomial outbreaks. selective culture media (macconkey and drigalski agar supplemented with cefotaxime and/or ceftazidime) have been proposed for detection of gnb resistant to expanded-spectrum cephalosporins (esc). media using chromogenic based substrates and selective antibiotics have been developed recently for the detection and presumptive identification of esbl-producing enterobacteriaceae directly from clinical specimens. detection of esbls based only on susceptibility testing is not easy due to the variety of b-lactamases and their variable expression of blactam resistance. commercially available esbl detection methods yield at most 90% accurate esbl identification, since some esbl-producers may appear susceptible to some escs. therefore, any organism showing reduced susceptibility to esc should be investigated using esbl confirmatory tests. these tests should be able to discriminate between esbl-producers and those with other mechanisms conferring esc resistance. these phenotypic tests (double-disk synergy test, esbl etest, and the combination disk method) are based on clavulanate inhibition and esc susceptibility testing. they often need slight changes by either reducing the distance between the disks of esc and clavulanate, the use of cefepime (not hydrolysed by ampcs), the use of cloxacillincontaining plates (that inhibits ampc), or by double inhibition by edta and clavulanate (masking metallo-enzymes). enzymatic tests have also been proposed for identification of esbl-producers. several pcr-based techniques (end-point or real time) have been developed on clinical samples or on colonies. several esbl genes have been detected using pcr coupled to either pyrosequencing, inverse hybridisation, to dhplc, or to fluorescent probes. these techniques even though more specific require technical knowledge, special equipment, are costly and detect only known genes, regardless of their expression. detection of esbl-producer remains a challenge for the microbiology laboratory and one shall be aware that esbl screening media are now available. resistance to antimicrobial agents has become common in many bacterial species, particularly those that cause human infections. the rapid detection of resistant organisms directly in clinical samples by real-time pcr coupled with molecular beacons, or of potentially resistant bacteria and yeast in blood culture bottles by peptide nucleic acid-fluorescence in situ hybridisation (pna-fish) is already having a positive impact on antimicrobial therapy. the direct detection of mycobacterium tuberculosis in sputum in approximately 2 hours with concomitant detection of mutations in rpob indicating rifampin resistance (as a surrogate for multidrug resistance) in the near future will likely improve the outcomes for tuberculosis patients in many developing and developed countries. several molecular technologies, including microarrays, bacterial tag encoded flx amplicon pyrosequencing (btefap), and ultra deep sequencing, have not yet transitioned to clinical laboratories but will likely provide even greater information about antimicrobial resistance not in just a single species, but in a whole community of microorganisms. complex wounds, like diabetic foot ulcers, containing multiple resistance genotypes are amenable to analysis by btefap. the implementation of these technologies in the clinical laboratory will be expensive but the potential to dramatically improve therapeutic outcomes especially for life-threatening diseases is unprecedented. objective: to determine the appropriateness of antimicrobial therapy (amt) in 11 dutch hospitals. method: data were obtained from a prevalence survey performed within the dutch surveillance network for nosocomial infections (prezies). amt administrated on the day of the survey was registered. antiviral and antifungal drugs, tuberculostatics, cements containing amt and prophylaxis administrated in the operation-theatre were excluded. the appropriateness of amt was assessed according to a standardised algorithm based on the local antimicrobial prescription guidelines. per patient a classification in appropriate use, inappropriate use and insufficient information was made. figure: relative risk of ia use of amt against largest hospital (hospital c). results: a total of 3,546 patients were included of which 1,075 (30%, range per centre (rpc): 23−37%) received amt. in the latter group, amt was considered appropriate in 70% (rpc: 57−84%), inappropriate in 17% (rpc: 3−32%) and was not judged because of insufficient information in 13% (rpc: 1−30%). there was considerable variation in inappropriate use among the participating centres (figure). in univariate analysis older age, the use of quinolones, being on the urology ward and presence of a suprapubical catheter were associated significantly with inappropriate use. admission on the icu and presence of an intravascular catheter were associated significantly with appropriate use. in a multivariate analyses the presence of suprapubical catheter, being on the urology ward and the use of quinolones were determinants for inappropriate use. this study showed large differences in overall use and appropriateness of use of amt between hospitals. based on these results it is possible to define targets for intervention to improve the prudent use of amt. the high fraction of patients with insufficient information in several centres may have influenced the analyses and should be addressed in future studies. m. struelens°, s. metz-gercek, r. mechtler, f. buyle, a. lechner, h. mittermayer, f. allerberger, w. kern objectives: the eu-project antibiotic strategy international (abs) qi team developed process qis for auditing the performance of key treatment and prophylactic practices. an international network of pilot hospitals tested these tools for feasibility, reliability and sensitivity to improvement. methods: qis included: 1. surgical prophylaxis (indication, drug choice, timing and duration of administration); 2. management of community-acquired pneumonia (cap) (blood culture and legionella antigen tests and drug choice for empirical treatment); 3. management of s. aureus bacteraemia (echocardiography, iv catheter removal and duration of therapy); and 4. iv-po switch for bio-available antibiotics. a minimum of 40 consecutive cases per centre and qi were retrospectively reviewed from clinical, laboratory and administrative records and assessed for data availability, inter-observer reliability, data collection workload and performance score. results: a total of 1240 patients were evaluated in 11 acute care hospitals from 5 countries, with a range of 80 to 500 cases and 2 to 9 centres per indicator. seven centres had already implemented antibiotic quality improvement and audit programmes. availability of data was >85% of cases and ranged between 87% (catheter removal in s. aureus bacteraemia) and 100% (diagnostic tests for cap). 13/14 indicators were found to be reliable with kappa 0.60 (good to excellent agreement). the workload per case ranged from a median time of 16 (cap) to 35 min (iv-po switch). the intention to treat qi scores showed high levels of adherence to the surgical prophylaxis qi bundle, with median values of 81 to 97% for hip prosthesis and 65 to 92% for colo-rectal surgery. for cap management, diagnostic testing appeared sub-optimal (<56% compliance with idsa guidelines). for s. aureus bacteraemia management, indicator results ranged from 60 to 65%. for use of bio available antibiotics, a median of 45% iv administrations were avoidable. there were marked differences of scores between centres for all qis. conclusions: the abs qis are reliable and broadly applicable tools for auditing antibiotic treatment and prophylactic practices. inter-hospital variation in adherence to recommended practice indicates substantial potential for improvement with different local priorities. these qis can be recommended for assessing the effect of quality of care interventions at either local or multi-centre level. d.j. noimark°, e. charani, s. smith, b. cooper, i. balakrishnan, s.p. stone (london, uk) introduction: reduction of clostridium difficile infection (cdi), which often follows use of third generation cephalosporins, is a national priority. over a three year period, antibiotic policies were reviewed and changed in an elderly medicine department according to local sensitivities of common pathogens and levels of cdi. a laminated pocket-sized card describing antibiotic policies was given to all doctors in the department on induction with instructions not to depart from these without microbiologists' approval. this prospective controlled interrupted time series examines whether this intervention increased compliance with antibiotic policy and decreased cdi incidence. methods: the department's "narrow-spectrum, no cephalosporin" antibiotic policy was changed on 1st august 2006 to replace trimethoprim with cephradine (1st generation cephalopsporin) as empiric treatment for urinary tract infection, reflecting local escheriscia coli sensitivities. in october 2007, all cephalosporins and quinolones were removed from the policy as cdi levels had increased. notional 7 day antibiotic usage was calculated from prospective pharmacy generated data with aspirin, calcium, bisphosphonate & laxative prescription use as a non-antibiotic control, and analysed by segmented regression with a robust variance estimator. cdi rates were prospectively collected separately & analysed by a poisson regression model. results: an immediate response to change in antibiotic guidelines was observed (figure) . from august 06-sep 07 there was a highly significant increase in cephalosporins (85-100% of which was cephradine alone) (p < 0.001), a significant fall in trimethoprim (p < 0.004) and a significant increasing trend in cdi ( no tools existed to assess the readiness of public hospitals to receive this technology, and therefore guide resource allocation to facilitate implementation. aim: to assess the readiness of victorian public hospitals to introduce electronic antimicrobial stewardship. method: literature on readiness for change, organisational culture and information technology acceptance were reviewed. group interviews with project teams at site initiation meetings, one on one interviews with project officers at subsequent meetings, and observation where appropriate were all used to determine potential barriers and enablers. this information was recorded using a 'readiness assessment tool' and analysed to identify a number of key domains. to triangulate the data, questionnaires were distributed to project officers asking them to assess their sites' readiness to implement the system. results: a novel 'readiness assessment tool' was developed. it covered the domains of technical readiness, skills readiness, process readiness, administrative support readiness, resource readiness and hospital organisational characteristics. assessments at several hospitals highlighted a variety of issues at different sites and allowed early efforts to address these. a formative readiness assessment can be used to identify systematic problems that might facilitate or hinder uptake of electronic antimicrobial stewardship and to inform the adopters of potential resources required. [1] buising, k, thursky, k, robertson, m, black, j, street, a, richards, m & brown, g (2008) . electronic antibiotic stewardship-reduced consumption of broad-spectrum antibiotics using a computerised antimicrobial approval system in a hospital setting. j antimicrob chemother. w.v. kern°, m. steib-bauert, a. pritzkow, g. peyerl-hoffmann, h. von baum, u. frank, m. dettenkofer, c. schneider, k. de with, h. bertz (freiburg, ulm, de) objectives: fluoroquinolone prophylaxis (fqpx) may reduce morbidity and mortality in cancer patients (pts) with neutropenia, but the development of fluoroquinolone resistance (fqr) in escherichia coli and other target organisms limits its usefulness. we evaluated changes in the incidence density of gram-negative bloodstream infection (gnb) and in the in vitro fqr rates after the introduction of fqpx (with levofloxacin) as a standard of care for pts with high risk neutropenia in a university hospital. methods: we collected individual data for 357 pts admitted during baseline and during the first months following the intervention to assess clinical outcomes. individual pt data were compared with aggregate data (3-month periods). aggregate data analysis (unit-wide antibiotic consumption, gnb and numbers of in vitro fqr bloodstream isolates) was continued for a total of eight 3-month periods for both the haematology-oncology service and for general internal medicine. the new policy was introduced in the second half of the year 2005 when unit-wide baseline fqr of e. coli and of coagulase-negative staphylococcal (cons) bloodstream isolates had been 15% and 80% in the haematology-oncology unit, and 8% and 60% in general internal medicine, respectively. the individual pt data analysis revealed that pts not given fqpx had a much higher incidence of gnb than those given fqpx ( -2007) . the monthly use of iv and oral quin was calculated based on data from the pharmacy department. statistical analyses were performed using segmented linear regression analysis. bayesian model averaging was used to account for model uncertainty. results: before the interventions the use of quin (both iv and total) was stable. the best fitting models indicated that the first intervention was associated with a stepwise reduction in iv use of 71 prescribed daily doses (pdd) (95% ci: 47, 95 (p < 0.001)). there was also an indication of smaller reduction in iv use associated with intervention 4, but only the intervention 1 effect was robust to model uncertainty. the overall use of quin was also significantly reduced (figure) with a large stepwise reduction of 107 pdd (95% ci: 58, 156) associated with intervention 2. this study showed that the hospital-wide use of quin can be significantly improved (and decreased) by an active policy consisting of multiple interventions. marwick°, j. broomhall, c. mccowan, s. gonzalez-mcquire, k. akhras, s. merchant, p. davey (dundee, high wycombe, uk; raritan, us) aim and objectives: to describe the antibiotic treatment and outcomes stratified by severity in a representative sample of adult patients aged 18 or older who were treated in hospital for skin and soft tissue infections. inadequate. we also judged that 43% of patients received unnecessarily broad spectrum therapy. conclusions: ssti is common and is associated with significant mortality. however, choice of empirical therapy is not evidence based, with significant under treatment of high risk patients. ab were mostly (16/17) prescribed by gps and delivered by public (n = 14) or hospital pharmacies (n = 3). surveillance of ab use in nhs was organised in only 4 ms. in 3 countries a nh specific pharmaceutical formulary was available. prescription profiles by prescriber were available in 5 countries. other quality improvement initiatives in nhs such as regular training of prescribers, promoting microbiological sampling, collection of antimicrobial resistance profiles or pharmacist advice on ab prescription were scarce. guidelines for ab treatment of most frequent infections were available in many countries but were focussing on ambulatory care and did not consider the specific nh situation. only in 1 country the presence of an infection control practitioner was compulsory and partnership with hospital infection control teams was legally imposed in 3 ms. conclusion: important structural, functional and regulatory nh differences exist between eu countries. specific tools to improve infection prevention and ab therapy in nhs should take into account these differences. a european nh network was created in the framework of the esac nh subproject, which will organise point prevalence surveys on ab use in 2009. c. escherichia coli in south-western finland j. jalava°, o. meurman, h. marttila, a. hakanen, m. lindgren, k. rantakokko-jalava (turku, fi) objectives: extended-spectrum betalactamases (esbls), especially enzymes of the ctx-m group, are spreading rapidly in europe. enterobacteriaceae with reduced susceptibility to third generation cephalosporins and a positive esbl confirmatory test are also increasing in southwest finland. the purpose of this work was to study the resistance genetics of these esbl-positive enterobacteriaceae. methods: the study comprises a total of 271 clinical enterobacteriaceae strains isolated from both inpatient and outpatient specimens. all enterobacteriaceae strains that were esbl confirmatory test positive between january 2004 and december 2008 were included in this study (263 escherichia coli, 8 klebsiella pneumoniae, one isolate per patient). of these strains, 225 (83%) were urine isolates. resistance determinations were done using disk diffusion method (clsi) or vitek 2 and esbl confirmations by the double disk method using cefotaxime and ceftatzidime with and without clavulanate. thus far, 219 strains (those collected by end of june 2008) have been analysed for the presence of the most important esbl genes (tem, shv and ctx-m) using pcr and pyrosequencing as described before (haanpera et al. aac, 52:2632; 2008) . results: in 2004 only 10 esbl-positive strains were found. all of them harboured a ctx-m type esbl gene. since then, the number esblproducing enterobacteriaceae strains has increased significantly being tenfold in 2008 compared to year 2004 (figure) . a high majority, 197 (90%) of the 219 strains analysed thus far had a ctx-m-type esbl gene. most of those (79%) belonged to the ctx-m-1 group according to the pyrosequencing results. ctx-m-9 group was the next common, with 20% of the ctx-m genes belonging to this group. only two strains with ctx-m group 2 enzyme were found. conclusions: enterobacteriaceae strains which produce esbl are increasing rapidly in southwest finland. this is especially true with e. coli strains isolated from urine. towards the end of the study period, the esbl enzymes were almost exclusively ctx-m, ctx-m-1 group being the most common. further research is needed to characterise genetic elements that carry these esbl genes. esbl strains and the proportion of ctx-m genes in 2004-2008. (2000) (2001) (2002) (2003) (2004) (2005) (2006) in france (n = 6), spain (n = 4), portugal (n = 6), uk (n = 11), kuwait (n = 2), canada (n = 13) and china (n = 10), including hong kong (n = 3) were studied. clonality was established by pfge and phylogenetic groups of ec and kp were determined as reported. susceptibility testing (clsi), blactx-m-14 transferability and location (i-ceu-i/s1 nuclease) were investigated. plasmid analysis included determination of inc group (pcr-replicon typing, hybridisation, sequencing) and comparison of rflp patterns. association of blactx-m-14 with isecp1, isecp1-is10 or iscr1 was established by pcr and sequencing. we identified 42 pfge types among 52 isolates: 38/47 ec, 3/4 kp and 1/1 cf. distribution among phylogroups were as follows: i) ec: a (n = 7), b1 (n = 3), b2 (n = 5) and d (n = 23), and ii) kp: kpi (n = 2) and kpii (n = 1). resistance to tetracycline (76%), nalidixic (74%), streptomycin (67%), sulfonamides (67%), ciprofloxacin (60%) and trimetroprim (43%) was common. were spreading horizontally in our hospitals and, here, we characterised the plasmids responsible in the major k. pneumoniae strains identified during the survey. methods: plasmids from representative k. pneumoniae strains with ctx-m-15 enzyme were extracted by alkaline lysis and compared by apai, psti and ecori restriction analysis. they were transferred into e. coli dh5a by electroporation. transformants were selected on cefotaxime-containing agar and were screened by pcr for beta-lactamase genes, the aminoglycoside resistance genes aac(6 )-ib and aac3-iib, and the plasmid-mediated quinolone resistance genes qnra/b/s. results: twelve isolates were characterised, representing 5 major strains (a-d, and f) found in the most-affected hospitals. restriction analysis divided their plasmids into several groups. representatives of strain a (n = 4) had essentially the same plasmid (group 1), as did the two representatives of strain d (group 2a). one strain f isolate had a plasmid (group 2b) very similar to plasmid 2a from strain d, indicating possible horizontal transfer. plasmids of group 3 were retrieved from representatives of strains b and c, again indicating probable transfer. plasmids from three other strains differed substantially from each other and from plasmids 1, 2a, 2b and 3. nevertheless, on all plasmids, blactx-m genes were linked to an upstream isecp1 element, known to be involved in their mobilisation. all encoded multi-resistance: all but one group 1 and one ungrouped plasmid carried aac(6 )-ib; blaoxa-1 and aac(3)-iia were detected on all except group 1 plasmids; blatem was found on group 1, 2b, one group 3 and two ungrouped plasmids. blashv and qnra/b/s genes were not detected. the considerable diversity of plasmids encoding ctx-m-15 enzyme in major slovenian k. pneumoniae strains suggested only limited transfer, even when multiple strains were present in the same hospital. evidence of plasmid transfer was between strains b and c, and possibly between strains d and f, although these plasmids were not strictly identical. analysis of resistance genes encoded by the plasmids revealed diversity, with groupings coinciding largely with those based on restriction profiles. a. ingold, g. borthagaray, a.k. merkier, d. centrón, h. bello, c.m. márquez°(montevideo, uy; buenos aires, ar; concepción, cl) objectives: to examine the genetic context of class 1 integron harbouring blactx-m-2 in fifteen nosocomial k. pneumoniae isolates from south america in order to enhance the understanding of the antibiotic resistance spread among the region. methods: dna was extracted with the use of axypreptm bacterial genomic dna miniprep kit. the analysis of the cassette array was carried out with the use of primers hs458/hs459 targeting adjacent conserved regions. the examination of the surroundings were performed using two pcr primer pairs, hs817/hs818 and hs825/hs826, to amplify the initial(iri) and the terminal(irt), inverted repeat boundary, respectively. the primer pair hs825/hs911 was used whenever a negative result was obtained with hs825/hs826. all pcr products were purified and sequenced and the data was analyzed with ncbi blast tool. the sequence obtained with primers hs817/hs818 revealed the presence of three different transposons backbones at the iri end. the tn5036-like module and the tn21-like module were present in 4 isolates, the tn1696-like module was present in 7 isolates. no amplicons were obtained with the use of primers hs825/hs826 that amplify a tn21-like insertion. two uruguayan isolates with a tn5036 boundary at the iri end were tested with hs825/hs911 that target a tn5036-like backbone and one generated a product consistent with a tn5036-like mer region. uruguayan isolates carried a single aada1 cassette (4/5) and the other one contained a dfra17-aada5 array, while the four argentinian isolates carried the combination aaca4-aada1-orfd. chilean isolates arrays are in process. conclusions: among the extended-spectrum beta-lactamases, the cefotaximases constitute a rapidly growing cluster of enzymes that have disseminated geographically. there is a high frequency of isolation of ctx-m-2 producing k. pneumoniae associated with a class 1 integron in the region. despite being common the presence of iscr1 linked to blactx-m-2 in k. pneumoniae isolates, this study provides new and relevant information in the sequence context at the iri. here we report about the cassette array diversity and the diversity of elements in which the class 1 integron are embedded. different integron/transposons carrying the blactx-m-2 gene seem to be circulating and different regional patterns could be emerging, this study highlights the ability of different genetic elements to act cooperatively to spread and rearrange antibiotic resistance. l. vinué, a. garcía-fernández, d. fortini, p. poeta, m.a. moreno, c. torres, a. carattoli°(logroño, es; rome, it; vila real, pt; madrid, es) objectives: ctx-m enzymes are frequently detected in europe. in particular, ctx-m-1 and ctx-m-32-producing strains have been recovered from both humans and farm animals in spain, italy, greece, and portugal, suggesting the existence of community reservoirs for these enzymes. the aim of this study was to compare escherichia coli strains and plasmids harbouring blactx-m-1 and blactx-m-32 genes isolated from human and animals. methods: four e. coli ctx-m-1 and eight ctx-m-32 epidemiologically unrelated producers from sick or healthy animals (pig, dog, cow and chickens) and from humans (urine, blood and faecal samples) were analysed by xbai-pfge, plasmid transferability, pcr-based replicon typing, plasmid restriction analysis and southern blot hybridisation. all isolates were from spain but the dog isolate was from portugal. the genetic context of the blactx-m genes was previously investigated for all the strains. results: three ctx-m-32 strains (one from healthy chicken and two from hospitalised patients) showed the same pfge pattern. a chromosomal localisation of the blactx-m-32 gene was suspected in these strains. the five remaining ctx-m-32 producers showed the blactx-m-32 gene on plasmids belonging to the incn (4 strains) or untypable groups (1 strain). two incn plasmids showed identical pvuiirestriction patterns: one was identified in a strain from a healthy chicken and one was from a hospitalised human patient; these two strains were isolated in 2002 and 2004, respectively and showed different pfge patterns. ctx-m-1 producers (three from animal strains and one a healthy human) did not show clonality by pfge and the blactx-m-1 gene was always located on plasmids, three belonging to the incn and one to the inci1 groups. two of the incn plasmids carrying the blactx-m-1 gene showed highly related restriction patterns: one was from a healthy dog and one from a healthy human. conclusion: this study demonstrated the presence of clonal e. coli ctx-m-32 producers in animal and human sources and also detected epidemic incn plasmids disseminating among unrelated isolates from humans and animals, clearly suggesting a potential animal reservoir for the blactx-m-1/32 genes. o309 characterisation of bladim-1, a novel integron-located metallo-beta-lactamase gene from a pseudomonas stutzeri clinical isolate in the netherlands l. poirel°, j. rodriguez-martinez, n. al naiemi, y. debets-ossenkopp, p. nordmann (k.-bicetre, fr; amsterdam, nl) objectives: characterisation of the mechanism involved in the uncommon resistance to carbapenems observed from a pseudomonas stutzeri isolate recovered from a patient hospitalised in the netherlands with a chronic tibia osteomyelitis. that strain was resistant to ticarcillin, piperacillin-tazobactam, imipenem and meropenem, of intermediate susceptibility to ceftazidime and cefepime, and susceptible to aztreonam. methods: screening for metallo-beta-lactamase (mbl) production was performed using the e-test method with a strip combining imipenem and edta. shotgun cloning was performed with xbai-digested dna of p. stutzeri and pbk-cmv cloning vector. selection was performed on amoxicillin and kanamycin-containing plates. results: e. coli top10 (pdim-1) recombinant strains were obtained, displaying resistance to penicillins and ceftazidime, reduced susceptibility to cefepime, imipenem and meropenem, and full susceptibility to aztreonam. sequence analysis identified a novel ambler class b betalactamase dim-1 for "dutch imipenemase" (pi 6.1) weakly related to all other mbls. dim-1 shared 52% amino acid identity with the most closely related mbl gim-1, and 45 and 30% identity with the imp and vim subgroups, respectively. dim-1 hydrolyzes very efficiently imipenem and meropenem, expanded-spectrum cephalosporins, but spares aztreonam. the bladim-1 gene was as a form of a gene cassette located at the first position in a class 1 integron, but the 59be of that gene cassette was truncated giving rise to a fusion with an aadb gene cassette encoding an aminoglycoside adenylyltransferase. the third and last gene cassette corresponded to the qach cassette encoding resistance to disinfectants. conclusion: a novel mbl gene was identified in p. stutzeri further underlining (i) the diversity of acquired mbl genes, especially among non-fermenters, (ii) that pseudomonas sp. may be a reservoir of these genes and (iii) the possibility of spread of important resistance determinants in northern part of europe. isolates in greece p. giakkoupi, o. pappa, m. polemis, a. bakosi, a. vatopoulos°( athens, gr) objectives: metallo-beta-lactamases of the vim family are the main mechanism of carbapenem resistance in p. aeruginosa in greece. in this preliminary report we attempted to survey the subtypes of vim betalactamase currently prevailing in p. aeruginosa clinical isolates in greek hospitals, the genetic relatedness of the respective isolates, as well as the genetic environment of the blavim gene. methods: fifteen mbl producing and epidemiologically unrelated p. aeruginosa clinical isolates were collected in september 2006 from fifteen different hospitals around greece. mbl production was initially identified by an edta synergy test. identification of blavim gene, as well as mapping of the blavim cassette carrying integrons were performed by pcr and sequencing of the products. the o serotypes of the isolates were determined by a slide agglutination test using p. aeruginosa antisera (biorad). molecular typing was performed by pulse-field gel electrophoresis of spei-restricted genomic dna. results: blavim-2 gene was detected in nine isolates, blavim-4 in five and blavim-1 in only one isolate. the blavim-2 cassette of all nine isolates was located on the 1600 bp variable region of a class i integron, preceded by aaca29 gene cassette. blavim-4 cassette of all five isolates was the first cassette of the 3200 bp variable region of a class i integron, followed by the aaca4 and blapse-1 gene cassettes. blavim-1 was the unique cassette of a class i integron. vim-2 producers belonged to o8, o11 and o12 serotypes, whereas four isolates were non-typeable. vim-4 producers belonged to the same three serotypes, whereas only one was non-typeable. the vim-1 producer belonged to o12 serotype. the nine vim-2 producing p. aeruginosa isolates revealed a great degree of variability in pfge molecular typing, belonging to seven types. contrary, the five vim-4 producing p. aeruginosa isolates displayed higher genetic similarity and fell into one major type with 85% homology, which also included the vim-1 producing isolate. there was no correlation between the results of serotyping and molecular typing. conclusions: mbl production in p. aeruginosa in greece seems to be mainly due to specific class i integrons harbouring either blavim-2 or blavim-4 genes. genetic variability was higher among bacteria carrying vim-2 beta-lactamase, a fact indicating wider intraclonar spread of the respective integron. j.m. rodriguez-martinez, l. poirel°, p. nordmann (k.-bicetre, fr) objectives: extended-spectrum beta-lactamases of ampc-type (esacs) contributing to reduced susceptibility to imipenem have been recently reported from enterobacteriaceae. the aim of the study was to evaluate the putative role of natural ampc-type beta-lactamases of p. aeruginosa in a similar resistance profile. methods: thirty-two non-repetitive p. aeruginosa clinical isolates recovered in our hospital in 2007 were included. they were selected on the basis of criteria of intermediate susceptibility or resistance to ceftazidime and intermediate susceptibility or resistance to imipenem. mics were determined by agar dilution and e-test techniques. the level of expression of the ampc beta-lactamases was evaluated by measuring specific activities. pcr, sequencing, and cloning allowed to characterise the different bla(ampc) genes. identified esacs were purified and their km and kcat values for beta-lactams determined by spectrophotometry. results: using cloxacillin-containing (an ampc beta-lactamase inhibitor) plates, the susceptibility to ceftazidime was restored for 25 out of 32 isolates, suggesting overproduction of the ampc. in addition, in presence of cloxacillin, reduced mic values were also observed with ceftazidime, cefepime and imipenem for 21 out of those 25 isolates. cloning and sequencing identified 10 distinct ampc b-lactamase variants among the 32 isolates. recombinant plasmids expressing the ampcs were transformed into reference p. aeruginosa strain and reduced susceptibility to cefepime and imipenem was observed only with recombinant p. aeruginosa strains expressing ampc beta-lactamases that had an arginine residue at position 105. the catalytic efficiencies (kcat/km) of the ampc variants possessing this arginine residue were increased against oxyiminocephalosporins and imipenem. in addition, in-vitro assays demonstrated that those ampc variants constituted a favourable background for selection of additional degree of carbapenem resistance. conclusions: some ampcs of p. aeruginosa possessing extended activity torward carbapenems may contribute to carbapenem resistance. background: most oxa-type esbls are oxa-10, oxa-2 or oxa-1 derivatives. they display a very low homology, the percentage of which is between 20% and 30%. oxa-type esbls are divided into five groups according to the different homology by frederic bert, etc. group 1 includes oxa-5, oxa-7, oxa-10 and its derivants;group 2 includes oxa-2, oxa-3, oxa-15 and oxa-20;group 3 includes oxa-1, oxa-4, oxa-30 and oxa-31; group 4 is named after oxa-9; group 5 only includes a single enzyme called lcr-1. oxa-type esbls has been reported widespread in the world since the first report in 1987, such as turkey, france, england and so on. but there is few report about it in china. objective: to investigate the prevalence and genotype distribution of oxa-type extended-spectrum beta-lactamases (esbls) in clinical pseudomonas aeruginosa strains isolated from xiangya hospital of central south university in changsha city, hunan province, china. methods: ninety-seven non-repetitive clinical isolates of p. aeruginosa were collected between october 2006 and january 2007 from the hospital. they were screened for oxa-type esbls production by polymerase chain reaction pcr with five pairs of primes specific for blaoxa genes, respectively. then amplification of oxa-type esbls production was performed by pcr with specific primers. the purified and amplified products were sequenced to confirm the genotype of the oxa-type esbls. results: the sequences of the three oxa-type esbls pcr products were then compared in genbank database and there were no the completely same ribonucleotide and amino acid sequence with them. they were two novel oxa-type esbls, named as blaoxa-128 and blaoxa-129, which have been registered in genbank database under accession numbers eu573214 and eu573215, respectively. conclusions: there have occurred infections caused by p. aeruginosa producing oxa-type esbls in xiangya hospital of central south university. two novel oxa-type esbls in p. aeruginosa strains have been discovered in our study, which are named blaoxa-128 and blaoxa-129, respectively. pneumonia is one of the most common nosocomial infections and is associated with high mortality. in the last 15 years, gram-positive bacterial pathogens have risen in prevalence as a cause of hospitalacquired pneumonia (hap), including that occurring during mechanical ventilation (ventilator-associated pneumonia; vap). in particular, staphylococcus aureus is a major cause of hap, including vap. the rise of multidrug-resistant infections is a source of concern, with methicillinresistant s. aureus (mrsa) accounting for >40% of s. aureus isolates in some european hospitals. this symposium will take the format of a question-and-answer roundtable session in which experts will answer questions and initiate discussion surrounding emerging concerns and appropriate therapeutic strategies in nosocomial pneumonia, including that caused by multidrug-resistant gram-positive pathogens. recently, shifts in the susceptibility of s. aureus to established therapeutic agents for nosocomial pneumonia have added to the challenge of selecting appropriate empiric therapy. in patients with suspected multidrug-resistant infections or those who are mechanically ventilated, prompt initiation of therapy, often before the pathogen has been confirmed, is critical. vancomycin is the gold-standard treatment for multidrug-resistant infections and resistance has been remarkably slow to emerge. however, clinical reports in europe of 'mic creep' and the emergence of vancomycin-intermediate s. aureus (visa), hvisa and linezolid-resistant mrsa have presented new clinical dilemmas. elevated vancomycin mics are linked to treatment failure and increased mortality. hence, while vancomycin remains a useful therapeutic tool, treatment decisions present an increasing challenge, especially in groups of patients in whom rapid eradication of infection with appropriate agents is critical. telavancin is a novel lipoglycopeptide under investigation for treatment of nosocomial pneumonia. a number of key features suggest telavancin as a potentially attractive option for nosocomial pneumonia. telavancin has a unique dual mechanism of action that disrupts both bacterial cell wall biosynthesis and cell membrane integrity. the agent is rapidly bactericidal against a broad range of clinically relevant grampositive bacteria, including mrsa. two pivotal phase iii studies have demonstrated telavancin efficacy equivalent to vancomycin in hap, including vap, including in seriously ill patient subgroups and in that caused by mrsa. hantaviruses are enveloped rna viruses, each carried primarily by rodents or insectivores of specific host species. they have coevolved with the hosts in which they cause almost asymptomatic and persistent infections. in humans some hantaviruses cause disease: haemorrhagic fever with renal syndrome (hfrs) in eurasia. in europe puumala (puuv) from bank voles and saaremaa (saav) from field mice cause mild hfrs and dobrava (dobv) from yellow-necked mice severe hfrs. in asia hfrs is caused mainly by hantaan and seoul viruses. in americas some viruses cause hantavirus cardiopulmonary syndrome: sin nombre, andes and other viruses carried by sigmodontine rodents, not found in eurasia. in addition, in europe the common vole carries tula and rats seoul virus. however, they have not been definitely associated with disease in europe, although both can infect humans. we discuss the epidemiology, molecular genetics, detection of infection in carrier hosts and humans (including rt-pcr and 5-min serological tests), functions of hantaviral proteins, risk factors for humans to catch hantavirus infection (including smoking) and disease (including risk and protective hla haplotypes), role and mapping of epitopes of cytotoxic t-cells, mechanisms of hantavirus-induced apoptosis, newly discovered clinical features (including hypophyseal haemorrhages in puuv infection), and long-term consequences and pathogenesis of hfrs (endothelial permeability, thrombocytopenia, tnf-alpha and il-6). puuv occurs widely in europe except in the far north and mediterranean regions, saav in northern, eastern and central europe and dobv mainly in the balkans. the epidemiological patterns differ: in western and central europe hfrs epidemics follow mast years with increased oak and beech seed production promoting rodent breeding. in the north, hantavirus infections and hfrs epidemics occur in 3−4 year cycles, driven by prey-predator interactions. the infections and hfrs are on the increase in europe, partly because of better diagnostics and partly perhaps due to environmental changes. in several european countries hantavirus infections are notifiable and in some countries (e.g. belgium, finland, france, germany, scandinavian countries, slovenia) their epidemiology is relatively well studied. in large areas of europe, however, hantavirus infections and hfrs have not been studied systematically and they are still heavily under-diagnosed. mrsa screening − will we ever agree? s330 mrsa: universal screening! the successful control of any outbreak or epidemic relies on detection of those harbouring the pathogen (infected and colonised persons) combined with eliminating spread to new individuals. the approach to containment and reduction of the global mrsa pandemic is now being discussed. a challenge for this infection is that most persons harbouring mrsa do not exhibit signs of disease and thus in order to detect all potential spreaders of this organism some surveillance must be done. the required level of detection (surveillance through screening) is not known and likely varies with the prevalence of colonisation and disease. for a given mrsa prevalence, the factor that seems most crucial in reducing spread is the percentage of potential isolation days captured. the operational processes that highly influence this are 1) the sensitivity of screening detection (including sites tested and laboratory methods used), 2) the speed at which results of newly detected positive patients are reported from the laboratory (assuming pre-emptive isolation is not employed), and 3) the selection of patient populations who are to undergo screening. laboratory testing has a major impact on detecting mrsa colonised patients with real-time pcr having a sensitivity of 98% and a possible 2 hour reporting time compared to direct chromogenic agar cultures with a sensitivity of 80% and >24 hour reporting and enriched chromogenic agar testing with a sensitivity of 90% and >48 hour reporting (am j clin pathol, 2009); both reduced sensitivity and prolonged reporting time negatively impacting the success of mrsa timely isolation. we have shown that capturing 33% of mrsa isolation days in a modest mrsa prevalence setting (9 infections/10,000 patient days) with a high sensitivity test having a >24 hour result reporting time did not reduce hospital-wide mrsa disease (ann int med 148:209, 2008) . others have demonstrated that surveillance in an icu with similar mrsa prevalence, again with a high sensitivity test having 1 day result reporting, did not reduce icu disease until preemptive isolation was initiated (crit care 10: r25, 2006) . finally, we demonstrated that universal admission surveillance and decolonisation capturing 85% of possible mrsa isolation days had a dramatic impact by reducing 70% of all in-hospital infections from mrsa. future research in this area should focus on better defining those patients that benefit from mrsa screening and the role of decolonisation in these programs. clostridium difficile infection (cdi) is a toxin-mediated intestinal disease and extraintestinal manifestations are exceptional. clinical outcomes can range from asymptomatic colonisation to mild diarrhoea and more severe disease characterised by inflammatory lesions and pseudomembranes in the colon, toxic megacolon or bowel perforation, sepsis, shock, and death. the main clinical symptoms, secretory diarrhoea and inflammation of colonic mucosa, can be in great part explained by the actions of two large protein toxins, toxin a (tcda) and toxin b (tcdb). both toxins are cytotoxic, destroy the intestinal epithelium and decrease colonic barrier function by disruption of the actin cytoskeleton and tight junctions resulting in a decreased transepithelial resistance allowing fluid accumulation. in addition, c. difficile toxins also cause release of various inflammatory mediators which affect enteric nerves, sensory neurons and promote inflammatory cells, adding to the fluid secretion, inflammation and transmigration of neutrophils. some experimental evidence points also to possible extraintestinal action of c. difficile toxin b. in zebrafish embryos tcdb caused damage and edema in cardiac tissue and in hamsters the same toxin caused lung damage. only recently efficient systems have been developed to genetically manipulate c. difficile. comparison of knock-out mutants producing only one of both toxins have shown that tcdb-positive-only mutants retain the ability to kill hamsters, whereas tcda-positive-only mutants were not virulent for hamsters. these results are in concordance with epidemiological findings that naturally occurring a-b+ strains still cause the entire spectrum of cdi, but are not in concordance with effects observed after intragastric challenge of hamsters with purified toxins tcda and tcdb. the role of the third toxin produced by c. difficile, binary toxin cdt in the development of human disease is not well understood. cdt was shown to have enterotoxic effect in rabbit ileal loop assay, but natural strains producing cdt but neither tcda nor tcdb colonised animals but were not lethal in hamsters. comparative genomic analysis will most likely reveal additional factors involved in pathogenesis and in increased virulence (including cell surface layer proteins, sporulation characteristics and antibiotic resistance). additionally, the role of the host immune response in cdi has just started to be better understood. since 2002, there has been an escalation in rates of clostridium difficile infection (cdi) with epidemic c. difficile (pcr ribotype 027/north american pulsed-field type 1 [nap1]) responsible for outbreaks of severe infection in north america and europe. while fluoroqinolone resistance and over-use are thought to be driving the epidemic, the ageing population and improved case ascertainment are contributing to the dramatic increase in cases. other factors may also be important, such as the increase in prescription of proton pump inhibitors. in the netherlands, since 2005, there has been an increase in prevalence of human cdi with ribotype 078 strains usually found in animals. these infections were in a younger population and more frequently community acquired. there was alarm when it was reported that 20% of retail beef samples in canada contained c. difficile. the figure is higher in the usa where more than 40% of packaged meats (beef, pork and turkey) from 3 arizona stores contained c. difficile. most animal isolates of c. difficile produce binary toxin, and both pigs and cattle harbour pcr ribotype 078 a strain that, like ribotype 027, also produces more toxins a and b, and binary toxin. in the eastern part of the netherlands where >90% of pig farms are located, >20% of human isolates are now ribotype 078, and human and pig strains of c. difficile are highly genetically related. it has been suggested that the overlap between the location of pig farms in the netherlands and the occurrence of human ribotype 078 infections involves a common source. that source is likely to be the environment. the upsurge in cdi has prompted diagnostic companies to try to either improve current tests or develop new ones. laboratory diagnostic methods can be divided into 3 groups; traditional faecal cytotoxin detection (with or without culture), enzyme immunoassays (eias) and molecular methods. faecal cytotoxin detection is specific but lacks sensitivity, culture is sensitive but lacks specificity. new eias should find a niche in medium sized laboratories. current in-house pcr methods have the potential for great sensitivity and specificity but have been available only in larger laboratories. new commerciallyavailable platforms will make this methodology more accessible to smaller laboratories. whatever method is chosen, it is necessary for the laboratory to have as fast a turn-around-time as possible, particularly in an outbreak situation. d. lévy-bruhl°(saint-maurice, fr) in 2005, the advisory board on immunisation (abi) has been asked to make recommendations to the ministry of health regarding the inclusion or not in the french immunisation schedule of the soon to be licensed first hpv vaccine. the main elements considered in the establishment of the benefit-risk balance of routine hpv vaccination were: on the benefit side: -the very significant potentially preventable burden of diseases; -the very high efficacy of the vaccine against persistent hpv 16/18 infections in naive subjects; -the expected additional impact on other hpv16/18 related lesions and cancers; -the fact that vaccination, by preventing the pre-cancerous lesions, has the advantage over screening to reduce the cost and anxiety related to their detection and management; -the available data in favour of a satisfactory safety profile; -the benefit of vaccination for the women not covered by the opportunistic screening program. on the "risk" side: -the high cost of vaccination; -the unknown duration of protection; -the need for continuation of screening, even for vaccinated women; -the fact that the majority of residual cervical cancers could be prevented by the organisation of the screening program; -the risk of a decrease in compliance to screening for vaccinated women; -the low benefit if vaccinated and screened women were the same. a cost effectiveness analysis, carried out on a multi cohort markov model, showed that, over a 70 years period, the impact of vaccinating 80% of 14 years old girls or of organising the screening were comparable (reduction of cancer deaths close to 20%). however, the cost-effectiveness ratio of the vaccination was higher than that of the screening organisation, resp. 45,200 and 22,700 € per life year saved (at a 3% discount rate). on the basis of the economical analysis, the screening organisation was therefore the first priority. however, if both interventions were implemented, the overall reduction in cervical cancer deaths was estimated at 32%. the cost-effectiveness of the addition of vaccination on the top of the organisation of the screening appeared acceptable (55,000 € per life year saved). based on those results, the abi issued in march 2007 a recommendation to include the hpv vaccination in the immunisation schedule for 14 years old girls, together with a catch up for 15 to 23 years old women not having started their sexual life more than one year ago. the vaccine cost has been reimbursed since july 2007. clinical microbiology − is outsourcing the way to go? s338 the (r)evolution of clinical microbiology in europe − is it good or bad? laboratory medicine in general and clinical microbiology in particular is presently subject to rapid (r)evolution. are we aware? are we in command? do we know where we are going? should we oppose or cooperate? do we have a choice? do we recognise a driving force other than money? is it good, bad or just plain necessary? and are we gaining or losing? it is not one evolutionary process -it is several parallel processes with varying emphasis in different areas. there are at least four distinctive major trends over the last 15 years; the gradual formation of bigger and bigger units (concentration), the amalgamation of many different laboratory services into one (laboratory medicine), accreditation and an explosion of professional proficiencies and backgrounds of staff in microbiological laboratories. personally i have withstood the first two, with pleasure succumbed to the latter. a recent 5th trend, outsourcing microbiology services to large private consortiums, is splitting clinical microbiology into a purely analytical high-throughput money-saving activity, often leaving the consultative, clinical part of microbiology and health care infection control adrift. what is driving the evolution? not only cost-saving but also our inability to recruit medically trained microbiologists, the need to broaden the knowledge base of microbiology laboratories, automation, the development of new techniques and apparatus common to many laboratory disciplines, computerised medicine, political trendiness, power struggles, and much more. there is much to be gained by both concentration and amalgamation but much to be lost as well and many consider the heart and soul of clinical microbiology at risk. over a period of years, rational high-throughput production has won over consultation and personalised microbiology. that may be fine for the production of negative hiv-antibody/antigen analysis as for the screening of blood-donors but certainly not for the bacteriological cultures taken in conjunction with a hip replacement. or when it comes to understand and advise on the intricacies of antimicrobial resistance development. in other cases "outsourcing" and/or "amalgamation" mean that blood cultures are sent to x-town, cmv-antibodies to y-town and everything else to z-ville. when that happens clinical microbiology is lost. there are several instances where concentration, amalgamation and/or outsourcing of clinical microbiological services, alone or with other services, have meant that the tie between clinical microbiology and infection control has been severed and that many, both small and large hospitals have lost the personalised service so necessary to control outbreaks of multi-resistant bacteria and other health care related infections. a good service requires a strong knowledgeable and enthusiastic champion. a service which encompasses too many branches of laboratory medicine cannot be expected to champion each and every one with equal strength and fervour. and when outsourced to "big companies", there is no "clinical", only "microbiology". in 2008 "medical microbiology" broke out from "laboratory medicine" in uems. we are now striving towards a strong "medical microbiology" service in europe. it will have many facets, much strength, some weakness, great opportunities, but many threats. escmid certainly intends to help shape microbiology in europe. the optimal organisation of microbiology laboratories in european metropolis is an evolutionary task, driven by the evolution in laboratory tasks, laboratory technologies, communication technologies, regulations and financial issues. in the past five-ten years, medical and societal query for a more rapid and refined detection and identification of pathogens and antimicrobial resistance determinants coincided with the expansion of internet-based and remote tools for communication, an unprecedented revolution in laboratory technologies and new financial constraints. the concentration of laboratory workforces into one unique laboratory is one way to address these apparently contradictory issues. the tertiary medical school hospital system in marseille, a 2-million metropolitan area in france, comprises four hospitals for a total of 3,500 beds. the system had once four microbiology laboratories which have been progressively embedded into a unique, 600,000 acts per year, laboratory which deals with bacteriology, virology and environmental microbiology and hygiene. the medical staff comprises of 17, the ingenior staff of 11, technical staff of 88 and support staff of 13 persons for a total of 129 persons. this organisation allowed reducing labour time for routine microbiology, to develop prospective and sophisticated time-consuming diagnostic methods and to develop advanced diagnostic methods such as molecular methods (real-time pcr-based tests, sequencing, and mass spectrometry identification) and new generation serology. new, sophisticated technologies such as automated serology and mass spectrometry were corner-stones on which to base the constant diminution of routine labour time and the development of time-consuming tasks such as fastidious organisms' isolation. these evolutions paralleled the exponential increase in the ratio of ingeniors in the laboratory. this paradigm allowed for the constitution of large collections of biological specimens for retrospective analyses, the specialisation of every medical senior in one particular field of internationally recognized expertise and the increase in knowledge output in terms of peer-reviewed papers, patents and grants. implantation of point-of-care in the emergency department, in permanent internetbased connection with the central laboratory, was the last, but not least, evolution of this system. when tuberculosis epidemiology is seen in a global perspective, and the millennium development goals are considered, it is clear that two regions of the world, africa and europe, are severely behind in the control of the disease. in africa, especially sub-saharan africa, the tb problem is closely related to the endemic hiv/aids situation. in europe, especially the eastern part and in parts of the former soviet union, the main obstacle to an effective tb control is related to drug resistant forms of m. tuberculosis. the prevalence of the most severe forms of resistance, mdr-and xdr-tb, is so high that it makes control efforts both extremely complicated and very expensive. unfortunately, increasing levels of drug resistant tb are today also seen in many african countries, and hiv infection is spreading in eastern europe. during the last ten-year period new tools, based on molecular fingerprinting of m. tuberculosis strains, have been increasingly adapted to study tb transmission. with such molecular methods to characterise clinical isolates of m. tuberculosis it is now possible to study the spread of individual strains of the bacteria in detail. the laboratory tools used, rflp, miru/vntr, spoligotyping and others, will be presented and their use exemplified. how molecular epidemiology contributed to the detection and characterisation of a major outbreak of drug resistant tb in the stockholm area will be discussed. molecular characterisation of clinical isolates from different parts of the world has led to an increased recognition of the differences between different families of m. tuberculosis strains. to further describe and understand the role of these differences in the clinical field as well as for tb epidemiology is an ongoing and interesting field of research. an increased understanding of how tb is transmitted will hopefully help in the efforts to control this global health threat both on the local level and in a global perspective. living in the era of increasing tuberculosis drug resistance, the importance of making an early and accurate diagnosis with drug sensitivities has never been greater. the epidemiology of tuberculosis defines the extent of latent disease and the proportion which becomes active. accurate diagnosis is vital if patients are to be treated in a timely manner and to reduce the amount of time infectious individuals go untreated in the community disseminating disease. in many areas of the world, dots programmes are at the forefront of tuberculosis control. however, as a diagnostic this currently relies on sputum smear microscopy which is known to miss 50% of cases of tuberculosis and provides no data on drug sensitivity. the second major issue around tb is the lack of worldwide diagnostic facilities. there is a need for a simple, low cost, easily implemented diagnostic test. this talk will briefly consider the issues around the diagnosis of latent and active disease which are quite distinct. the focus will be on the diagnosis of active infection. in particular, the use of mods (microscopic observation drug-susceptibility) assay in diagnosis of tuberculosis will be discussed. the potential for using this in resource poor countries will be reviewed as well as the way sophisticated technology maybe harnessed to improve reporting and allow translation to all parts of the world. the important issue of how to distinguish patients with latent and active disease will also be considered. key issues and principles in diagnosis both now and in the future will be reviewed. in terms of treatment, there are 2 main issues. the first is that even short-course therapy is prolonged being a minimum of 6 months leading to issue of compliance. this may result in drug resistance. the massive rise of multi-drug resistant tuberculosis to approximately 500,000 cases world-wide with around 50 countries reporting extensively drug-resistant disease means that the need for new approaches to therapy are urgent. the second part of this talk will review different approaches to using current anti-mycobacterial drugs, the emergence of a small number of new drugs such as the diarylquinolones and entirely novel approaches to control and treat tuberculosis. there has been great success and also many threats in the field of infectious diseases during the previous year. the antimicrobial resistance, especially increasing carbapenem resistance among aerobic gram-negative rods and xdr mycobacterial tuberculosis strains are already big threats in some countries and they will probably spread to many other areas all over the world in the future and we will need new drugs for these indications but unfortunately very few new promising drugs seem to be in the pipeline at the moment for these purposes. the virulent clostridium difficile 027 strain spreads rapidly to many new countries and e.g. in finland it killed many times more people compared with mrsa and esbl strains in 2008. however, it is possible to stop its spreading but it needs new thinking in antibiotic use policy and infection control policy in hospitals. clostridium difficile 027 infection has a high relapse rate after metronidazole or vancomycin therapy, but an experimental "stool exchange treatment" is a promising therapy although controlled studies are needed to prove this assumption. an interesting research area during the last years has been the role of infections in the etiopathogenesis of chronic diseases like cancer, atherosclerosis, cardiovascular diseases and many autoimmune diseases. we can fight against many cancers like liver cancer and cervix cancer with virus vaccines and gastric cancer with antimicrobial drugs. also the high incidence of malignant tumours seems to decrease during haart treatment in hiv patients. the role of infections in the etiopathogenesis of cardiovascular diseases and atherosclerosis is complex. it is obvious that infections play a role in the etiopathogenesis of atherosclerosis, stroke and myocardial infarction but the undirected routine antimicrobial treatment is not recommended for these patients but there seems to be subgroups in patients with various cardiovascular diseases which may benefit from antimicrobial treatment. recent studies seem to suggest that there are hla types which protect or make people susceptible for coronary heart disease. the hla type hla-b*35 seems to be a risk factor for coronary heart disease but it is also a risk factor for chronic chlamydia pneumoniae infection. the feared pandemia due to h5n1 influenza a did not appear during the recent year and the world is now much more prepared to meet the next pandemia which, however, hopefully does not come during the next year. ø. samuelsen°, c. giske, u. naseer, s. tofteland, d.h. skutlaberg, a. onken, r. hjetland, a. sundsfjord (tromsø, no; stockholm, se; kristiansand, bergen, oslo, førde, no) objectives: the worldwide dissemination of kpc-producing multidrugresistant enterobacteriaceae is worrisome. the first kpc-producing klebsiella pneumoniae in norway was isolated late 2007 from a patient after hospitalisation in greece. throughout the following year seven additional kpc-producing k. pneumoniae isolates have been detected in clinical samples from six new patients. the aim of this study was to perform molecular characterisation of the strains and examine their epidemiological relatedness. materials and methods: antimicrobial susceptibility was examined by etest. molecular characterisation was performed by mlst, pfge and sequencing of the blakpc genetic structure. plasmid analysis was carried out by pfge of s1 nuclease-digested total dna and southern blot hybridisation using a blakpc probe. relevant epidemiological data were collected retrospectively. results: eight kpc-producing clinical isolates of k. pneumoniae have been identified from seven patients in two different regions of norway from the following specimens: blood culture (n = 3), urine (n = 2), expectorate (n = 1), perineal swab (n = 1) and wound secretion (n = 1). two blood culture isolates with clonally related but different pfgeprofiles were observed in one patient. the detection of kpc-producing k. pneumoniae isolates in norwegian patients was associated with import in four cases after hospitalisation in greece. two patients had been hospitalised at the same hospital in greece. isolation of a kpc-producing isolate in a fifth patient was epidemiologically linked to one of these imported cases and was a case of nosocomial transmission in norway. for the latter two cases no risk factors were identified with respect to recent hospitalisation or travel abroad. molecular analysis of six isolates has shown genetically related pfge-patterns and a common sequence type (st258). st258 has been associated with dissemination of ctx-m-15 in hungary. the blakpc gene was localised in tn4401 on a~97 kb plasmid. the two most recent isolates are currently undergoing similar analysis. conclusion: the first seven cases of kpc-producing k. pneumoniae in norway are associated with hospitalisation abroad, nosocomial transmission in norway, or urinary tract infections in outpatients without obvious risk factors. the clonal relationship between isolates underlines the existence a biological fit genetic lineage of kpcproducing k. pneumoniae with an epidemic potential. objectives: two recent publications have reported the isolation of kpc producing k. pneumoniae from infections in two patients, one in france and one in sweden, who originally had been hospitalised in greece. since this resistant mechanism had not been identified before in this country, the purpose of this report was to confirm the presence of blakpc producing k. pneumoniae in greece, to assess the extent of its spread and to study the genetic relatedness of the respective bacterial strains and the transferability of the blakpc harbouring plasmids. methods: for a three month period (february to april 2008) 40 hospitals participating in the greek system for surveillance of antibiotic resistance (www.mednet.gr/whonet) were asked to seek for possible kpc producers among k pneumoniae isolates displaying reduced susceptibility to imipenem (equal or higher than 1 mg/l), a positive hodge test for the presence of carbapenemase and a negative edta synergy test for the presence of metalloenzymes. the presence of blakpc gene in these strains was confirmed by pcr and sequencing. mics to carbapenems were determined by etest. conjugation experiments were carried out both in broth and on agar. the possible absence of ompk36 porin was detected by pcr. molecular typing was performed by pulse-field gel electrophoresis of xbai-restricted genomic dna. results: ninety two k. pneumoniae clinical isolates (one per patient) from 13 hospitals all over greece were found to harbour blakpc-2 gene. although colonies present in the inhibition zone made the exact determination of imipenem mic difficult, the absence of ompk36 porin was always associated with mic of imipenem higher than 32 mg/l. all isolates exhibited resistance to all other drug classes except colistin, tetracycline and tigecycline. pfge analysis revealed that 85 isolates from 12 hospitals displayed more than 95% similarity and were classified into one pulsotype, whereas the remaining seven isolates belonged into four different pulsotypes. blakpc-2 gene could not be transferred by conjugation from strains belonging to the main pulsotype. however, it was transferred from strains belonging to three out of the four remaining pulsotypes. conclusion: production of kpc-2 betalactamase seems to be a new emerging resistance mechanism in klebsiella pneumoniae in greece. blakpc-2 gene's possible clonal spread imposes the urgent need of implication of infection control practices in the affected hospitals. i. galani, m. souli, e. papadomichelakis, f. panayea, n. mitchell, a. antoniadou, g. poulakou, f. kontopidou, h. giamarellou°(athens, gr) background: until now, carbapenem resistance among klebsiella pneumoniae (kp) clinical isolates in greek hospitals has been attributed to the dissemination of vim-1 metallo-beta-lactamase. we describe the first outbreak of kpc-producing kp in greece; the first to occur outside the usa or israel. setting: 21-bed icu of attikon university hospital, athens. methods: kp isolates with an imipenem mic > 1 mg/l and a negative edta-imipenem disk synergy test were submitted to boronic acid disk test, to pcr for a kpc gene with specific primers and sequencing. records from patients colonised or infected with a kpc-producing kp were retrospectively reviewed for clinical and epidemiological data. environmental cultures for kpc-producers were performed. clinical isolates were submitted to molecular typing using pfge. results: from february to november 2008, 552 kp were isolated from 95 patients, 132 (23.9%) of which were boronic acid positive and produced kpc-2. most of them (126/132, 95.5%) were isolated since august. a total of 24 patients were identified as colonised or infected by a kpc producer which in 22 of them belonged to the same genetic clone. the source was faeces (73), bronchial secretions (26), blood (7), cvc tip (5), urine (15), pus (4) and throat (2). among patients whose medical records were available, median age was 74, apache ii score; 21, length of preceding hospital stay; 28 days, total length of stay; 50 days, immunosuppresion was identified in one and crude mortality was 71%. the kpc-producing kp was more frequently icu acquired whereas in a minority of patients it was already present on icu admission. seventy percent of the patients had previously received a carbapenem for a median of 15 days. environmental colonisation was not identified. ten (7.6%) of the kpcproducers from 8 (33.3%) patients were identified as the cause of an infection: bacteraemia (7), ventilator-associated pneumonia (2) and surgical site infection (1) and exhibited mic90 (mg/l) for imipenem, >8; meropenem, >8; gentamicin, 4; ciprofloxacin, >2; fosfomycin, >128; colistin, 0.5 and tigecycline, 4. most patients were successfully treated with a colistin-containing combination mostly with a beta-lactam. there was no attributed mortality. isolates from the same bacterial species were typed by pfge or automated ribotyping. kpc-encoding gene was fully sequenced. plasmid preparations and i-ceu digestion of total dna were resolved in agarose gels, blotted and hybridised with a blakpc probe. the blakpc-carrying element (tn4401) was amplified with various primer pairs, digested with eag i and sequenced. results: 30 strains each carried kpc-2 and kpc-3. one e. cloacae carried kpc-4. 13 k. oxytoca were kpc-2-producers and 2 s. marcescens harboured blakpc-3, all from usa. great genetic diversity was observed among the isolates (41 different types). one clone of 10 e. cloacae was detected in new york state (2006) (2007) . small clusters of 2 and 3 strains were detected among e. coli, e. cloacae, k. oxytoca. plasmids were present in all but 3 isolates. persistence of clones throughout the years was not observed. in 35 isolates the kpc-encoding gene was located in high molecular weight plasmids (>54 kb). blakpc was located in the chromosome of 11 strains (e. cloacae, e. coli and k. oxytoca) and the location of this gene could not be determined in 15 strains. small plasmids were present in several strains, but did not harbour blakpc. tn4401 carried blakpc in 46 isolates, and the transposon element was conserved. this structure was not detected in 12 strains. conclusions: kpc-encoding genes were most often located in tn4401 among several enterobacteriaceae species collected in usa and israel. this blakpc-carrying element was located in plasmids and on the chromosome. this study highlights the importance of tn4401 in the dissemination of blakpc genes in several genetically diverse bacterial species. blakpc was not associated with tn4401 in only 12 of 61 strains. these strains are under further investigation. objective: to evaluate the carbapenem resistance mechanism in a raoultella planticola bacteraemia isolate recovered from a patient hospitalised in ohio, usa. methods: species identification was performed by vitek 2 and confirmed by 16s rrna sequencing. susceptibility testing used clsi broth microdilution method. blakpc was amplified and sequenced. the blakpc genetic element (tn4401) was amplified and sequenced. plasmid extractions and conjugation experiments were carried out and the isolate was screened for esbl-encoding genes, qnr and qepa. a 83 year old female patient was admitted to a hospital located in akron with a diagnosis of cap in may/2008. sputum, paracentesis and blood cultures were negative. urine culture grew e. coli and patient received courses of moxifloxacin, ceftriaxone, azithromycin and meropenem. the patient was discharged and returned after three weeks with respiratory problems. tracheal aspirate grew a multidrug resistant a. baumannii and the blood culture grew the enteric-like gramnegative bacillus. the isolate was identified as r. planticola by the vitek 2, which was confirmed by 16s sequencing. r. planticola strain demonstrated resistance against most b-lactams, including carbapenems. screening for kpc-encoding genes was positive and this strain carried blakpc-2. fluoroquinolone and aminoglycoside mic values were elevated. kpc-2-encoding gene was located in tn4401, but conjugation experiments failed. esbl and qnr/qepa genes were not detected. conclusions: kpc serine-carbapenemases have been detected in several gram-negative species commonly isolated from clinical specimens. kpc genes are embedded in transposon-like structure usually harboured in conjugative plasmids carrying multiple antimicrobial resistance mechanisms. this is the first report of kpc-producing r. planticola that is an environmental organism related to klebsiella spp. the similarity between these organisms could facilitate the transfer of genetic material. kpc-producing isolates appear to be prevalent among different enterobacteriaceae species in usa hospitals and was detected in an isolates of apparent environmental origin. objectives: it is long known that not all individuals with a specific disease present with the same clinical manifestations, nor do they have identical prognoses or responses to treatments. it has become clear that variations in the human genome are likely to have an impact on these aspects. tank-binding kinase 1 (tbk1) is a central molecule in the induction of a.o. the type i interferon response to pathogens. our goals for this study were 1) to investigate the frequency of single nucleotide polymorphisms (snps) in the promoter and coding region of tbk1 in a dutch caucasian population and 2) to search for potential associations between these snps and bloodstream infections. methods: whole blood samples or samples of positive blood cultures were collected and after genomic dna was isolated, pcr and sequencing were performed for snp identification. functional studies included promoter activity measurements using a luciferase assay as well as electrophoretic mobility shift assays (emsa) to study binding of the transcription factor usf1 to the wt and mutant promoter. snp incidences were studied in a case control study. results: in samples from dutch caucasian healthy volunteers, 4 snps were found with allele frequencies higher than 5% whereas 6 other known snps had frequencies lower than 5% in our cohort. two snps (rs89208169 and rs89208163) located in the promoter region were studied in a larger cohort of 350 anonymised patients from the maastricht university medical center with either gram-positive or gram-negative blood cultures. we found that the prevalence of rs89208169 was significantly increased in patients with positive blood cultures in comparison with those with negative blood cultures or healthy volunteers. further investigation of this snp showed that it is located just outside a usf1-binding site. measuring the promoter activity using luciferase assays, the mutant promoter exhibited a decreased activity of <35%. this observation was confirmed by emsa which showed that recombinant usf1 protein had a reduced binding affinity to the mutant promoter. conclusions: snp rs89208169 in the promoter region of tbk1 has a significant association with gram-positive infections. our results demonstrate that this is likely due to a decreased expression of tbk1 due to reduced binding of the transcription factor usf1 to the mutant promoter. our results support recent findings that tbk1 plays also an important role in the host response to gram-positive infections. objective: lymphocyte apoptosis has been recognized as an important factor contributing to both the onset of sepsis post infection and to the progression into septic shock. animal data suggest that prevention of lymphocyte apoptosis by caspase inhibition stabilises the immune system, improves bacterial clearance and decreases mortality in experimental sepsis. the present study evaluated the potential of vx-166, a novel broad caspase inhibitor, as a therapy for sepsis. methods and results: initial characterisation of vx-166 in a number of enzymatic and cellular assays clearly demonstrated that the compound is a broad caspase inhibitor with potent anti-apoptotic activity in vitro. in vivo, vx-166 was tested in a murine model of endotoxic shock and a clinically relevant model of peritonitis. in the endotoxic shock model, male cd-1 mice (n = 28 per group) were administered lps (20 mg/kg iv) and survival was monitored for 96 h. vx-166 administered by repeat iv bolus (0, 4, 8 and 12 h post-lps) significantly improved survival in a dose-dependent fashion (p < 0.0001). in the rat peritonitis model, adult male sprague-dawley rats (n = 12 per group) underwent caecal ligation and puncture (clp) and survival was monitored over 10d. continuous administration of vx-166 by mini-osmotic pump (0.9 mg/kg/h) immediately following surgery significantly improved survival (p < 0.01) from 38% in the control group to 88% in the compound-treated group. mode of action studies in the rat clp model confirmed that vx-166 reduced thymic atrophy and lymphocyte apoptosis (p < 0.01), supporting the anti-apoptotic activity of the compound in vivo. in addition, vx-166 reduced plasma endotoxin levels (p < 0.05), strongly suggesting an improved clearance of bacteria from the bloodstream. most importantly, we demonstrated that vx-166 fully retained its efficacy when dosed 3 hours after insult (p < 0.01) by improving survival to 92% versus 42% in control animals, further highlighting the potential of anti-apoptotic therapy in sepsis. overall these data demonstrate that vx-166 inhibits lymphocyte apoptosis, improves the clearance of bacterial endotoxin and improves survival in experimental sepsis. importantly vx-166 improves survival in the clp model when dosed post insult, and therefore represents significant progress in the development of therapeutically viable broad caspase inhibitors for the treatment of this disease. v. vankerckhoven°, s. van voorden, n. hens, h. goossens, g. molenberghs, e. wiertz (wilrijk, be; leiden, nl; hasselt, be) objectives: toll-like receptors function as key regulators of both innate and adaptive immunity. lactobacilli modulate the immune system in different ways. the aim of this study was to examine toll-like receptor (tlr2, tlr2/6 and tlr4) signalling induced by clinical and probiotic lactobacillus strains. methods: a total of 45 lactobacillus strains (19 l. paracasei and 26 l. rhamnosus) of different origin (22 probiotic, 2 faecal, and 21 clinical) were tested for tlr2, tlr2 in combination with tlr6, and tlr4. tlr signalling was measured as relative il-8 promotor activation in transfected human embryonic kidney (hek) 293 cells. il-8 concentrations were measured using an enzyme-linked immunosorbent assay. heat-killed listeria monocytogenes (hklm) was used as positive control in all assays, whereas pam3, pam2, and lps were used as positive controls for, respectively, tlr2, tlr2/6, and tlr4. all assays were performed at least in duplicate. linear mixed model analyses and stepwise model selection were used to identify the statistically significant effects. random effects were used to account for heterogeneity across and homogeneity within isolates. p < 0.05 was considered statistically significant. results: hek-tlr2 and hek-tlr2/6, but not hek-tlr4, cells released il-8 upon stimulation with uv-inactivated lactobacilli, which was enhanced by co-transfection with cd-14. interestingly, the production of il-8 was shown to be variable for the different lactobacillus isolates. although similar results were seen for all isolates for tlr2 and tlr2/6, il-8 production was significantly higher for tlr2 (8.4 log pg/ml) compared to tlr2/6 (6.05 log pg/ml) (p < 0.0001). no significant differences in il-8 production were seen between clinical and probiotic isolates. however, l. rhamnosus isolates induced a significantly higher il-8 production compared to l. paracasei isolates in both cell lines, 7.88 and 6.84 log pg/ml, respectively (p = 0.0004). intra-isolate correlation was found significant (p < 0.0022). conclusions: our study shows that lactobacilli activate both tlr2 and tlr2 in combination with tlr6. our results also indicate that heterodimerisation of tlr2 with tlr6 does not lead to an improved recognition of lactobacilli. furthermore, taking intra-isolate correlation into consideration proved to be important. finally, our results suggest that differences in immunomodulation by lactobacilli may be related to differential signalling through tlrs, including tlr2 and tlr2/6. m.c. gagliardi, v. sargentini, r. teloni, m.e. remoli, g. federico, m. videtta, g. de libero, e. coccia, r. nisini°(rome, it; basel, ch) objective: to gain insights into the mechanisms used by mycobacterium tuberculosis and bacillus calmette guérin to cause human monocytes differentiation into cd1 negative dendritic cells (my-modc), unable to present lipid antigens to specific t cells. methods: human monocytes infected or not with mycobacteria were induced to differentiate into dc with gm-csf and il-4 in the presence or absence of p38 or erk specific inhibitors. kinases activation was detected by western blot using antibodies specific for phosphorylated and non phosphorylated isoforms. differentiation of monocytes into dc and the cd1a, cd1b and cd1c expression was evaluated by flow cytometry and by real time pcr at different time points from infection. functional expression of cd1 molecules was assessed by recognition of lipid antigens by cd1 restricted t cell clones. results: we show that mycobacteria trigger phosphorylation of erk and p38 mitogen-activated protein kinase in human monocytes as well as of activating transcription factor (atf)-2. mycobacteria-infected monocytes treated with a specific p38 inhibitor, but not with a specific erk inhibitor become insensitive to mycobacterial subversion and differentiate into cd1 positive my-modc, which are fully capable of presenting lipid antigens. data indicate that phosphorylation of p38 is directly involved in cd1 inhibition. conclusions: we propose p38 signaling as a pathway exploited by mycobacteria to affect cd1 expression, thus representing a novel target of possible pharmacological intervention in the treatment of mycobacterial infections. s. ebert°, s. ribes, r. nau, u. michel (gottingen, de) objective: activin a (act a) is a multifunctional cytokine with roles in the immune system and the inflammatory response. act a levels are elevated in the cerebrospinal fluid of patients with meningitis. microglial cells, the major constituents of innate immunity within the brain, express toll-like receptors (tlrs) recognising exogenous and endogenous ligands. upon stimulation with tlr agonists, primary mouse microglial cells become activated and release nitric oxide (no), cytokines, and also act a, suggesting that they are a source of elevated conclusions: pre-treatment with act a enhances no release from microglial cells activated by agonists of the principal tlrs involved in the recognition of bacteria. these findings provide further evidence for a role of act a in the innate immune response and suggest that act a acts as an pro-inflammatory modulator during infection and inflammatory processes in the cns. insertion sequences (is) are genetic tools that can mediate expression of previously silent genes or be responsible for the overexpression of certain genes (in each case by providing promoter sequences). in addition to be involved in gene transcription levels, is elements also play a very important role for gene acquisition/mobilisation. an is is usually made of of two inverted-repeat sequences (irs) bracketing a gene encoding the transposase which activity enables this entity to replicate and target another sequence. the is-related mechanisms at the origin of antibiotic resistance gene acquisition are diverse, including composite-transposition, rolling-circle transposition, one-ended transposition. is elements may be also involved in gene acquisition by mediating co-integration processes, or recombination events as hypothetized for is26 in relation with blashv extendedspectrum b-lactamase (esbl) genes originating from the chromosome of klebsiella pneumoniae. the blactx-m esbl genes known to be extremely widespread worldwide are encoded on plasmids, and have been found in association with isecp1 (acting by one-ended transposition) or iscr1 (acting by rolling-circle transposition). in that case, iss have played a role in the mobilisation from the chromosome of kluyvera spp. being the blactx-m progenitors and then in their expression. also, genes encoding acquired ampc b-lactamases, being of the blaacc, bladha, and blacmy-types, are mostly found in association with iscr1 or isecp1. sometimes antibiotic resistance genes are mobilised by composite transposons which are made of two copies of a given is bracketing the mobilised fragment. in acinetobacter baumannii, the worldwide disseminated blaoxa-23 carbapenemase gene is part of a composite transposon structure made of two copies of isaba1, forming transposon tn2006 which had mobilised a chromosomal fragment from acinetobacter radioresistens that actually corresponds to the progenitor of blaoxa-23. another possibility can be the forming of composite transposon structure bracketed by two different is (sharing similar irs) as observed with the blaper-1 esbl gene in pseudomonas aeruginosa. this diversity of iss elements at the origin of mobilisation/acquisition of antibiotic resistance genes is therefore responsible for the very efficient dissemination of many of them. s362 resistance islands − their role in the accumulation and spread of antimicrobial resistance genes historically, multi-antibiotic resistance in many bacterial species was largely attributed to the acquisition of resistance (r)-plasmids encoding one or more resistance determinants. however, over the last decade the r-plasmid paradigm has begun to be challenged. 'resistance islands' comprising large, chromosomally-integrated spans of alien dna harbouring multiple antibiotic resistance genes have been identified in the major hospital pathogens methicillin-resistant staphylococcus aureus (mrsa) and multi-resistant acinetobacter baumannii, and the foodand water-borne diarrhoeal pathogens shigella, salmonella and vibrio cholerae. in addition, comparative genomics analysis of the archetypal haemophilus influenzae conjugative resistance element that had spread worldwide revealed that it belonged to a large syntenic family of integrative islands, members of which could be found in at least 15 other b-and g-proteobacteria. with the exception of the a. baumannii island, these elements can be described as classic self-excising, -circularising and -integrative elements. all three functions are mediated by short island-flanking direct repeats and cognate integrase proteins encoded by the islands. in 2006 fournier et al. described an 86 kb a. baumannii island (abar1) which harboured 45 resistance genes packaged within a highly mosaic, integron-rich element that had almost certainly evolved via recombination, transposition and integron-mediated cassette capture from an 'empty' ancestral prototype. abar1 probably represents a new class of resistance island as it exhibits several features reminiscent of complex nested transposons, suggesting a distinct functional natute. however, despite the widespread distribution of resistance and genomic islands only a minority are known to code for part or all of the conjugative machinery necessary for their dissemination; others have been mobilised by helper plasmids or bacteriophages. regardless, data on the mechanisms of mobilisation of the vast majority of similar nonresistance islands remain sparse. importantly, resistance islands may not consists merely of packages of resistance genes. on the contrary, these diverse and frequently hybrid entities could potentially confer upon their hosts other advantageous traits relating to host-pathogen interaction, virulence, survival in the environment and/or transmissibility, truly justifying the label 'selfish islands' and further explaining their evolutionary success. due to the availability of new techniques, genome sequencing of bacteria has become fast and inexpensive. furthermore, recent methods using paired-end reads located several kb apart in the genome eases the assembling process, even though no reference sequence is available. in a reasonably close future, it should be possible to obtain the fully assembled sequence of a bacterial isolate overnight. the new sequencing techniques generate enormous amounts of genomic data and, thereby, a need for new tools. these should able to quickly analyze genomes and point to zones of interest, prompting further analysis on a reduced number of regions or genes, such as genomic islands. pathogenicity islands, a subset of genomic islands, carry genes such as toxins or resistance genes and have the particularity to be mobile, i.e. they may transfer to other species or strains. thereby, they confer their new hosts a more resistant or infectious phenotype, making this phenomenon particularly important to study. nucleotide composition of genomes is fairly homogeneous inside bacterial genomes. in general, horizontally transferred regions can be spotted due to their particular nucleotide content, because they tend to retain the composition of their original host and don't share the one of their new hosts. to do an analogy with languages, genomes speak dialects, and as one would easily spot a paragraph in finnish in an english text while not knowing finnish, one can spot genomic and pathogenicity islands transfers in a given genome. several techniques relying on various compositional aspects and on different algorithmic methods have been recently developed to detect pathogenicity islands in bacterial genomes. even very simple measures of the genome composition, such as the variation in t vs. a bias (ta skew) can lead to the identification of all known prophages in streptococcus pyogenes. it can even trigger the discovery of a putative ancient genomic island carrying a large number of genes related to pathogenicity in all strains of that species. in conclusion, with the rise of fast and inexpensive genome sequencing, new quick and simple methods are being developed. they take the advantage of the homogeneous nucleotide composition of bacterial genomes to uncover mobile genetic elements carrying genes involved in pathogenicity. in the past 10 years, significant progress has been achieved in the management of chronic hepatitis b with the successive development of six potent antiviral medications (lamivudine, adefovir dipivoxil, pegylated interferon alpha, entecavir, telbivudine and tenofovir). however, the clinical results of antiviral therapy have been limited by the emergence of antiviral drug resistance especially with the first generation of nucleoside analogs (lamivudine, adefovir and telbivudine). furthermore, the unique mechanism of viral genome replication and persistence within infected cells is responsible for viral persistence even after prolonged therapy with the newer antivirals (entecavir and tenofovir). this is the major reason why life-long treatment is envisaged in the majority of patients, which may expose them to long-term risk of developing resistance. the use of in vitro phenotypic assays has been crucial for the characterisation of newly identified resistant mutants and determine their cross-resistance profile. results allowed to understand the different mechanism of viral resistance to lamivudine and adefovir, the mechanism of primary failure to adefovir therapy, the unique mechanism of entecavir resistance, and to characterise the emergence of multi-drug-resistant strains in patients receiving sequential antiviral therapy. the crossresistance profile for the main resistant mutants was determined which allowed to provide recommendation to clinicians for treatment adaptation based on molecular virology data. the understanding of the development of hbv drug resistance has allowed to significantly improve the management of antiviral resistance and to design better treatment strategies to prevent resistance. the current standard of care relies on treatment initiation with antivirals combining a strong antiviral potency and a high barrier to resistance. a precise virologic monitoring is required to measure antiviral efficacy, and to diagnose partial response or viral breathrough at an early stage. this allows to adapt antiviral treatment preferrably using an add-on strategy with a drug having a complementary cross-resistance profile. this strategy has been shown to be efficient in controling viral replication and preventing liver disease progression in the majority of patients. treatment of chronic hepatitis b virus (hbv) infection is aimed at suppressing viral replication to the lowest possible level. in many prospective clinical trials it has been shown that a sustained hbv dna response was correlated with serologic, histologic, or biochemical responses. despite the recent progress in hepatitis b antiviral treatment, it is shown that antiviral drug resistance is inevitable against many of the nucleoside analogs. the emergence of antiviral-resistant strains of hbv leads to viral and subsequently biochemical breakthrough and may lead to disease progression and increased death. most of the data on the clinical impact of antiviral resistant hbv came from the data derived from studies of lamivudine therapy. there is limited data on other hbv antiviral drugs like adefovir. it is shown in several studies that treatment of hbeag-negative chronic hepatitis b with lamivudine effectively suppresses hbv replication and results in biochemical remission and histologic improvement in more than two thirds of patients. however, relapse has occurred in the majority of hbeag-negative patients after the cessation of therapy. there are several studies to support the occurrence of severe hepatic flares, and liver failure after the emergence of lamivudine resistance. several studies, where liver biopsies were taken, demonstrated that histological improvement was reduced in those patients experiencing lamivudine resistance. the clinical outcome for patients with antiviral resistance is related to their age, the severity of the underlying liver disease and the severity of the hepatic flares. on the other hand in a different study it was found that long-term lamuvidine treatment was associated with a reduced chance of developing cirrhosis and hcc in patients without advanced disease but, although resistant mutants reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients. results of several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalisation of liver function and reverse histological progression in patients with antiviral resistance. consequently, well-tolerated, potent therapies that offer a strong genetic barrier against the development of resistance are desirable, since antiviral resistance and poor adherence are key risk factors for treatment failure and subsequent reversal of clinical improvement. resistance of enteric fever-causing and non-typhoid salmonella serovars to agents traditionally used to treat these infections in the past shows extensive geographical variation. decreased susceptibility to ciprofloxacin is rapidly increasing all over the world with target alteration and increased efflux being the most important mechanisms behind. infections with such strains often result in extended hospitalisation or even in therapeutic failures. furthermore, it is likely that moderately increased mic values facilitate the development of strains with higher level of resistance, i.e. a pattern described at various locations. screening methods based on quinolone sensitivity testing may fail to indentify decreased fluoroquinolone susceptibility both in typhoid, as well as in non-typhoid salmonella. plasmid mediated quinolone resistance genes are detected increasingly all around the world although neither the frequency nor the variety of genes identified has approached that seen in some other members of enterobacteriaceae. treatment with gatifloxacin or azithromycin are alternative options for invasive and systemic infections caused by strains with decreased susceptibility to ciprofloxacin. at some parts of the world resistance to extended spectrum cephalosporins reached such incidence that may have therapeutic implications particularly when initial, empiric treatment of invasive infections is concerned. resistance is due to plasmid coded ampc type beta lactamases (particularly to cmy-2), and most often to esbls of which usually some of ctx-m types are the frequently encountered ones. carbapenem resistance is still rare, albeit does occur, among salmonella isolates. the recent description of a non-typhoid salmonella strain with the blaimp-4 gene co-located on a class-1 integron with several other resistance determinants on a conjugative plasmid is of particular concern. campylobacters exhibit natural resistance to a variety of antimicrobials. the drugs of choice used to be fluoroqunolones or macrolides. however, the current incidence of ciprofloxacin resistance made the former drugs already obsolete or seriously limited their use at several parts of the world. with the exception of few locations the incidence of macrolide resistance is still relatively low and is seen more frequently in c. coli than in c. jejuni. however, strains exhibiting resistance against both groups of drugs have been emerging, particularly in south-east asia. neisseria meningitidis, the meningococcus, is a major cause of meningitis and septicaemia worldwide while neisseria gonorrhoeae, the gonococcus, is responsible for one of the most widespread sexually trasmitted disease. the behaviour of these two species towards antibiotics is very different: resistance in n. gonorrhoeae is now widespread occuring as both chromosomally and plasmid mediated to a variety of drugs, whereas, besides resistance to sulphonamides, n. meningitidis remains largely susceptible to antibiotics used both for therapy and prophylaxis. however, as in the gonococcus, the resistance to antibiotics of n. meningitidis is also evolving, as documented by the ever higher frequency of strains with intermediate resistance to penicillin in many countries. transformation has apparently provided both species with a mechanism by which they can increase resistance to penicillin by replacing part of their pena gene, which encodes pbp2, with part of the pena gene of related species that fortuitously produces forms of pbp2 less susceptible to the antibiotic. n. meningitidis is still at this step, whereas n. gonorrhoeae has acquired also mutation in the pona gene that encodes pbp1, mutation in porin ib, increased expression of efflux pump and the tem-1 b-lactamase plasmid. the emergence and the spread of gonococci fully resistant to penicillin since the second half of the 1980 s years led to the recommended use of fluoroquinolones as primary therapy. however, this class of antibiotics became rapidly unefficacious, mainly in asia, due to the emergence of mutations in gyra and parc which are able to block the activity of the quinolones on gyrase and topoisomerase iv. since 2006, cdc no longer recommends their use for treatment of gonococcal diseases. fortunately, the occurrence of quinolone resistant meningococci, due to mutations in gyra, is still rare but even if cases are still few they are of great concern for the epidemic potential of this pathogen and the required prophylaxis of contacts. also for the other antibiotic, frequently used to this aim, rifampicin, some meningococci have showed to be resistant, again for the presence of mutations, in this case in the rpob gene coding for the b-subunit of the meningococcal rna polymerase. the molecular epidemiological identification of clonal clusters for both neisseria species with distinct resistance profiles is required to monitor ongoing trends that may pose problems both in therapy and prophylaxis. l. brookes-howell°, c. butler, k. hood, l. cooper, h. goossens (cardiff, uk; antwerp, be) introduction: grace is a european network of excellence established to focus on antibiotic use for community-acquired lower respiratory tract infection (lrti) and antimicrobial resistance across europe. grace-02, the second study to begin within grace, is a large qualitative study that explores the attitudes of clinicians and patients to antibiotic use for lrti and antibiotic resistance. aims: this presentation will focus on clinicians' accounts of the factors that contribute to variation in management of lrti and patient views on when antibiotics are necessary. methods: semi-structured interviews with 81 clinicians and 121 patients were conducted in primary care networks in nine european countries. interviews were audio-recorded, transcribed and, where necessary, translated into english for analysis. themes were identified, organised and compared using a framework approach. results: analysis of clinician interviews shows that, beside clinical findings, factors which influence the management decision for patients can be divided into two main areas. firstly, within each european network there is a group of country specific factors imposed by the system in which consultations take place. these factors include: near patient test usage, self-medication, patients' finances and lack of consistent, local prescribing guidelines. secondly, there is a group of factors, similar across all networks, that relate to personal characteristics of certain groups of clinicians. these include clinicians' professional ethos, self-belief in decision making and attitude towards the doctorpatient relationship. analysis of patient interviews shows that beliefs about antibiotic use tend to draw on clinical factors, namely the severity of specific symptoms (fever and/or coughing). many patients also implied a period of waiting or alternative action required before antibiotics are used − to identify whether the immune system would fight the infection or whether nonantibiotic management was effective before turning to antibiotics. discussion and conclusion: with a greater understanding of the factors that contribute to the decision to prescribe, we discuss ideas to enhance appropriate prescribing. this analysis highlights the need for interventions to be sensitive to factors relating to the systems in which different european networks operate, to target the individual characteristics of specific groups of clinicians and to build on the clinical beliefs already held by patients. o377 pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock k. kopanakis, i. tzepi, e.j. giamarellos-bourboulis°, a. macheras (athens, gr) objective: clinical trials of immunointervention with anti-endotoxin antibodies in patients with severe sepsis have failed to disclose survival benefit. these failures led us to the assumption that the opposite approach with a low endotoxin stimulus may result to low level immunoaralysis and subsequent survival benefit. this approach was tested in an experimental setting. methods: a total of 36 male c57b6 mice were studied divided into two groups: group a stimulated with the ip injection of sodium saline followed after one day by the ip injection of 30 mg/kg of lipopolysaccharide (lps) of escherichia coli o155:h5; and group b stimulated with the ip injection of 3 mg/kg of lps of the same isolate followed after one day by the ip injection of 30 mg/kg lps. lps was diluted in sodium saline and the volume of each injection was 0.2 ml. survival was recorded at six hour time intervals. results: survival of group b was considerable prolonged compared with group a (log-rank: 5.435, p: 0.020) as shown in figure 1 . thirteen mice of group a died (72.2%) compared with seven mice of group b (38.9%, p: 0.044 between group). conclusions: administration of low doses of lps prolongs survival after lethal endotoxic shock. this approach opens a promising novel pathway for immunointervention in sepsis. fragilis isolates with an mxf mic of 2 mg/ml (n = 5), 4 mg/ml (n = 20) and 8 mg/ml (n = 8), which were virulent in the mgp model, were used to determine the efficacy of mxf. for the mgp model, pouches were created by injecting 5 ml of air and 0.5 ml of 0.1% croton oil in olive oil under the skin of the back. on day 3, the air was withdrawn and replaced by 1 ml soft agar. on day 5, a bacterial suspension was injected into the pouch. infected mice (n = 6 mice/group) were treated with mxf 100 mg/kg iv, b.i.d. for 2 days. this dose simulates the auc of the human 400 mg once-daily mxf iv dosage. efficacy was assessed by the reduction in colony forming units (cfus) in pouch exudates 48 hours post-infection compared with the untreated infection control. results: in the mgp model, mxf, 100 mg/kg b.i.d., displayed good efficacy in term of cfu reduction against all used strains in this study. there were no non-responders in terms of cfu reductions. conclusion: the loss of atle had no impact on the mics of cloxacillin and vancomycin. conversely, the mutant atle(−) strain was less susceptible to bactericidal activity of both antibiotics, supporting the implication of atle in the tolerance of s. epidermidis to cell wall active antibiotics. the loss of atle did not alter the virulence of s. epidermidis in the mouse peritonitis model, whereas it decreased virulence in previously published experiments using an intravenous catheter infection model. therefore, the mouse peritonitis model was suited to compare antibiotics efficacy against atle(+) and atle(−) strains. our results showed that the loss of atle did not alter significantly the activity of cloxacillin and vancomycin in the mouse peritonitis model. this study shows that the loss of atle results in decreased susceptibility to bactericidal activity of cell wall active antibiotics, with no apparent impact on the activity of these antibiotics in the mouse peritonitis model. in infant rat pneumococcal meningitis, ceftriaxone plus daptomycin versus ceftriaxone attenuates brain damage and hearing loss while ceftriaxone plus rifampicin versus ceftriaxone does not d. grandgirard, m. burri, k. oberson, a. bühlmann, f. simon, s.l. leib°(berne, ch) objectives: lytic antibiotics for therapy of bacterial meningitis (bm) increase the release of pro-inflammatory bacterial compounds which, in turns, induce inflammation. exacerbation of the inflammatory response in cerebrospinal fluid (csf) contributes to the development of neurological sequelae in survivors of bm. daptomycin, a nonlytic antibiotic acting on gram-positive bacteria has been shown to decrease inflammation and brain injury vs. ceftriaxone in experimental pneumococcal meningitis. with a view on the clinical application for empiric therapy of paediatric bacterial meningitis we investigated, whether therapies combining daptomycin or rifampicin with ceftriaxone are beneficial when compared to ceftriaxone monotherapy in infant rat pneumococcal meningitis. methods: eleven day old wistar rats were infected by intracisternal injection of s. pneumoniae and animals were treated with daptomycin (10 mg/kg, s.c., daily) plus ceftriaxone (100 mg/kg, s.c., bid), rifampicin (20 mg/kg, i.p., bid) plus ceftriaxone or ceftriaxone alone. csf was sampled at 6 h and 22 h after the initiation of therapy and assessed for concentrations of chemo-and cytokines (mcp-1, mip-1a, il-1b, il-6, il-10; il-18 and tnf-a). a subset of animals was sacrificed 40 h post infection (h pi) and brain damage quantified by histomorphometry. the remaining animals were treated for 3 d and were tested for hearing loss, by assessing the auditory brainstem response (abr) at 3 weeks after infection. results: compared to ceftriaxone alone, daptomycin plus ceftriaxone significantly (p < 0.04) lowered csf concentrations of mcp-1, mip-1alpha and il-6 at 6 h and mip-1a and il-1b at 22 h after initiation of therapy, led to significantly (p < 0.01) less apoptosis assessed at 40 h pi, and significantly (p < 0.01) improved hearing capacity. while rifampicin plus ceftriaxone also led to lower csf inflammation (p < 0.02 for il-6 at 6 h), apoptosis and hearing loss were not significantly different from the ceftriaxone group. conclusion: compared to ceftriaxone monotherapy, daptomycin plus ceftriaxone lowers the level of pro-inflammatory mediators in the csf and reduces hippocampal apoptosis and hearing loss in infant rat pneumococcal meningitis. d. croisier-bertin°, l. piroth, p.e. charles, d. biek, y. ge, p. chavanet (dijon, fr; alameda, us) objectives: ceftaroline (cpt) is a novel, parenteral, broad-spectrum cephalosporin exhibiting bactericidal activity against gram-positive organisms, including methicillin-resistant s. aureus (mrsa) and multidrug-resistant s. pneumoniae, as well as common gram-negative pathogens. the efficacy of simulated human dosing with cpt or ceftriaxone (cro) was evaluated in a rabbit model of penicillin-resistant pneumococcal pneumonia. methods: 3 s. pneumoniae strains were used to induce pneumonia in rabbits: pssp, pisp, and prsp. mics (mg/l) were 0.06/0.015, 1/0.125, and 4/0.25 for cro and cpt, respectively. the animals were randomised to no treatment (controls), intravenous (iv) cpt human equivalent (he) dosage (600 mg/12 h), iv cro he dosage (1 g/24 h), or intramuscular (im) cpt (5 or 20 mg/kg) for prsp-infected rabbits. serum levels were measured by microbiological assay and pk data were obtained. evaluation of efficacy was based on bacterial counts in lungs and spleen (per gram tissue). results: 5−7 animals/group were tested. for iv cpt/iv cro, mean auc0−24 was 155/938 mg.h/l, cmax was 20/158 mg/l and cmin was 1.3/6 mg/l, respectively. bacterial counts in target tissues are listed in the iv cpt and iv cro were highly efficacious against pssp and pisp. iv and im cpt were superior to iv cro against prsp with a quasi sterilisation of lungs and spleen. combined results from the iv and im studies indicated that %t > mic for cpt of 30% and 45% were associated with 50% and 100% bacterial count reductions, respectively. in this rabbit model of penicillin-resistant pneumococcal pneumonia, cpt administered iv (with he dosing) or by im administration was more effective against prsp than iv cro. r. endermann°, d. hoepker, k. merfort, m. glenschek-sieberth (wuppertal, de) objective: moxifloxacin (mxf) is approved in the usa and other countries for the treatment of complicated intra-abdominal infections (ciais). we compared the efficacy of mxf with piperacillin/tazobactam (pip/taz), a commonly used treatment for ciais, in three different models: ( . c. clp model: survival over 10 days was significantly higher in the mxf group than in the pip/taz group (p < 0.0001). conclusions: using humanised dosages, mxf had greater antimicrobial activity and provided higher survival rates that pip/taz in three different models for ciai. m. nairz, i. theurl, a. schroll, m. theurl, s. mair, t. sonnweber, g. fritsche, r. bellmann-weiler, g. weiss°(innsbruck, at) mutations in hfe predispose to hereditary haemochromatosis type i, a frequent genetic disorder characterised by progressive parenchymal iron deposition and eventual organ failure. since hfe mutations are associated with reduced iron levels within mononuclear phagocytes, we hypothesized that hfe deficiency may be beneficial in infections with intramacrophage pathogens. using hfe+/+, hfe+/− and hfe−/− mice in a model of typhoid fever, we found that animals lacking one or both hfe alleles are protected from systemic infection with salmonella typhimurium, displaying prolonged survival and improved bacterial control. this increased resistance can be referred to an enhanced production of the siderophore-binding peptide lipocalin 2 and the reduced availability of iron for salmonella engulfed by hfe deficient macrophages. this effect is mediated via stimulation of lipocalin 2-dependent iron export from infected cells since hfe−/− macrophages concurrently knocked out for lipocalin 2 are unable to efficiently control the infection or to withhold iron from intracellular salmonella. correspondingly, infection of hfe+/+ and hfe−/− mice with siderophore deficient salmonella abolishes the protection conferred by the hfe defect. thus, by inducing the formation of the iron-capturing peptide lipocalin 2, the hfe mutation harbours a genetically determined immunological advantage towards infections with intracellular pathogens such as salmonella. i. koutelidakis, a. kotsaki, p.d. carrer, k. louis, a. savva, e.j. giamarellos-bourboulis°(thessaloniki, athens, gr) objective: the majority of clinical trials of immunointervention in severe sepsis have failed to disclose survival benefit. a likely explanation may be administration of therapy when immunoparalysis of the septic host supervenes. in an attempt to reverse immunoparalysis, injection of mononuclear cells was attempted in experimental sepsis by multidrugresistant pseudomonas aeruginosa (mdrpa). methods: peripheral blood mononuclear cells (pbmcs) diluted in rpmi were isolated from five healthy human volunteers after gradient centrifugation over ficoll. 1×10 7 /kg of one mdrpa live or heat-killed isolate from one patient with severe sepsis was injected intraperitoneally for bacterial challenge. a total of 72 male c57b6 mice were studied divided into four groups: group a (n = 26) pre-treated with rpmi and challenged after one hour with live isolate; group b (n = 26) pretreated with 5×10 7 pbmcs/kg and challenged after one hour with live isolate; group c (n = 10) pre-treated with rpmi and challenged after one hour with heat-killed isolate; group d (n = 10) pre-treated with 5×10 7 pbmcs/kg and challenged after one hour with heat-killed isolate. survival was recorded for 20 mice of groups a and b and for all mice of groups c and d. six mice of groups a and b were sacrificed six hours after challenge. blood was collected from the lower vena cava and tnfalpha and il-6 were estimated in serum by an enzyme immunoassay. bacterial growth of liver and lung at the same time was assessed. results: median survival of group a was 24 hours and of group b 88 hours (log-rank: 4.524, p: 0.033). nineteen animals of group a died (95%) compared with eight animals of group b (40%, p: 0.038). four animals of group c died (40%) compared with nil animals of group d (0%, log-rank: 4.274, p: 0.03). median serum tnf-a of groups a and b at sacrifice was 31 and 184 pg/ml respectively (p: 0.048). respective values for il-6 were 2084 and 2231 pg/ml (pns); for liver bacterial cells 3.63 and 4.99 log10 cfu/g (pns); and for lung bacterial cells 2.56 and 4.22 log10 cfu/g (pns). conclusions: allogeneic transplantation with pbmcs prolonged survival in experimental sepsis by mdrpa. its mechanism of action was related with a) blockade of cell wall structures as shown by survival experiments with heat killed isolate; and b) reversal of immunoparalysis as evidenced by increase of serum tnf-a. this approach creates a promising novel perspective for immunointervention in sepsis. a. marangoni°, c. nanni, m. donati, r. aldini, d. di pierro, s. trespidi, s. accardo, s. fanti, r. cevenini (bologna, it) objectives: chlamydia trachomatis is one of the world's major causes of sexually transmitted diseases of the cervix and urethra and it is a major agent of pelvic inflammatory disease. genital tract infection of female mice with chlamydia muridarum closely mimics acute genital tract infection in women. aim of this study was to assess the predictivity of 68ga-chloride small animal positron emission tomography ( o387 inadequate statistical power of published comparative cohort studies on ventilator-associated pneumonia to detect mortality differences between the compared groups m. falagas°, v. kouranos, a. michalopoulos, s. rodopoulou, a. athanasoulia, d. karageorgopoulos (athens, gr) objective: comparative cohort studies are often conducted to identify novel therapeutic strategies or prognostic factors for ventilator-associated pneumonia (vap). we aimed to evaluate the statistical power of such studies to provide statistically and clinically significant conclusions. methods: we searched in pubmed and scopus for comparative cohort studies evaluating the mortality of patients with vap. we calculated for each of the included studies the statistical power to detect the observed difference in mortality between the compared groups (observed power), as well as 3 expected, clinically relevant, effect sizes (expected power). we identified 39 (20 prospective) comparative cohort studies on vap as eligible for inclusion in this analysis. the median observed power of these studies was 17.9% [interquartile range (iqr), 9.8−52.4%]. the median expected power was 10.0% (iqr, 7.2−13.6%) for a risk ratio for mortality of 0.85 between the compared groups; 14.7% (iqr, 10.6−21.8%) for a risk ratio of 0.80; and 7.9% (iqr, 6.3−10.2%) for a reduction in mortality from 30% to 25%. all expected power measures were significantly lower than the observed power. the statistical power of most cohort studies to detect the observed difference in mortality between compared groups of patients with vap is low. the power is even lower when expected, clinically relevant, differences in mortality are considered. for a wiser utilisation of resources allocated to research, we favour the conduction of cohort studies with larger sample size so that potential differences between the compared groups are more likely to be shown. objective: to clarify issues regarding the frequency, prevention, outcome, and treatment of patients with ventilator-associated tracheobronchitis (vat), which is a lower respiratory tract infection involving the tracheobronchial tree, while sparing the lung parenchyma. methods: we performed a systematic review and meta-analysis of relevant available data, gathered though searches of pubmed, scopus, and reference lists, without time restrictions. a conservative random effects model was used to calculate pooled odds ratios (or) and 95% confidence intervals (ci). results: out of the 564 initially retrieved articles, 30 papers were included. frequency of vat was 10.2%. selective digestive decontamination was proved an effective preventive strategy against vat. presence, as opposed to the absence, of vat was not associated with higher mortality (or: 1.18, 95% ci 0.90−1.53). administration of systemic antimicrobials (with or without inhaled ones), as opposed to placebo or no treatment, in patients with vat was not associated with lower mortality (or: 0.56, 95% ci 0.27−1.14). most of the studies providing relevant data noted that administration of antimicrobial agents, as opposed to placebo or no treatment, in patients with vat was associated with more ventilator-free days and lower frequency of subsequent pneumonia, but without shorter length of intensive care unit stay or shorter duration of mechanical ventilation. conclusions: approximately one tenth of mechanically ventilated patients suffer from vat; an infection potentially prevented by the implementation of selective digestive decontamination. antimicrobial treatment of patients with vat may protect against the development of subsequent ventilator-associated pneumonia. degranulation. subsequently, allergen specific ige to chlorhexidine was demonstrated and skin prick/intradermal testing was positive to chlorhexidine, confirming the diagnosis of chlorhexidine-precipitated anaphylaxis in each patient. a detailed review of the case-notes revealed that each patient had manifest evidence of minor cutaneous reactions to pre-operative chlorhexidine use that had not been ascribed to chlorhexidine at the time. discussion: fda issued a public health notice [1998] following 1st description of anaphylaxis to chlorhexidine coated central venous catheter. a recent case cluster has also been reported from another cardiac centre in the uk [3-cases over a 9-month period]. references to be presented. it is interesting that these reports of chlorhexidine anaphylaxis have all occurred in patients undergoing cardiac surgery. these patients receive multiple exposures to chlorhexidine during their pre-operative investigations and preparation. this has increased recently as a result of the drive to reduce the incidence of hospital-acquired infections. we wish to postulate that these patients have been sensitised by repeated topical exposure to chlorhexidine and have exhibited anaphylaxis when this allergen was presented to the patient in the form of the chlorhexidine coated central venous catheter. type i strains of helicobacter pylori possess the cag pathogenicity island to deliver virulence factors. cag is a specialised type iv secretion machinery that is activated during infection and comprises 31 genes originated from a distant event of horizontal transfer. after translocation the effector protein caga is phosphorylated on tyrosine residues restricted to a previously identified repeated sequence called d1. this sequence is located in the c-terminal half of the protein and contains the five amino acid motif epiya, which is amplified by duplications in a large fraction of clinical isolates. tyrosine-phosphorylation of caga is essential for the activation process that leads to dramatic changes in the morphology of cells growing in culture. in addition, we observed that two members of the src kinases family, c-src and lyn, account for most of the caga-specific kinase activity in ags cell lysates. translocated caga interacts with the zo-1 and jam host-cell proteins causing disruption of the apical junctional complex. transfection of the caga gene into polarised epithelial cells induces disruption of cell-to-cell contacts and altered morphology. strikingly caga-expressing cells become migratory and invasive penetrating into collagen gel. the study of different portions of the molecule revealed the presence of two distinct functional domains and both are necessary to induce abnormal cell differentiation through interactions with host cell morphogens. cell polarity and invasion have been suggested to contribute to both early and late stages of cancer formation. these results suggest a mechanism by which caga may acts at the early stage of tumorigenic progression causing loss of cell polarity, increased cell motility and invasiveness of epithelial cells. after a period of 50 years of silence, a disease with an unpronouncable name, "chikungunya" (chik), has recently become a medical reality and reached the public throughout the world. conclusion: low mhla-dr expression after septic shock independently predicts ni. this promising biomarker may be of major interest in identifying patients at increased ni risk who could benefit from targeted and tailored therapy aimed at restoring immune functions. pneumonia, the leading infectious cause of death in the us, kills more people annually than aids, tuberculosis, meningitis and endocarditis combined. from a wide range of observational studies of communityacquired pneumonia (cap), only half of the cases had an aetiologic agent identified. streptococcus pneumoniae was consistently the predominant bacterial aetiology. this lecture will primarily focus on the innate immune response to pneumococcal pneumonia. toll-like receptors (tlrs) are key molecules that recognize pathogen associated molecular patterns (pamps) and induce an inflammatory response. pneumolysin, an intracellular toxin found in all s. pneumoniae clinical isolates, is an important virulence factor of the pneumococcus that is recognized by tlr4. although tlr2 is considered the most important receptor for gram-positive bacteria, tlr2 does not play a decisive role in host defence against s. pneumoniae pneumonia; likely, pneumolysin-induced tlr4 signalling can compensate for tlr2 deficiency during respiratory tract infection with s. pneumoniae. besides tlr2 and tlr4, tlr9 contributes to an effective host defence against s. pneumoniae in the airways. the importance of tlr signaling for host defence against pneumococcal pneumonia is illustrated by the fact that mice lacking the common tlr adaptor protein myd88 are highly susceptible to this infection. activation of tlrs results in the production of proinflammatory cytokines. there is ample evidence that underlines the importance of tumour necrosis factor (tnf) and interleukin (il)-1 in host defence in bacterial pneumonia: in a murine s. pneumoniae pneumonia model, treatment with a neutralising anti-tnf mab strongly impaired antibacterial defence. in addition, il-1a receptor type i deficient mice infected with s. pneumoniae displayed an increased bacterial outgrowth. of considerable interest, treating il-1 receptor deficient mice with a neutralising anti-tnf antibody made them extremely susceptible to pneumococcal pneumonia. infection of the lower airways by s. pneumoniae is associated with complex interaction between the pathogen (e.g. cell wall components, pneumolysin) and the host (e.g. tlrs, cytokines). these interactions play a crucial role in the outcome of this clinically important infection. severe bacterial pneumonia remains uncommon unless specific conditions exist that tip the balance between the host and pathogen in favour of the microorganism. such conditions include: persons at the extremes of age; exposure to especially virulent organisms; patients with concomitant illness impairing pulmonary clearance mechanisms; and immunocompromised hosts. pathogens overcome an array of innate and acquired host defences to successfully invade the host. the known virulence traits of three common respiratory pathogens (streptococcus pneumoniae, staphylococcus aureus, and pseudomonas aeruginosa) will be briefly reviewed. the capsular polysaccharide of pneumococci is the major anti-phagocytic virulence trait but many other factors contribute to disease pathogenesis including the critically important exotoxin known as pneumolysin, bacteriocins, adherence factors, choline binding proteins, lipoteichoic acid, iron, manganese and magnesium transporters, pili, competence and biofilm capacity, and virulence genes that promote invasion and impair clearance once the organism has entered the blood stream. s. aureus is notorious for the numerous a/b type toxins, cytotoxins, and superantigens it generates during the course of invasion. staphylococci deploy a complex series of quorum sensing signals that coordinate adhesin and invasion genes within biofilms or between planktonic organisms and likely contribute to the success of this pathogen. p. aeruginosa produces an array of extracellular exotoxins and cytotoxins delivered by type iii secretion systems. these include elastase, phospholipases c, a series of apoptotic and anti-phagocytic exotoxins, along with an alginate capsule and an unusual and variable lps structure that participate in microbial invasion. the pathogen expresses at least three interacting, quorum sensing systems to coordinate virulence and biofilm formation. a detailed understanding of these virulence factors is now providing therapeutic options to control these respiratory pathogens. surface expressed and extracellular toxins of pneumococci have been selected as new vaccine targets. inhibitory peptides and small molecule inhibitors of quorum sensing and biofilm formation are under investigation for staphylococcal and p. aeruginosa infections. these innovative and non-antibiotic treatment strategies are gaining greater importance as progressive antibiotic resistance threatens the management of these severe bacterial infections in the future. brucellosis, possibly the commonest zoonotic infection worldwide, has troubled humans since antiquity. recent years have seen the expansion of the animal reservoir of the disease to a wide spectrum of wildlife species, extending to marine mammals, and the recognition of novel brucella species. furthermore, animal and human disease has re-emerged in numerous countries which were brucellosis-free, and currently the most important endemic foci include near east and central asia. complex socioeconomic and political factors may be incriminated for these alterations in endemicity. the complex mechanisms by which brucella evades immune response and survives intracellularly are progressively clarified. novel diagnostic techniques as real time pcr may shed light in the life cycle of brucella inside the human host; preliminary studies have indicated that the pathogen may persist in latent form for years after apparent clinical cure, in asymptomatic individuals. treatment principles have not evolved significantly. the expert guidelines issued recently under the name of "ioannina recommendations" support the need for a six-week combined treatment that includes traditional antibacterials and is modified accordingly in serious complications as spondylitis and central nervous system involvement. the road to the development of a vaccine for humans seems long though. anthrax is ancient diseases and relatively a forgotten disease in western world until 2001 when spores were mailed in usa causing five deaths. currently, human anthrax is seen most commonly in agricultural regions of the world where anthrax in animals is prevalent, in which countries of middle east, in africa, central asia and south america. it is also an endemic disease in turkey. human cases may occur in an agricultural or an industrial environment. the infection is an occupational hazard of workers who process hides, hair, bone and bone products, and wool and of veterinarians and agricultural workers who handle infected animals. the main route of transmission is contact with or ingestion of contaminated meal with or inhalation of bacillus anthracis spores. leptospirosis is a very old disease that has been known for more than a hundred years and possibly even longer since the time of hippocrates. it remains a major cause of illness in many tropical and subtropical countries and thus in travellers. it has also been identified as a zoonosis in europe and north america. it is a disease that can surprise us because the clinical presentations are not always typical. in recent years, pulmonary and other atypical presentations have been more widely recognised. there is no effective vaccine but chemoprophylaxis is effective in selected populations. prompt recognition and early institution of appropriate treatment as with most other infectious diseases appear to be critical in ensuring a good outcome for our patients. there are interesting new developments in diagnostics and molecular epidemiology but clearly there are many challenges remaining in this field. objectives: the spread of carbapenemase genes within gram negative bacteria is of great cause for concern. in 2008, the first report of a blaoxa-58 gene outwith acinetobacter baumannii was reported in acinetobacter genospecies 3. we had also identified a genospecies 3 isolate encoding a blaoxa-58-like gene, and the aim of this study was to examine the genetic environment of the gene to investigate the mobilisation between species. methods: restriction analysis of rrna was used to confirm identity to the species level. susceptibility to imipenem and meropenem was determined through the plate doubling dilution method. screening by pcr for blaoxa-51-like, blaoxa-23-like, blaoxa-40-like and blaoxa-58-like genes was carried out. analysis of the genetic environment surrounding the blaoxa-58-like gene was conducted by sequencing inverse pcr products and gene-walking fragments. the structure of the surrounding sequence was confirmed using internal primers, which were also used to screen other blaoxa-58-like positive isolates in our collection. results: restriction analysis confirmed the isolate belonged to acinetobacter genospecies 3. the isolate showed reduced susceptibility to imipenem and meropenem with mics of 2 mg/l for both antibiotics. the isolate was negative for a blaoxa-51-like, blaoxa-23-like or blaoxa-40-like gene, but positive for a blaoxa-58-like gene. analysis of the genetic environment of the blaoxa-58-like gene revealed the gene was within a novel genetic structure. upstream of the blaoxa-58-like gene was the left-hand end of an isaba3 element, interrupted by an isaba125 element. the elements contained putative promoter sequences. downstream was an arac1 and a lyse gene, followed by a sequence similar to the re27 element described previously. following this was a complex region containing the right-hand end of an isaba3 tnpa gene, interrupted by an incomplete tnpa gene with 99% similarity to isaba3, itself interrupted by an isaba125 sequence. this region was followed by a second blaoxa-58-like gene. all other blaoxa-58-like positive isolates in our collection were negative for isaba125 upstream of blaoxa-58. this study is the first to report multiple copies of a blaoxa-58-like gene in an acinetobacter genospecies 3 isolate, and has identified a novel structure containing two blaoxa-58-like genes and two isaba125 sequences. the isaba125 elements may be responsible for the duplication of the blaoxa-58-like gene. objective: acinetobacter baumannii is an important nosocomial pathogen with wide intrinsic resistance. however, due to the dissemination of the acquired resistance mechanisms; such as extended-spectrum beta-lactamase (esbl) and metallo betalactamase (mbl) production, multidrug resistant strains have been isolated more often. per-1 was first detected in turkey and was found to be widespread among acinetobacter spp. and p. aeruginosa. since then, per-1 has been discovered in other countries, and most recently found in northern italy and in korea. in this study, the presence of per-1 type esbl was investigated in caftazidime resistant a. baumannii strains isolated from bloodstream infections by pcr and also the clonal relatedness of the isolates were investigated by random amplified polymorphic dna (rapd) and pulsed field gel electrophoresis (pfge) in all per-1 producing a. baumannii strains. methods: a. baumannii strains isolated from bloodstream infections was included in this study. the isolates were identified as a. baumannii by conventional methods and phoenix 100 bd automated system system (becton dickinson diagnostic systems, sparks). ceftazidime resistance was determined by e-test. per-1 genes were screened by these clusters encode: (i) resistance genes and transporters plausibly involved in drug efflux (30 transporters of the mfs, dmt, abc, rnd, mop and acr3 families were unique of drug resistant strains and absent in the susceptible sdf strain); (ii) pili and fimbriae systems related to biofilm formation and motility; (iii) haemolysin-and haemagglutininrelated proteins differently distributed among the four genomes, (iv) iron uptake and other metabolic genes. conclusion: genome comparison identified unique features of a. baumannii epidemic clones and provided novel insights into the genetic basis of multidrug resistance and pathogenesis in this species. this study may contribute to understand the concept of infection, invasiveness and colonisation in the emergent pathogen a. baumannii. hard to swallow − emerging and re-emerging issues in food-borne infection (symposium arranged with efwisg) s460 mrsa in food products: cause for concern or case for complacency? in 2003 first, a switch from intravenous-to oral medication (01-2006); second, education programs for interns/residents and physicians and the release of a new antimicrobial formulary (05-2006); third, a restriction note was printed on all laboratory rapports (10-2006) and fourth, active monitoring and giving feedback on prescriptions (01-2007). susceptibility patterns for e. coli including ciprofloxacin, cefuroxim, ceftazidim, co-trimoxazole and tobramycin from hospitalised patients were analyzed starting in 2004. statistical analyses were performed using segmented poisson regression models to look at effect of interventions on resistance (both sudden stepwise changes and changes in trends). bayesian model averaging was used to account for model uncertainty. results: before the start of the interventions the resistance rate was increasing by an average of 2.6% per year. the interventions resulted in a significant reduction of quin use from on average 550 prescribed daily doses to 350 pdd per month. in the best fitting poisson model for the resistance data, a significant stepwise decrease was found to be associated with interventions 2 and 4. however, there was substantial uncertainty in the model choice, and after accounting for this there was no conclusive evidence in support of any particular intervention, although there was evidence that at least one of the interventions was associated with the observed reduction in resistance. there were no stepwise decreases or decreasing trends in resistance rates to other antimicrobials during the study period. conclusion: many mds prescribe antibiotics often and believe their practice may have an effect on antibiotic resistance. results indicate that mds value information, interventions and surveillance in order to support responsible use of antibiotics. there is an ongoing effort in germany to address these findings at the national level e.g. by establishing a surveillance system for antibiotic resistance and antibiotic usage. table) . . ir for pn, er and tt were always higher in children (ch) than in adults (ad). significant differences were found for pn (1995), er (1997 er ( , 2004 er ( , 2006 er ( , 2007 er ( , 2008 , tt (2004 tt ( , 2006 . generally, cp-ir was higher in ad than in ch. ir was lower in the north (n) than in the south (s). significant differences: pn (2005 pn ( , 2006 , er (2003 er ( , 2004 er ( , 2005 , tt (2005) . both n and s knew a deceasing ir tendency: pn= n (12.1−8.1), s (18.8−13.2); cp= n (11.6−5.9), s (18.9−5.9); tt= n (27.4−21.5), s (35.9−23.5). er increased in the n (20.9−29.7). total outpatient antibiotic use (did) decreased from 26.2 (1999) to 22.7 (2004) and increased to 24.2 (2006) . did for pn and fq increased, mls stabilised and tt decreased. conclusions: since 2001-2003 an ir decrease was noted for pn, cp and tt. er-ir increased further over the years. the decrease paralleled the start of public campaigns on antibiotic use. ir rates remain higher in ch than in ad. the n/s difference became less marked. objectives: parachlamydia acanthamoebae is a new recognized member of the order chlamydiales. growing evidences suggest that this bacteria may have a pathogenic role in humans causing respiratory diseases. it has also been recently identified as an agent of bovine abortion and may be a cause of miscarriage in women. in contrast, little is known about the pathogenic role of rhabdochlamydia crassificans, another related chlamydiales. molecular diagnostic tools are useful to detect these obligate intracellular bacteria because of their inability to grow on conventional culture media. the aim of this work was (i) to develop a real-time pcr for the diagnosis of rhabdochlamydia infection and (ii) to study respiratory secretions of newborns for the presence of parachlamydia and rhabdochlamydia dna. methods: a new quantitative real-time taqman pcr (q-pcr) to be used on abi prism 7900 was developed. the q-pcr was then blindly applied to 41 consecutive respiratory samples (endotracheal or nasopharyngeal secretions) taken from 29 critically-ill newborns admitted in the neonatology ward of our university hospital. these samples were also tested using a previously developed parachlamydiaspecific pcr. results: most newborns (28/29) were premature (median gestational age: 28.6 weeks; range: 24.6−41.2). initial respiratory distress syndrome was present in 86% of them. positive pcr results were obtained in 12/29 (41%) patients (8 parachlamydia, 3 rhabdochlamydia, 1 both species) at a median of 17.5 days (range: 2-230) after birth. when compared to the control group (17 patients with negative pcr), these 12 newborns had a significantly worse primary adaptation and a higher incidence of resuscitation maneuvers at birth (table) . duration of noninvasive mechanical ventilation and stay in neonatology ward were also significantly longer. a fatal issue was observed in 3 infected cases, as compared to no death in controls (p = 0.06). gestational age at birth as well as the incidence of pulmonary or systemic infections did not differ between cases and controls. conclusion: a high prevalence of parachlamydia and rhabdochlamydia dna was observed in respiratory secretions of premature critically-ill newborns. the presence of dna of these microorganisms was associated with a worse primary adaptation, a more severe respiratory distress syndrome and a trend towards a higher mortality. their pathogenic role should be further investigated. the genus kingella consists of 3 species, k. kingae, k. oralis and k. denitrificans. all are gram negative, sometimes difficult to stain, rod shaped bacteria that are normal respiratory and genitourinary flora. they are slow-growing and fastidious. although improved recovery was shown when using fan or peds-f blood culture bottles, the majority of these infections remain undetected, especially in pre-treated patients. we report the use of real time polymerase chain reaction (rt-pcr) assays for detection of k. kingae and s. aureus in paediatric osteoarticular infections. methods: 116 synovial fluid samples from 97 patients, 1 month and 17 years of age, were collected over 19 months (03/2006 to 10/2007). the samples were from 54 knees, 39 hips, 9 ankles, 6 elbows, 4 shoulders, 2 wrists and 2 femur abscesses. after automated dna/rna extraction, specimens were subjected to 4 hour pathogen-specific rt-pcr. samples were inoculated onto sheep blood and chocolate agar as well as a peds-f bottle. final species identification and antimicrobial susceptibilities were determined by phoenix (tm). results: 45 patients (56 specimens) had positive culture and/or rt-pcr, resulting in an overall positivity rate of 46%. s. aureus was the predominant pathogen accounting for 31 specimens of 23 patients (12 mrsa, 11 mssa) and. 37% of positive specimens (18 patients) were due to k. kingae (n = 21). among children 0−2 years (n = 35), k. kingae was the predominant pathogen accounting for 16 positive patients (46%), followed by mssa in 4 patients (11%). the positivity rate for this age group was 57%. only 2 children >2 years (5 and 9 years) were positive for k. kingae. mrsa was the predominant pathogen in 6−12 year olds, and mssa was evenly distributed among children 3−17 years old. culture detected only 5 of 21 specimens positive for k. kingae and 25 of 31 s. aureus. 4 other pathogens were detected by culture only. the use of these molecular assays enhances detection of organisms, especially for k. kingae (19% vs. 5% for culture). additionally, faster identification (tat 4 hrs) allows for rapid targeted therapy. this improvement in tat could lead to shorter hospital stays in about 54% of cases. results: genotyping revealed a high degree of diversity, indicative of a panmictic bacterial population. further, there was no association between genotype and colonisation frequency, or year of isolation. pcr screening for virulence genes revealed an incidence of 98% for uspa1, 81% for hag, 82% for uspa2 and 18% for uspa2h. no significant difference was observed in the prevalence of virulence-associated genes between isolates originating from children who were colonised only once or children colonised on all 3 occasions (p = 1). pcr-rflp analysis of uspa1, hag and uspa2 showed many gene variants, with no association between pcr-rflp patterns and colonisation frequency, or year of isolation. conclusion: even in relatively localised geographical settings, the genotypic diversity of m. catarrhalis isolates colonising children is large, with no yearly pattern of genotype predominance. children serially colonised with m. catarrhalis isolates appear to clear a particular genotype only to become subsequently colonised with a different genotype. the incidence of virulence genes in this relatively localised study group is remarkably similar to that reported in global m. catarrhalis isolates, possibly indicating that similar selection pressure exists for m. catarrhalis at both the local and global level. virulence gene variation appears to be high, even in this relatively restricted geographical group. these results could have consequences for vaccines designed against virulence genes. a. naessens°, i. foulon, a. casteels, w. foulon (brussels, be) objectives: to evaluate the epidemiology of cytomegalovirus in pregnancy and to evaluate the risk for delivering a child with congenital cmv (ccmv). methods: between 1996-2006, 11825 unselected mother-infant pairs were included. in the mother a serological screening was performed consisting in the detection of cmv igg and igm antibodies at the first prenatal visit and at birth. in the neonate cmv urine culture was performed to diagnose congenital infection. when a pregnant woman was found to have a second trimester spontaneous abortion or a death in utero, an investigation for possible congenital cmv infection was carried out. results: serological screening at the first prenatal visit showed no immunity in 4701 women, evidence of past infection (igg positive igm negative) in 6877 women (58.2%) and in 250 women (2.0%) both igg and igm antibodies were detected. after investigation of stored and follow up samples from these 250 patients, 14 could be classified as having a primary cmv infection during pregnancy, 99 patients had previous immunity before the current pregnancy and from 137 patients the type of the maternal cmv infection could not be determined. follow-up serology of the 4701 women without immunity revealed a seroconversion in 58 of them (1.2%). a total of 61 (0.52%) congenital infections (ccmv) were diagnosed. the incidence of the ccmv among the different groups of women are summarised in the table. conclusion: ccmv infection occurs in 0.52% of our population of pregnant women. ccmv was considered to be due to a primary maternal cmv infection in 54% of the infants; 33% due to a recurrent maternal cmv infection and in 13% the type of maternal infection could not be determined. the risk for a seronegative pregnant woman of acquiring cmv during pregnancy is 1.2%. the transmission risk after a maternal primary infection is 45%. women with prior immunity have a very low risk (0.20%) for ccmv, this risk increases to 3% when igm are find in women with know prior immunity. the risk for women with undetermined infectious status in early pregnancy to give birth to a congenitally infected neonate is 5.8%. this report provides the first data on rotavirus epidemiology and disease burden in norway. further studies are needed to assess the economic impact of rotavirus disease and the cost-effectiveness of vaccination to inform decisions on introduction of rotavirus vaccines into the national program of childhood immunisation. pseudomonas aeruginosa may colonise the lungs of cystic fibrosis patients over years but may also cause acute infections in mechanically ventilated patients and immuno-compromised hosts within a matter of days. despite aggressive antibiotic treatments the organism is rarely eradicated. instead p. aeruginosa adapts to its host environment by developing resistance mechanisms and changing its lifestyle and virulence properties. focusing on mechanically ventilated patients, we will detail the dynamics of resistance emergence and persistence of p. aeruginosa lung populations during antibiotic therapy. we further discuss how p. aeruginosa populations evolve naturally in the absence of any antimicrobial treatment within the lungs of intubated patients by changing their virulence properties. the relevance of these findings both with respect to concepts of social evolution and the development of novel anti-infective strategies will be highlighted. the genome of p. aeruginosa encodes many potential efflux systems. however, only a few of them appear to play a significant role in antibiotic resistance. in this respect, the mex (for multiple efflux) systems are of particular interest because of their ability to extrude a wide range of antimicrobials. these polyspecific machineries result from the assembly of (i) a drug/proton antiporter, (ii) a periplasmic adaptor protein, and (iii) an outer membrane gated channel. it is now well established that the constitutive expression of the tripartite pump mexab-oprm provides p. aeruginosa with a relatively high intrinsic resistance to quinolones, blactams (except imipenem), tetracyclines, macrolides, chloramphenicol, trimethoprim, and novobiocin. this protective mechanism is potentiated by the poor permeability of the outer membrane and activity of another pump, mexxy/oprm, whose expression is induced by substrates targeting the ribosome (e.g., tetracyclines, macrolides, aminoglycosides). accumulating reports indicate that multidrug resistant mutants upregulating one or both of these systems are quite common in the clinical setting. such mutants, which are readily selected by sub-optimal treatments with fluoroquinolones, b-lactams or aminoglycosides, tend to accumulate various resistance mechanisms without loosing the wildtype pathogenicity of p. aeruginosa. whether the low resistance levels (mic x 2-to 8-fold) conferred by efflux may promote second-step mutants with altered drug targets (gyra, gyrb, parc) or derepressed ampc b-lactamase has not been confirmed in vitro. in the specific context of cystic fibrosis (cf), a recent study from our laboratory showed that the mexxy/oprm pump can be responsible for much higher resistance levels to aminoglycosides (64-to 128-fold). this increased efficacy of the system partially results from adaptive mutations in the mexy gene. in contrast, subpopulations deficient in mexab-oprm tend to emerge during long-term colonisation of cf airways. while easily selected in vitro on selective media, mutants overexpressing other mex systems (mexcd-oprj, mexef-oprn, mexghi-opmd, mexjk/oprm, mexvw/oprm) have been rarely described in cf and non-cf patients. some data support the notion that up-regulation of mexcd-oprj or mexef-oprn might be detrimental to the virulence of p. aeruginosa. in conclusion, therapeutic strategies based on efflux inhibitors should target the mexab-oprm and the mexxy/oprm systems in priority. european aspects of malaria s478 rapid diagnostic tests for malaria: twenty years to convince . . . prompt diagnosis and treatment of malaria are critical factors in reducing morbidity and mortality. microscopy has long been the gold standard for malaria diagnosis, but the newer rapid diagnostic tests (rdts) now offer considerable advantages, especially so in endemic countries. after close to twenty years of development and operational research, the diagnostic performance of rdts is now established in all settings. meta-analyses have clearly demonstrated equivalence of rdts over expert microscopy to detect parasites, and clear superiority over routine microscopy. actually, one of the major reasons that have delayed successful implementation of rdt in endemic areas was the use of poor quality microscopy that has impeded reliable measurement of sensitivity and specificity and undermined confidence of health workers in rdts. other factors were poor product performance, inadequate methods to determine the quality of products and a lack of emphasis and capacity to deal with these issues. for the potential of rdts to be realised, it is crucial that high-quality products that perform reliably and accurately under field conditions are made available and that quality insurance is performed on all steps of the procedure. in achieving this goal, the shift from symptom-based diagnosis to parasite-based management of malaria can bring significant improvement for the management of fever in endemic areas. for travelers returning in temperate climates with fever, rdts have also the potential to improve diagnostic procedures, especially so in hospitals where reliable microscopy is not available out of hours. in patients with no danger sign or significant thrombopenia, a negative rdt is sufficient to exclude malaria and allows waiting 12−24 hours for performing or reading the microscopy slide. rdts should be repeated every 12−24 hours for three consecutive days if fever persists and in the absence of alternative diagnosis. rdts represent a revolution in the fight against malaria and will tremendously help to manage appropriately patients with fever, especially so when malaria is declining and hence other causes of fever increasing. the ambitious deployment that is foreseen in the coming years in africa through large grants from the global fund should contribute to achieving the millennium goals. fever is the key symptom of malaria among returning travellers (97%). headache, chills, myalgia, sweating and lack of a focus are frequently recorded, but non-specific. nausea and vomiting are often seen in children. the differential diagnosis of other infections, mainly of viral origin, is further difficult because (dry) cough and (mild) diarrhoea are often present. laboratory findings (thrombocytopenia, low or normal leucocyte count) can be helpful in the assessment of mild to moderate malaria. clinical signs and symptoms, e.g. fever, may be mitigated in semiimmune patients (visiting friends and relatives, foreign visitors) seen in non-endemic countries who represent the majority of cases diagnosed in industrialised countries. caution is warranted in assessing such patients as many of them may no longer be exposed to malaria in their countries of origin, thus no longer partially protected and also at risk of suffering from severe complications. up to 10% of all imported malaria cases may be severe, presenting with jaundice, impaired consciousness to coma, acute renal failure, and, in the course of events, acute respiratory failure. delay in diagnosis and start of treatment is partly responsible for fatality rates of 1% and more in some countries. if you don't look for them, you won't find them: anaerobes revisited s481 anaerobic microbiota of the mouth − friend or foe? anaerobes form a major part of the commensal microbiota in the digestive tract where they constitute an integral component of the function on mucosal surfaces. in the mouth, teeth create a unique, non-shedding environment for bacteria to attach and to form biofilms. there is an age-related succession order of species in bacterial colonisation of the mouth, and once established, individual anaerobic species tend to remain as members of the oral microbiota. the agerelated pattern of the colonisation of anaerobic bacteria is partly connected with the development (or loss) of the dentition. interactions between different bacteria residing in the same microenvironment influence the composition of the microbiota − or the development of pathologic conditions. although commensal bacteria are regarded beneficial to the host, some anaerobic members of the oral microbiota contain characteristics potentially detrimental for the health status of an individual. molecular means of characterisation have resulted in increased knowledge about the "normal" microbiota of the mouth and in detection of new species and genera as well as phylotypes, which can be associated with infectious situations in the mouth. oral infections are multifactorial and polymicrobial in nature, and their aetiologic organisms originate mainly from the oral resident microbiota. the involvement of anaerobes is most obvious in infections of root canals, periodontal tissues, and tissues surrounding erupting wisdom teeth where typical anaerobic findings are gram-negative rods. in addition, gram-positive anaerobic cocci and non-spore-forming gram-positive anaerobic rods are common in odontogenic infections. on some occasions, anaerobes of localised dentoalveolar infections can spread to adjacent tissues and even to the bloodstream, resulting in severe complications in extraoral sites. interestingly, a relatively limited number of anaerobic species are involved in clinically severe infections, however, microbial findings seem to vary depending on geography. concomitant with the increase in the number of immunosuppressed patients, the number of opportunistic infections caused by commensal anaerobes may increase. identification to the species level will help to establish associations between individual anaerobic species and specific disease states. studies on the bacteriology of diabetic foot infections (dfi) have yielded varied and often contradictory results. the role of anaerobes is particularly unclear, often because the type and severity of the infection is poorly defined, recent antibiotic therapy is unknown, and specimen collection and culture techniques are inadequate. when optimal collection, transport, and culture techniques are used, multiple organisms including aerobes and anaerobes are usually recovered from severe dfi. interactions within these polymicrobial soups lead to production of virulence factors, such as haemolysins, proteases, collagenases, and short chain fatty acids, which promote inflammation, impede healing and contribute to the chronicity of the infection. to better define the bacteriology of diabetic foot infections, we analyzed our data from a large prospective u.s. multicentre trial of patients with moderate to severe infection that required initial parenteral antibiotic therapy and used optimal post-debridement sample collection, transport and culture procedures. of the 427 culture-positive specimens (of 454 total), only 16.2% were pure cultures while 30.4% yielded 5 or more organisms. a total of 462 anaerobes (range 0−9, average 2.3, per specimen) were recovered from 49% of patients, with gram-positive cocci (gpc) accounting for 45.5% of all anaerobic strains. s485 is culture still the gold standard, really? tremendous technological advances are made in culture-independent methods of detection and identification of human bacterial pathogens, such as pcr or hybridisation of their genomic dna. yet, time honoured pastorian bacterial culture in liquid and solid nutritive media still remains the gold standard for the laboratory diagnosis of a majority of bacterial infections. this unusual robustness of a 19th century technology stems from its unmatched operational characteristics: 1. broad range of detected agents, depending on adequate combination of media/incubation conditions; 2. unlimited source of clonal population for individual isolate, allowing versatile characterisation of antibiotic susceptibility and/or pathogenic factor production and/or epidemiological subtyping; 3. possibility of storage/bio-banking of cells for complementary clinical testing, research and diseases surveillance collections; 4. proof of pathogenic role of agent at the time of viable cell isolation from the site of infection, in contrast to false-positive results with molecular tests (tissue translocation or persistence of bacterial dna, soluble antigen,. . . ). major drawbacks of bacteriological culture include long turn-around time, cost and labour/skill intensity. these are partly alleviated by new technologies, including automated processing, physical/chemical growth detection and rapid molecular fingerprinting (maldi-tof, raman spectrometry, 16s rdna snp detection). it is likely that the next decade will see a complete redefinition of the place of direct detection methods and culture-based confirmation methods in clinical bacteriology, enabling a rejuvenation rather than elimination of culture as a daily diagnostic tool. the advent of real-time pcr revealed instrumental to the successful implementation of molecular methods in routine clinical microbiology laboratories. automated nucleic extraction platforms can now be coupled to robotic handling for large-scale detection and quantification purposes, mostly in virology. i will review here the attempts of implementing home-brew and commercial nucleic-acid based detection methods directly from blood samples and highlight hopes and pitfalls. i will then expand on two promising nucleic acid amplification methods: lamp (loop mediated isothermal amplification) and a protein-free method called dnazyme. these isothermal amplification methods share several strengths: robustness across highly diversified physico-chemical conditions, versatility in assay development and minimal requirements (if any) for sample preparation. they will definitely compete against current real-time pcr assays and might become a novel standard, due to lower costs and improved performances. the ribosomal rna (rrna) approach to microbial evolution and ecology has become an integral part of microbiology. rapidly growing databases exist that encompass besides the 16s rrna sequences of almost all validly described bacteria and archaea also numerous 16s rrna sequences of so far uncultivated microbes, directly retrieved from the environment by pcr or metagenomics. based on the patchy evolutionary conservation of rrna genes oligonucleotide probes can be designed in a directed way with specificities ranging from species up to large evolutionary entities like phyla or even domains. when such probes are labeled with fluorescent dyes or the enzyme horseradish peroxidase they can be used to identify single microbial cells by fluorescence in situ hybridisation (fish) directly in complex environmental samples. an update on recent applications and methodological improvements will be given which includes the identification of small bacterial cells by catalyzed reporter deposition (card)-fish. with optimised methods and proper controls fish yields exact cell numbers and spatial distributions for defined bacterial populations also in highly complex mixed microbial communities. r. amann & b.m. fuchs (2008) nature reviews microbiology 6:339-348. quick and reliable species identification of microorganisms is of great importance in medical microbiology. several bacterial and fungal species can be identified only using laborious and time-consuming methods. furthermore, in many cases misidentification occurs due to e.g. limited biochemical reactivity, different morphotypes or limited information in reference panels. in this talk, matrix-assisted laser desorption/ionisation time-of-flight (maldi-tof) mass spectrometry will be presented as a method for species identification. this technology applies protein pattern matching based on mass spectrometry. during the identification process, a mass pattern is generated for each organism. the subsequent comparison of this pattern with a database comprising reference patterns derived from well-characterised reference strains leads to species identification. as examples, the identification of various nonfermenting bacterial strains isolated from clinical specimens in comparison to partial 16s rdna sequencing will be shown. moreover, speed, accuracy in comparison to other methods, and inter-and intra-laboratory reproducibility of maldi-tof ms-based species identification will be discussed. o489 trends in invasive streptococcus pneumoniae serogroup 1 sequence types in belgium t. goegebuer, k. van pelt, j. verhaegen, j. van eldere°(leuven, be) objectives: s. pneumoniae serogroup 1 (sg1) isolates frequently cause invasive pneumococcal disease, particularly in children. from 2003 onwards a marked increase in sg1 isolates was observed; overall prevalence increased from 8. 2% (1998-2002) to 13.6% (2003) (2004) (2005) (2006) . we determined the sequence types (st) in sg1 isolates in order to better understand trends in sg1 resistance and spread. methods: as national reference centre, we receive all invasive isolates from more than 100 of 182 laboratories in belgium. 124 randomly chosen sg1 isolates from all ages from 1998 to 2006 were analysed via multi-locus sequence typing (mlst) as described by enright & spratt (microbiol. 1998; 144: 3049−60) . we also included data on strain characteristics and patient characteristics. results: 10 different sequence types (st) were identified: st350 (n = 66), st306 (n = 24), st304 (n = 13), st227 (n = 10), st228 (n = 5), st2915 (n = 2), st305 (n = 2), st612 (n = 1), and st217 (n = 1 mutations usually increase the mic slightly, but enhance the probability of further mutations. efflux pumps like pmra reduce antibiotic concentrations in the bacterial cell, enabling longer survival. we hypothesised that efflux positive bacteria are more likely to develop resistance than efflux negative bacteria. the following questions were addressed: 1. do the efflux pump inhibitors reserpine and verapamil reduce the mutation frequency? 2. do fluoroquinolone-susceptible efflux positive pneumococci exhibit higher parc or gyra qrdr mutation frequencies than efflux negative isolates? 3. does efflux phenotype impose a fitness cost? methods: matched efflux positive and negative pneumococcal isolates with identical or similar genotype according to multi-locus sequence typing collected by the german community acquired pneumonia network capnetz were analysed (n = 17). strains tigr4 and r6 were included as efflux negative controls. ciprofloxacin (cip) mics and efflux phenotype were measured by agar dilution method, for efflux detection reserpine (10 mg/l) was added and a fourfold decrease in mic was considered as efflux positive. mutation frequencies were determined by plating bacterial suspensions onto agar with and without cip. after incubation colonies were counted and the ratio of cfu/ml yielded the mutation frequency. equally, the mutation frequency was determined adding different concentrations of verapamil (10, 25, 50, 100, 500 mg/l) or reserpine (0.01, 0.1, 1, 5, 10 mg/l). biological fitness was calculated as the maximum slope of growth curves recorded in a microtitre plate reader. results: 1) even at low concentrations, reserpine clearly reduced the mutation frequency of efflux positive and, to a lesser extent, efflux negative pneumococci when exposed to cip (figure 1); verapamil exhibited this effect merely at high concentrations. 2) efflux positive isolates produced more frequently mutants (8/9) than efflux negative isolates (2/10) (p = 0.005, fisher's exact test). 3) efflux phenotype had no measurable impact on the biological fitness. conclusion: a positive efflux phenotype increases the qrdr mutation frequencies in the presence of fluoroquinolones and this effect can be inhibited by very low concentrations of reserpine. as a matter of concern, efflux is not associated with decreased biological fitness. background: use of fluoroquinolone (fq) has been associated with increasing fq resistance in s. pneumoniae. because respiratory fqs (levofloxacin (levo) and moxifloxacin (moxi)) are first line therapy for serious respiratory infections, increasing fq resistance (fqr) in sp is a concern. levo targets parc, and moxi targets gyra, which may permit differentiation of degree of selective pressure. we examined fq use, and changes in the prevalence of fqr and qrdr mutations in canadian isolates of sp. methods: cbsn is a canadian collaborative network of microbiology laboratories that has performed surveillance for antibiotic resistance in sp since 1988. antimicrobial resistance is performed in a central lab to clsi standards. we sequenced qrdr regions of all fqr isolates and a stratified sample of fq susceptible isolates. population fq use was obtained from ims canada. results: from 1995 to 2007, fq use increased from 53 to 97 rx/ 1000pop/yr; levo use from 0 to 10 rx/1000pop/yr, and moxi use from 0 to 17 rx/1000pop/yr. 31081 isolates were available for testing. levo r rates increased from 0 in 1993 to 1.8% in 2002 then remained stable until 2008 (1.6% in 2008). moxi r rates increased to 0.6% in 2004, then stabilised (0.7% in 2008). the prevalence of parc only mutations has not increased significantly in the last decade (see table) . the prevalence of isolates with both parc and gyra mutations increased until 2002, but has decreased in 2008. the first gyra only mutant was detected in 2000; the prevalence of gyra only mutants since then has increased, but remains very low (7/2044, 0.34% in 2007) . conclusion: despite increasing use of respiratory fqs, fqr in pneumococci is very low and not increasing in canada. the prevalence of isolates with parc mutations is decreasing. isolates with mutations in gyra alone remain extremely rare, suggesting that moxi exerts minimal selective pressure for resistance. in streptococci, two well characterised macrolide resistance have been described: target modification and active drug efflux. target site modification is mediated by the erm genes -erm(b), erm(a), erm(c)which confers the mlsb phenotype. target modification by mutations in 23s rrna as well as mutation in l4 and l22 ribosomal proteins have also been reported. expression of mef(a) genes activate an efflux mechanism responsible for m-type resistance we characterised a clinical isolate of s. agalactiae mb56gbs022 exhibiting the mlsb phenotype and tetracycline resistance. in this study, we determined the resistance genes, their association, and their localisation and mobility by conjugation. methods: the macrolide and tetracycline resistance genes were confirmed by pcr. the association between macrolide and tetracycline genes was investigated by long-pcr and sequencing. conjugation experiments were performed by filter matings. the genetic localisation of resistance genes was determined by endonuclease i ceui -followed by pfge and southern blot. the hybridisation study was performed using three specific probes for the 16s and 23s rrna genes, for erm(b) and tet(o) genes. results: s. agalactiae mb56gbs022 carried erm(b) and tet(o) genes on the same amplicon of 7 kb in size. the nucleotide sequence analysis of the entire product was identical to the peoc01 of 11 kb from pediococcus acidilactici that contains four orfs, of which orf2 and orf3 encode a putative resolvase and topoisomerase type i, respectively. the endonuclease i ceui method, that easily distinguishes between plasmid and chromosomal localisations as i-ceui only cuts chromosomal dna, revealed the localisation of resistance genes on the plasmid. all attempts to transfer erm(b)-tet(o) structure by conjugation from s. agalactiae mb56gbs022 to og1ss e. faecalis as recipient failed. conclusion: our results show the first case of the association between erm(b) and tet(o) genes on the unique mosaic structure in s. agalactiae, probably on the plasmid, as demonstrated by the i ceui-assay. further studies are on going to characterise the entire genetic element carrying resistance genes. o499 improving influenza pre-analytic collection systems: alternative collection systems to inactivate, preserve, or extract influenza for rapid testing s. castriciano°, k. luinstra, m. ackerman, a. petrich, m. smieja (brescia, it; hamilton, ca) objectives: in this study, 3 alternative influenza sample collection systems were evaluated for potential use in a pandemic situation. the objectives were to develop: 1) a non-temperature dependent swab collection and transport system, that inactivates influenza virus infectivity but preserves cell morphology and nucleic acid (na) for the detection of suspected influenza infections and/or 2) a system compatible with direct na testing without the need for purification prior to detection by a rapid real-time rt-pcr. methods: flocked nasopharyngeal swabs (nps) collected in utm (u) were compared to nps collected in a cymol (c), m-swab (m) or dry (d) flocked swab collection system (copan, italia). cymol is an alcoholbased medium that preserves cells for dfa testing. the m-swab contains 600 ul of medium and 150 ul of glass beads, and requires no na purification step. shell vial culture was used to assess influenza virus inactivation after 30 minutes exposure to the collection media. a mockinfected influenza a virus sample was absorbed to duplicate swabs then placed into the 4 collection systems. the infected collection media were held at rt for 30 minutes and then inoculated in duplicate into shell vial culture and stained after 48 hours. influenza a stability and na recovery after mock infection of each collection system was assessed after 1, 7, 14 and 21 days (d) at 4ºc, −20ºc, room temperature (rt) and 37ºc. aliquots of infected collection media were extracted by easymag and 5 ul of purified na tested by a quantitative influenza a rt-pcr on the roche lightcycler. m-swab collected samples were also tested directly or after boiling, without na purification. results: shell vial culture found that influenza a virus was inactivated after 30 minutes exposure to the c medium but not when exposed to the u and m media. influenza a was detected by dfa from the u and c cell smears. quantitation of influenza a rna was constant after 1, 7 and 14 d in u, c, m and d collection systems at −20, 4ºc and rt. the quantity of rna recovered declined significantly after 14 d at 37ºc in all 4 collection systems. m with boiling yielded data comparable to the easymag extraction. the copan cymol medium inactivates influenza infectivity, preserves cells and stabilises rna up to 14 days at −20, 4ºc and rt. cymol medium is a potential alternative for safe sample collection during a pandemic influenza situation. the m-swab presents a rapid testing alternative. luminex respiratory viral panel in respiratory specimens from children r. selvarangan°, s. selvaraju, d. baker, k. estes, l. hays, d. abel, s. hiraki (kansas city, us) objective: luminex respiratory viral panel (rvp) is a multiplex pcr capable of detecting and differentiating twelve different respiratory viruses and their subtypes; influenza a (flu a) (subtypes h1 and h3), influenza b (flu b), respiratory syncytial virus (rsv) (subtypes a and b), adenovirus (adv), parainfluenza 1 (piv 1), parainfluenza 2 (piv 2), parainfluenza 3 (piv 3), human metapneumovirus (hmpv) and rhinovirus (rhv). the aim of this study was to evaluate the analytical performance characteristics of rvp assay and to evaluate its ability to detect respiratory viruses from nasopharyngeal aspirates obtained from children. method: analytical sensitivity, specificity, accuracy and precision of the luminex rvp assay were determined using control viral stocks and respiratory specimens previously tested by rmix shell vial culture. result: luminex rvp assay reliably detected atcc viral stocks of flu a, flu b, rsvb, rhv and piv3 in the range of 10e-2 to 10e-4 tcid50/ml. no cross reactivity was noted with cmv, hsv, hhv6, ebv, vzv, piv4, cornoavirus 229e and oc43. among 146 respiratory specimens previously characterised by culture 138 specimens were accurately detected with overall accuracy of 95%. the median coefficient of variation in mean fluorescent index values of signals from replicate analyses of influenza a, b and rsv was 9% (7% to 25%). the 146 clinical specimens tested by rvp assay included 109 culture positive and 37 culture negative specimens. respiratory viruses isolated from the culture positive specimens include the following; 19 adv, 11 flu a, 10 flu b, 19 rsv, 9 piv1, 6 piv2, 5 piv3, 19 hmpv and 14 rhv. rvp assay detected all of the respiratory viruses except one each of rsv, piv1 and piv2 virus with overall sensitivity ranging from 88% to 100% for the different respiratory viral groups. among the 37 culture negative specimens 20 respiratory viruses were detected by rvp of which 15 were subsequently confirmed by repeat analyses. conclusion: luminex rvp assay is a highly sensitive and specific test useful in the detection of commonly encountered respiratory viruses in respiratory specimens. the addition of rvp assay to the viral testing algorithm of respiratory infections in children provides rapid results, improves diagnostic yield and may result in decreased antibiotic usage, reduced diagnostic testing and reduced hospital stay. m. savvala, i. daniil, i. berberidou, a. koutsibiri, a. stambolidi, m. papachristodoulou, n. spanakis, d. petropoulou°, a. tsakris (athens, gr) objective: in developed countries, viruses, particularly noroviruses, are recognized as the leading cause of acute gastroenteritis. we determined the aetiology, prevalence and seasonal distribution of viral gastrointestinal infections in hospitalised patients with acute diarrhoea. methods: during one-year period (november 2007-november 2008), a total of 201 faecal specimens were collected from 165 children, 21 premature neonates and 15 adults who were hospitalised with symptoms and signs of acute gastroenteritis. stool samples were tested for the presence of rotavirus, adenovirus, astrovirus and norovirus. rotavirus, adenovirus and astrovirus antigen detection was performed by chromatographic immunoassays (rotavirus and adenovirus, vikia ® -biomerieux, france; h&r astrovirus-vegal farmaceutica, spain). noroviruses were detected by an enzyme immunoassay (ridascreen ® rbiopharm, germany) and confirmed by reverse transcription-pcr. data were analyzed for seasonality of infection and possible transmission mode. the overall incidence of viral identification in acute diarrhoeal stool was 24% (48 of 201 patients). fifty one viral antigens were detected one patient with positive antigen detection is suffering from a disease of unclear aetiology. so, an association of replication of cihhv-6 with the disease might be considered. in contrast, the other patient did not show any symptoms at the time of antigen detection. this patient shows a special mode of acquisition of cihhv-6 (by bmt) possibly resulting in differences in the immunological priming and response. in addition, in the latter patient cihhv-6 is restricted to blood cells. two other patients did not show antigen expression. so, it is unclear how the transcription and translation of viral genes is influenced? furthermore, is there a pathophysiological impact of viral replication in individuals with cihhv-6? objectives: several case studies have reported on meningo-encephalitis caused by a primary epstein-barr virus (ebv) infection. we aimed to investigate the viral loads, and the inflammatory characteristics of this thus far poorly defined disease entity. we evaluated all cases from 2003-2008, in which an ebv polymerase chain reaction test (pcr) was requested on a cerebro spinal fluid (csf) sample. primary infection was defined as a clinical presentation with sore throat/pharyngitis/malaise in combination with lymphocytosis, and detectable heterophile antibodies or positive ebv igm antibodies. patients with proven neuroborreliosis served as control group. leukocyte response and ebv viral loads in csf, and serum were compared between primary ebv and neuroborreliosis cases. results: we identified six cases with a primary ebv infection (median age: 22, male: 4) with neurological symptoms ranging from meningeal signs to encephalitis. these were compared to 14 patients with neuroborreliosis (median age: 27, male: 6). in four out of six patients with a primary ebv infection with neurological symptoms ebv dna was detected in csf and in serum, whereas all neuroborreliosis cases were ebv pcr negative in both compartments. viral loads were lower in csf as compared to serum. in blood, leukocytes, lymphocyte, and monocyte counts were significantly increased as compared to the neuroborreliosis cases (see table 1 ). specific for vp7 and vp4 genes, using pools of g and p type specific primers. all strains (niv/brv/68, niv/brv/79, and niv/brv/86) were not typeable for the vp4 and vp7 genes. after purification by "qiaquick gel extraction kit" (qiagen, germany), the vp4, vp6, vp7, and nsp4 first amplicons of the borv-a strains were subjected to sequence analysis with automated sequencer abi 3130 xl dna analyzer (applied biosystems, usa). phylogenetic analysis was performed using mega version 4.0. objectives: dengue is a flavivirus and is among the most widely-spread viral diseases. our previous report demonstrates existence of live dengue virus in blood and urine even in the convalescent postfebrile period. in some cases, excretion in the patient's urine can be detected as late as 28 days after the onset of illness. this goes along with the model of west nile virus, another type of flavivirus, which can be excreted in the urine for months after acute infection in both animal studies and human case report. here we report a pilot study to address a magnitude of such findings. methods: between april 2007 and october 2008, paediatric and adult febrile patients suspected of dengue infection were enrolled. diagnosis of dengue was based on standard specific serology on paired sera. patients with negative serology served as controls. blood and urine specimens were collected at several time points. whole blood was separated into plasma and peripheral blood mononuclear cells (pbmc). these have been aliquoted and used for earlier studies and some stored in freezers. available plasma, pbmc, and urine were processed and inoculated into aedes aegypti. surviving mosquitoes at 14 days after inoculation were employed for viral detection by dengue-specific rt-pcr. indirect fluorescence antibody (ifa) staining of mosquito heads was performed on all positive rt-pcr specimens, except for the one from pbmc (awaiting ifa result). results: 5 and 45 cases of primary and secondary infections, respectively, and 4 negative controls were included. these translated into 55 and 59 early and late dengue specimens, and 6 and 4 early and late negative-control counterparts, respectively. dengue virus were isolated in some blood and urine specimens as late as 46 days after the onset of illness. no virus was isolated from control specimens. all but 5 positive rt-pcr specimens also demonstrated positive ifa. 4 out of 5 negatives were from early-phase specimens. conclusion: our study demonstrates prolonged survival of dengue virus after clinical recovery. this finding has pathologic and epidemiologic significance, adding a potential role of urine in the transmission of the disease. spread of the virus to humans might occur through infectious urine with help from arthropod vectors. this research could provide new insights into our understanding of the pathogenesis of denv infection. isolation of dengue virus from blood and urine specimens during early (days 1−7 after onset of illness) and late (days 8−46) phases of infection (specimens with dengue isolated/total specimens for mosquito inoculation) early phase late phase plasma 16/25 (64%) 0/13 (0%) pbmc not performed 1/2 (50%) urine 8/29 (28%) 12/44 (27%) all specimens 24/54 (44%) 13/59 (22%) dna copies) 226 (<50-1461) † ; n = 2 <dl all <dl ebv pcr in serum (dna copies) 1507 (<50-14127) † ; n = 2 <dl all <dl data presented as median (interquartile range). *p < 0.05; † p < 0.01; comparison by mann-whitney u-test. csf: cerebrospinal fluid. ebv: epstein-barr virus y. achermann°, c. spormann, c. kolling, c. remschmidt, j. wüst, b. simmen, m. vogt (baar, zurich, ch) objectives: elbow arthroplasty is increasingly used for treatment of rheumatic or posttraumatic arthritis. data on epidemiology, characteristics and treatment outcome of elbow prosthetic joint infection (pji) is limited. furthermore, no validated therapeutic algorithm exist as for hip or knee pji. we analyzed all pji, which occurred in a cohort of implanted elbow prostheses during a 13-year-period. methods: between 01/1994 and 12/2007, all cases with implanted elbow prosthesis at our institution were retrospectively included. elbow pji was defined as visible purulence, acute inflammation on histopathology, sinus tract or microbial growth in periprosthetic tissue. patients were regularly follow-up at outpatient orthopedic visits and were in addition recently contacted by phone. a kaplan-meier survival analysis was performed. results: during the study period, 358 elbow prostheses were implanted. overall, 25 of 358 cases (7%) developed elbow pji (median age 61 y, range 41−82 y, 40% males). among them, 14 (56%) had a rheumatic disorder and 11 (44%) a posttraumatic arthritis. 12 infections were early ( 3 months), 3 were delayed (3−24 months) and 10 were late ( 24 months). more infections were acquired intraoperatively (n = 15, 60%) than haematogenously (n = 10, 40%). the following pathogens were cultured: staphylococcus aureus (n = 11), coagulase-negative staphylococci (n = 7), streptococcus agalactiae (n = 2), corynebacterium sp. (n = 1), enterococcus sp. (n = 1), enterobacter cloacae (n = 1), mixed infections (n = 1) and culture-negative (n = 1). treatment approaches included débridement with implant retention (n = 19), one-stage exchange (n = 2), two-stage exchange (n = 1), resection arthroplasty (1) and antibiotics only (n = 2). at follow-up, 16 (64%) patients were free of infection (median follow-up time 2.6 y, range 0.7−11.3 y) and 9 (36%) had a relapse (median time to infection 0.4 y, range 0.1−4.0 y). one patient died due to infectious endocarditis with secondary haematogenous elbow pji. the relapse-free survival (95% confidence interval) was 75% (58%-93%) after 1 year, 70% (52%-89%) after 2 years, 62% (39%-85%) after 3 years and 52% (27%-78%) after 4 years. the infection incidence after elbow arthroplasty was higher (7%) than reported after hip (<1%) or knee arthroplasty (<2%). most infections (48%) manifested early ( 3 months). underlying rheumatic disorder were common in elbow pji (58%). the relapse-free survival after elbow pji was 75%, 70%, 62% and 52% after 1, 2, 3 and 4 years. e.a.n. oostdijk°, a.m.g.a. de smet, h.e.m. blok, e.s. thieme groen, j.a.j.w. kluytmans, m.j.m. bonten (utrecht, breda, nl) introduction: selective digestive tract decontamination (sdd) and selective oropharyngeal decontamination (sod) aim to eradicate gram-negative bacteria (gnb) from the intestinal en respiratory tract in intensive-care-unit (icu) patients. we aimed to quantify effects of sdd and sod on bacterial ecology in 13 icus that participated in a clustered group-randomised cross over study in the netherlands, in which sdd, sod or standard care (sc) was used during consecutive periods of 6 months (nejm 2009; 360:20) . the order of periods was randomised per icu. methods: point prevalence surveys of rectal and respiratory samples were performed once monthly in all patients in icu (receiving or not receiving sod/sdd). selective media were used to detect gnb and mic testing was done for ceftazidime (cft), ciprofloxacin (cip) and tobramycin (tob). effects of sdd on rectal carriage were determined by comparing data from 6 sdd months in each icu to data from all months preceding and following (in which sod or sc was given). combined effects of sdd/sod on respiratory tract carriage were determined by comparing data from 12 months sdd/sod (in any order) to data from the 6 sc months before and afterwards. results: 2583 rectal and 2023 respiratory tract samples were analysed. during sdd average proportions of patients colonised with gnb resistant to either cft, tob, cip were 5%, 7% and 7% and these proportions were 15%, 13% and 13% during the post-intervention period (p < 0.05 in each case). this effect is most explicit for cft with resistance levels increasing from 2.6% in the last month of sdd to 11.4% in the 1st month after sdd (p < 0.05). during sdd and sod resistance levels in respiratory tract samples were <6% for all three antibiotics, but prevalence increased gradually (for cft and tob resistance; p < 0.05 for trend). after discontinuation of sdd and sod average proportions increased to levels >10% for all three antibiotics (p < 0.05 in each case). cft resistant isolates in rectal samples mainly included enterobacteriaceae not being escherichia coli and klebsiella spp, whereas tob and cip resistant isolates mainly included e. coli. conclusion: sod and sdd have marked effects on the bacterial ecology in an icu with a rapid and persistent increase in resistance after intervention. antibiotic resistance remains a major concern associated with these infection control measures. o391 throwing caution to the winds? three cases of anaphylaxis to chlorhexidine coated central venous catheters from a regional cardiac centre in northwestern england this blaoxa-58-producing clone showed resistance to several b-lactams (including imipemem), susceptibility to ceftazidime, netilmicin and minocycline, and variable susceptibility to meropenem, cefepime, and aztreonam. mics for colistin and tigecycline ranged from >16 mg/l and from 0.25−4 mg/l, respectively. all oxa-58-producing isolates presented the isaba3 downstream of the blaoxa-58 gene. hybridisation assays revealed a plasmidic location for the blaoxa-58 gene with ca 90kb. plasmid sequencing showed an isaba3-like truncated at the 3 end upstream of the blaoxa-58 gene, a fact that may explain the observed negative carbapenemase-production bioassay. conclusion: blaoxa-58-carrying a. baumannii is, apparently, more ancient than initially imagined. although undetected from 2004 onwards, the fact that it possessed a non-expressible gene, due to alterations in the promoter region, suggests that this information might have been incorporated from a still unidentified source. twenty-seven (45%) were male. isolates were recovered from respiratory secretions (33 isolates, 55.0%), blood (11, 18.3%), urine (7, 11.7%), catheter (5, 8.3%) and other secretions (4, 6.7%). only 24 (40.0%) of 60 patients received appropriate antimicrobial therapy either with polymyxin b (79.2%), ampicillin-sulbactam (12.5%) or tigecycline (8.3%). overall 30-day mortality of patients with crab was 50%. mortality rates were 3.2 per 1000-patient/day. these rates were significantly higher among patients who have not received appropriate therapy (1.2 per 1000-patient/day) compared with those who have received it (0.3 per 1000-patient/day; p = 0.001; figure 1 ). in the cox regression model only receiving appropriate treatment (hazard ratio [hr] 3.29; 95% confidence interval [ci] 1.35−8.02); p = 0.009) was independently associated with 30-mortality. positive blood culture for crab remained in the final model (hr 1.85; 95% ci 0.86−4.00; p = 0.12). all 25 isolates submitted to pcr were positive for blaoxa-23. all these isolates were susceptible to polymyxin b and tigecycline. conclusion: high 30-day mortality occurred in this icu outbreak. many patients did not receive appropriate therapy, which significantly increased mortality. other clinical risk factors for mortality in this outbreak are currently under investigation. acinetobacter baumannii in norwegian strain collections reveal major discrepancies to phenotypic identification and the presence of carbapenemase-producing clonal lineages baumannii isolates the per-1 gene was identified in 18 (23%). the similarity of the bands were calculated according to "dice smilarity coefficients" and all per-1 positive isolates were found as clonally related. conclusion: in our study the prevalence of per-1 was lower than the previous studies. but the presence of high ceftazidime resistance rates among these isolates may indicate the presence of other beta-lactamases. dna analysis by pfge and rapd revealed an outbreak caused by a unique clone. detection of clonal related isolates among different services may be because of the treatment of these patients at the same services before and this may explain the spread of per-1 positive strains.o442 resistance genomic islands related to abar1 are common in acinetobacter baumannii strains belonging to european clone i l. krizova°, m. maixnerova, l. dijkshoorn, a. nemec (prague, cz; leiden, nl) objective: acinetobacter baumannii strains belonging to european (eu) clone i are commonly resistant to multiple antimicrobial agents. a number of resistance genes were recently detected on an 86-kb genomic resistance island (abar1) inserted in the atpase gene of eu clone i strain aye. the aim of this study was to assess the presence of abar1related structures in epidemiologically unrelated strains of eu clone i. methods: the study set included 25 multi-drug resistant (mdr) strains of eu clone i collected in 19 european countries in 1978-2004 and 10 genotypically unique, fully susceptible strains. using pcr, all strains were investigated for the presence of the atpase gene and for nine genes found to be associated with abar1. furthermore, the strains were tested for the disruption of the atpase gene using pcr primers directed against the 3 and 5 ends of this gene. strains with the disrupted gene were investigated for the presence and structure of the atpase gene-abar1 connecting regions using pcr mapping and rflp. pcr primers were derived from the known sequence of strain aye. results: all strains were positive for the atpase gene. the 10 susceptible strains had an intact atpase gene whereas all mdr strains failed to produce the expected amplicon in the atpase disruption test. all eu clone i strains yielded positive results for the atpase gene-abar1 connecting regions, the structure of which corresponded to those of aye. these findings suggest the presence of atpase integrated elements in clone i strains, the integration of which had invariably taken place at the same locus site. none of the abar1-associated resistance genes were found in any of the susceptible strains. in contrast, the mdr strains harboured the following abar1-associated genes (% positive strains): aacc1 (21), aada1 (21), aadb (4), apha1 (21) stra (3), mera (20), teta (18), cat (23), the gene encoding heavy metal detoxification protein (25). individual mdr strains carried from one to nine abar1-associated genes in 11 different combinations. there was a good correlation between the content of resistance genes and resistance phenotypes. conclusion: genetic structures related to abar1 are common in strains belonging to eu clone i. the heterogeneity of resistance patterns in this clone is likely to result from the variations in the content of abar1related structures. supported by grant 310/08/1747 of the grant agency of the czech republic. objectives: to study the differences in mutation frequency and evaluate the possible correlations between drug resistance development and mutation rate in acinetobacter baumannii (ab). the mutation frequency (mf) of rifampicin (rif) resistance was used as a surrogate measure of differences in mutation rate and for detection of the presence of mutator phenotype. 10-and 100-fold higher when larvae were infected with atcc17978 and sdf, respectively. thus, the sdf genome was used as reference genome to identify functions acquired by pathogenic strains with a possible role in antibiotic resistance and pathogenicity. sixty-two clusters, corresponding to almost 870 cdss, were identified in the acicu and aye genomes (and partially in atcc17978) that were absent in sdf. this study found that targeted interventions that reduce the use of quin were associated with a decrease of the quin resistance rate in e. coli. e. velasco°, w. espelage, i. noll, a. barger, t. eckmanns (berlin, de) objectives: growing populations of older and immunocompromised patients, changes in epidemiology and unchecked use of antibiotics can led to a rise in consumption as well as resistance to certain treatments. medical doctors (mds) often have an important role alongside contributing factors. we conducted a national survey of mds in germany on their behaviours and expectations for intervention. we aimed to assess md behaviours with and influences on antibiotic prescribing and the potential for related interventions that address antibiotic resistance.methods: a representative sample comprised 10,610 mds with differing practice specialties, from both stationary and ambulatory settings (respectively: 36% and 0% internists, 0% and 54% general practitioners, 32% and 11% surgery, 3% and 4% ear/nose/throat, 10% and 10% paediatrics, 5% and 3% urology, 9% and 13% gynaecology, 2% and 4% dermatology, 3% and <1% other) in 15 federal states. we developed study questions to capture baseline information on mds and their practice with antibiotics. questions also focused on selected influences that may affect behaviour in practice. other questions solicited opinions about interventions that may improve practice. mailed questionnaires were distributed to participants via state medical associations. results: among survey respondents (n = 3,613; response rate = 34%), 66% reported that they prescribe antibiotics daily, and 90% indicated they do so at least weekly. of all surveyed mds, 60% reported that they think their own prescribing practice has an influence on antibiotic resistance in their region. of all mds, 83% found it "important" to continually improve use of antibiotics through industry independent experts providing consultation, audits and feedback. of all mds, 96% found it "important" to have provision of regional coverage of antibiotic resistance with appropriate feedback for practicing mds, and 82% found it "important" to have provision of antibiotic regulations of prescriptions with appropriate feedback for practicing mds. (results in table 1 .) -a not all results shown and remaining percentages are as follows: a closed three category scale was used for options "yes", "no", "do not know". a closed four category scale was used with options "very important", "important", "less important" and "not important". a closed five category scale was used for options "daily", "weekly", "monthly", "seldom" and "never". a closed five category scale was used for options "strongly agree", "agree", "neutral", "disagree" and "strongly disagree". objectives: to investigate the mlsb and tetracycline resistance and the emm gene distribution among the invasive streptococcus pyogenes (gas) strains. methods: between january 2006 and december 2008, a total of 991 strains responsible for invasive infections for adult patients were sent to the french national reference center for streptococci to be studied. antibiotic susceptibility testing was done by disk diffusion method according to the ca-sfm guidelines. mics were determined by e-test method. streptococcal emm sequence was done according to the cdc protocol. detection of macrolide and tetracycline resistance genes: erm(b), erm(tr), mef(a), tet(m), tet(o), tet(k), and tet(l) was performed by pcr. results: among the 991 streptococcus pyogenes invasive strains; more than ten different emm-types were identified. the most frequent emm sequence types were emm1, emm28 and emm89. a total of 80 strains (8%) were resistant to erythromycin. erythromycin resistance prevalence had decreased during the three years period (12. 2%-2006, 7.6%-2007, 5.5%-2008) . 69 had an mlsb constitutive (65 strains) or inducible (4 strains) phenotype due to erm(b) or erm(tr) resistance gene. 11 with the m phenotype and mef(a) gene were susceptible to clindamycin. among the 132 (13.3%) tetracycline resistant isolates tet(m), tet(o) and tet(l) genes were detected in 86, 27 and 19 strains, respectively. tetracycline resistance prevalence had also decreased during the three years period (16. 8%-2006, 14%-2007, 8.7%-2008) . conclusion: most of the invasive french gas isolates remained erythromycin and tetracycline susceptiple during three years. nontheless, the resistance rates have had the tendency to decrease slightly. taking into account the resistance trends helps to guide the therapy for penicillin-allergic patients. objectives: during a survey on antimicrobial susceptibility in betahaemolytic group c and g streptococci (gcgs) from portugal, a macrolide resistance rate higher than previously reported in other european countries was found (22%) among s. dysgalactiae subsp. equisimilis isolates. to gain further insights into the resistance mechanisms involved and the clonal structure of the resistant population, we undertook the phenotypic and molecular characterisation of macrolide resistant s. dysgalactiae subsp. equisimilis isolates and compared it with the susceptible population. methods: antimicrobial susceptibility testing and macrolide resistance phenotype were determined by disk diffusion. all the macrolideresistant isolates were further characterised by mic testing and genotype determination by pcr. a combination of emm typing and pulsed-field gel electrophoresis (pfge) was used to type the population and the simpson's index of diversity (sid) with 95% confidence intervals was calculated as previously described.results: a total of 69 isolates were resistant to erythromycin (mic range, 4 to >256 ug/ml). the vast majority of isolates presented a mlsb phenotype (n = 64) and carried the erm(a) gene (n = 55), while the mefencoded m-phenotype was expressed by only 5 isolates. among resistant isolates, 13 distinct emm types were found distributed by 10 pfge clusters that overlapped with the main clusters detected in the susceptible population. the emm types stg480, stg6, stg485 and stg2078 accounted for approximately two thirds of the resistant isolates. pfge did not always separate neither macrolide-resistant from susceptible isolates nor erm(b) and mef(a) from the prevailing erm(a) isolates. the sids of emm and pfge calculated for resistant isolates were not statistical different from the overall population. the two most prominent mls resistant lineages were one with stg480/erm(a) isolates (n = 8) and stg485/mef(a) (n = 3), and another including stg2078/erm(a) (n = 8).conclusion: although most of the resistant isolates presented a mlsb phenotype and carried an erm(a) gene, molecular typing revealed extensive diversity in both emm types and pfge clones. macrolide resistance had a polyclonal origin, with resistance emerging among most susceptible clones. monitoring of macrolide resistance patterns in s. dysgalactiae subsp. equisimilis is essential as this pathogen is increasingly recognised as an important human pathogen. a.s. simões°, r. sá-leão, s. nunes, n. frazão, a. tavares, h. de lencastre (oeiras, pt) while performing pneumococcal nasopharyngeal colonisation surveillance studies among children attending day care centres (dcc) in portugal, we observed that the rate of strains with penicillin mic 2 ug/ml more than tripled from 1.8% in 2006 to 6% in 2007 (p = 0.002). the aim of this study was to characterise the 20 isolates recovered in 2007 which had a mic to penicillin 2 ug/ml. methods: pneumococci were isolated and identified on the basis of selective growth on gentamycin blood agar plates, optochin susceptibility, colony morphology, and alfa-haemolysis. susceptibility to antimicrobials agents was performed according to the clsi recommendations and definitions. strains were serotyped by the quellung reaction and/or multiplex pcr using specific primers for each serotype. pulsed-field gel electrophoresis (pfge), after restriction of the total dna with smai, was performed to compare genetic backgrounds. results: sixteen of the 20 isolates belonged to serotype 14, three were serotype 19a and one was of serotype 15a. strains of serotype 14 were also resistant to sulfamethoxazole-trimethoprim and belonged to a single pfge cluster identified as clone spain 9v st156. the penicillin resistant serotype 14 strains were isolated in two dcc, from nine children vaccinated with the 7-valent pneumococcal conjugate vaccine (pcv7), four non-vaccinated children and three children with unknown vaccination status. five of these carriers had received antibiotics recently. in these two dcc the overall proportion of children vaccinated with pcv7 was 64%; 27% of the children had received antibiotics within the previous month and 16% had received three or more courses of antibiotics in the last six months. since the introduction of the pcv7 in portugal, in june 2001, the proportion of penicillin resistant pneumococci recovered from colonisation has been stable (c.a. 2%). the sudden increase in the levels of penicillin resistance observed in the 2007 surveillance study was found to be largely due to the dissemination of clone spain 9v st156 serotype 14 variant in two dcc with high consumption of antibiotics. the observations suggest a combination of high antibiotic selective pressure and transmission rates resulting in an outbreak-like situation with a penicillin resistant vaccine type clone being disseminated among children in day care despite use of pcv7. background: beside target mutation, active efflux is another common resistance mechanism to fluoroquinolones (fq) in s. pneumoniae. two main efflux systems have been described so far, namely pmra (member of the mfs superfamily) and the two abc transporters pata/patb. we have studied the inducibility of pmra, pata and patb genes expression when bacteria are exposed to subinhibitory concentrations of fq. we used a wild-type sensitive strain (atcc49619), two clinical strains resistant to fq (sp13 and sp295), and two efflux mutants (sp334 and sp335; selected in vitro after exposure to ciprofloxacin [jac 2007, 60:965-972] ). mic were determined according to clsi. induction was obtained by growing bacteria in todd-hewitt broth added by half the mic of each fq (cip, nor, lvx, mxf, gmf) for 4 h at 37ºc in 5% co2 atmosphere. expression levels of pmra, pata and patb genes were determined by real-time pcr. reversibility of induction was tested by re-cultivating bacteria for 4 h in drug-free medium. results: antimicrobial susceptibilities for cip and mxf and gene expression at basal level and after exposure to these fq are shown in the in women with single infection, the most common hpv types were hpv-6 and hpv-16, followed by hpv-51, hpv-31, hpv-53 and hpv-66, whereas in women with multiple infections hpv-6 was the most commonly detected type, followed by hpv-66, hpv-31, hpv-16 and hpv-51. a different distribution of hpv types and a higher rate of multiple infections were observed in young vs. older women, suggesting the existence of a natural selection of hpvs which preserve a better fitness. high-risk hpvs were detected in all high-grade cervical intraepithelial lesions, with hpv-16, hpv-18, hpv-31, and hpv-51 as the most frequent types. however, hr-hpv types were detected also in a high rate of women with a negative pap test as well as in women with a negative cervical biopsy, suggesting the need to improve the accuracy of available cervical cancer screening tests. the results of this study, which provide information on the epidemiology of hpv infection and type distribution in women from south italy, should be taken into consideration in the implementation of local vaccination programs. objectives: chromosomal integration of the hhv-6 genome (cihhv-6) into the human genome occurs in 1−2% of healthy individuals and leads to persistently high levels of hhv-6 pcr copy numbers in blood and tissue. consequently, this may be interpreted as persistent active hhv-6 infection. although hhv-6 mrna has been detected in a few individuals with cihhv-6, there is no evidence of replication of viral particles up to now. viral cultures have shown negative results. so, cihhv-6 is thought not to be linked to any disease. methods: we performed hhv-6 antigen detection in pbmcs of 4 individuals with fish proven cihhv-6 by means of antibodies directed against hhv-6 variant a and b (indirect immunoperoxidase staining). results: in 2 unrelated female adolescents (both with cihhv-6 variant a) we detected hhv-6 antigen. one patient is suffering from recurrent parotitis since 5 years and from hypoimmunoglobulinaemia. the other patient (15a) was treated with allogeneic bone marrow transplantation (bmt) for acute myeloid leukaemia (aml) and acquired cihhv-6 from the healthy donor. so, cihhv-6 is only found in blood cells. in the latter patient only symptoms attributable to the post bmt course have been observed (prolonged mixed haematological chimerism, protracted mucositis, transient hypertension and transient neuropathy). at the time of antigen detection 5 years after bmt the patient was clinically well. in 2 individuals (a girl after fatal myocarditis and her healthy father − both with variant b) no hhv-6 antigen has been detected. discussion: up to now cihhv-6 is considered not to cause any disease. for the first time we show the expression of hhv-6 antigen, which indicates the replication of viral particles. this might have a pathophysiological impact. sixty-seven % of cases with ebv meningo-encephalitis have detectable viral dna amounts in csf and serum, whereas neuroborreliosis patients do not. cases with primary ebv meningoencephalitis have increased systemic leukocytosis, with higher lymphocyte, and monocyte levels compared to neuroborreliosis patients.o506 incidence of post-herpetic neuralgia in treated and untreated patients with herpes zoster followed for 1 year in an italian prospective cohort: preliminary results g. parruti°, f. sozio, c. rebuzzi, m. tontodonati, e. polilli, a. agostinone, a. manna, f. di masi, a. consorte, g. congedo, l. cosentino, d. d'antonio, l. pippa, l. manzoli, c. granchelli (pescara, chieti, it) objectives: a large prospective cohort of patients with herpes zoster (hz) was enrolled between may 2006 and june 2008 in pescara, italy, with a planned 1-year follow-up after clinically and/or molecularly assessed diagnosis. aim of the study was to evaluate predictors of prolonged acute course and/or incidence of post-herpetic nevralgia (phn). methods: data from all enrolled patients were collected by a network of 51 general practitioners. suspected cases and patients with intense acute pain were referred to our institution for immediate evaluation. clinical and demographic information was mandatory at baseline, as photographs of enrolled patients. for uncertain cases, varicella-zoster virus (vzv) antibodies and vzv dna pcr on plasma and/or vesicular eluates (whenever available) were performed. follow-up data were collected at outpatient control visits or by phone calls at 1, 3, 6 and 12 months after onset of hz. phn was diagnosed when pain persisted or relapsed at least one month after complete clearing of dermatomeric lesions. adverse events other than pain were classified according to who grading scale and reported if 2. all statistical calculations were performed by stata 8.0 software package. results: 523 patients were enrolled, 306 (58.5%) females, with a mean age of 57.7 years, 1-year follow-up data being now available for 489. hz was localised at thorax in 45.4% and head in 20.7%; pain in the acute phase was reported as intense or very intense by 127 (25.97%) patients; 54 (11.04%) patients were referred for molecular diagnosis as clinically uncertain, 37 (68.5%) being confirmed as vzv-related cases. forty eight (9.82%) patients were not prescribed any antiviral drug at diagnosis by referring physicians, in spite of extensive support in the study plan. during follow-up, 163 (33.3%) patients reported any type of adverse event (at a mean of 91.2±74.8 days), including 93 (19.02%) patients reporting phn. phn was significantly more frequent in untreated vs treated patients (37.5% vs 17.0%, p = 0.001), as were total adverse events (54.2% vs 31.1%, p = 0.001). untreated patients did not significantly differ from those treated by age (56.3% vs 57.7%, p = 0.66) and sex (females vs males 11.9% vs 6.9%, p = 0.056), whereas they complained for more intense pain (15.0% vs 8.0%, p = 0.024) at presentation. conclusion: our study confirms the importance of early diagnosis and prompt antiviral treatment at the onset of hz in order to minimise the risk of phn. methods: faecal specimens (n = 78) from apparently healthy and diarrheic calves (aged <1 year) were collected per-rectally and investigated for detection of group a rotavirus by antigen capture elisa (generic assay, germany). elisa positive specimens (n = 3) were investigated further for molecular characterisation. genotyping of borv-a strains was carried out on dsrna extracted from 10% pbs faecal suspensions by a nested and/or heminested rt-pcr key: cord-001221-due9tloa authors: nan title: ecr 2014, part a date: 2014-02-27 journal: insights imaging doi: 10.1007/s13244-014-0316-6 sha: doc_id: 1221 cord_uid: due9tloa nan percutaneous needle biopsy has been a mainstay of oncologic diagnosis for almost three decades, since the advent of ultrasound and ct. the basic principles of fine-needle aspiration and core needle biopsy can be applied to almost any site in the body, with subtle differences in technique depending on the organ being investigated and the imaging modality utilised. while excisional biopsy is still appropriate in certain cases, percutaneous needle biopsy has become the standard of care in the diagnosis of most tumors throughout the body and is also used to diagnose noncancerous conditions, such as infection. percutaneous biopsy is also beneficial in the staging of patients with cancer, particularly when another treatment method may be more appropriate than surgical resection. the advantages of percutaneous biopsy over surgical excisional biopsy include time and cost savings and reduction in morbidity. the aim of this course is to discuss the practical aspects of biopsy, needle selection, and guidance techniques and to show how to approach difficult lesions and avoid complications. imaging after treatment of breast cancer is for confirmation of lesion removal, identification of postprocedural fluid collections, detection of residual or recurrent cancer and screening for metachronous cancers. posttherapy changes -which include fluid collections, edema, skin thickening, architectural distortion, scarring and calcifications -are mainly due to surgery, axillary dissection and radiotherapy. the greatest treatment-related changes occur 6-12 months after therapy, and mammographic stability is achieved after two to three years. for mammography, pre-and all posttherapeutic images have to be compared. ultrasound is the method of choice for evaluation of fluid collections. mri is for problem solving (i.e. differentiation between scar and relapse) and should not be performed prior to 12 months after therapy to avoid false-positive diagnoses. dystrophic calcifications may develop in areas of fat necrosis mimicking malignancy. fat necrosis predominantly occurs at the treated site; however, it can develop anywhere in the ipsilateral breast. its appearance may be indistinguishable from cancer at all imaging modalities. to differentiate between fat necrosis and other common post-treatment changes from relapse, it is important to know the timeline when these changes occur and schedule follow up imaging accordingly. mammography serves as the basis for postoperative surveillance. ultrasound is helpful in the early postoperative phase, whereas mri is the method of choice, especially for differentiation of scar and relapse in the later postoperative phases. breast radiologists need to be familiar with post-treatment imaging findings in patients with breast cancer, but often patients are also imaged after a diagnosis of benign entities which are treated surgically (fibroadenomas, radial scars, papillary lesions) or after a percutaneous diagnosis of a high-risk lesion which has undergone a surgical biopsy to avoid underestimation (atypical ductal hyperplasia, lobular neoplasia or flat epithelial atypia). these procedures will leave an imprint on the breast which can be a cause of concern due to the surgical scar. furthermore, imaging findings after plastic surgery for mastopexy, reduction mastoplasties, implants or auxiliary techniques (lipofilling, hyaluronic acid) are becoming frequent in our daily practice and have their peculiarities that can overshadow breast cancers. interventional percutaneous procedures can also be a cause of tissue distortion. there are advanced systems for biopsy (bles) and for percutaneous removal of benign lesions (fibroadenomas, papillomas), which use large-gauge needles and have to be accounted for due to their trace in the breast tissue. endoscopy is currently considered the reference standard for the evaluation of colonic disease activity in patients with inflammatory bowel disease (ibd). however, it only allows evaluation of the mucosal surface and is not always complete. it cannot, therefore, help to estimate the depth of involvement of transmural inflammation and extraluminal complications, both characteristics of ibd. an evolving role for cross-sectional imaging in the evaluation of patients with ibd is increasingly recognised, especially in the setting of crohn's disease (cd) since the cross-sectional imaging has been demonstrated to have a high diagnostic accuracy not only for assessing the presence and extension of luminal disease, but also for evaluating the cd-related acute or chronic complications. available evidence suggests that ultrasound, computed tomography and magnetic resonance have similarly high diagnostic accuracy in the detection of disease activity, location, severity and complications: in particular, the penetrating and stricturing lesions which are characteristic of cd. thus, the choice of the technique for assessing cd may be influenced by local availability or expertise. in the case of ulcerative colitis, cross-sectional imaging, although less evaluated, may also be helpful in certain circumstances. there is evidence indicating that cross-sectional imaging is an alternative problem-solving tool to endoscopy whenever tissue sampling is not required and can provide valuable guidance for performing medical and surgical treatment with maximised efficacy and safety. overall, findings from crosssectional imaging accurately reflect disease activity and provide reliable information for decision-making and patient care optimisation. learning objectives: 1. to learn about optimised examination protocols for ulcerative colitis and colonic crohn's disease in the acute, subacute and chronic disease setting. 2. to become familiar with the criteria for the assessment of disease activity through ct, mri and ultrasound. 3 . to learn about an integrated approach to the use of cross-sectional imaging in colonic inflammatory bowel disease. liver transplantation is the accepted treatment of patients with irreversible liver cell failure and some metabolic disorders and in a selected group of patients with hepatocellular carcinomas. over the last decade, major transplant centres have reported improving survival rates, though during this period they have developed more complex surgical techniques, including split-liver, auxiliary and live-related transplantation, and have treated more marginal higher risk patients. this successful outcome has been dependent on appropriate recipient selection, robust surgical technique, improvements in immunosuppression and intensive care management and the prompt recognition and treatment of complications. diagnostic and interventional radiology have been core specialties in achieving the goals of improved graft and patient survival. improvement in surgical techniques has decreased the more common vascular and biliary complications, but the newer techniques present differing diagnostic and interventional challenges, particularly in paediatric recipients. developments in mr and mdct allow many of these vascular, biliary and infective complications to be diagnosed non-invasively. vascular techniques of angioplasty and stent placement may reverse the sequel of graft ischaemia or portal hypertension. mrc allows the diagnosis of biliary strictures that may be treated by dilatation or stent placement. imaging is also important in the diagnosis of recurrent disease and the acquired diseases of prolonged immunosuppression including atypical infections and the post-transplant lymphoproliferative disorders (ptld). this interactive session will present these appearances by case example and provide guidance of the appropriate diagnostic and treatment paradigm. learning objectives: 1. to understand the common imaging findings after liver transplantation. 2. to recognise significant complications following liver transplantation. a-010 16:45 b. imaging of treated liver tumours i. bargellini; pisa/it (irenebargellini@hotmail.com) imaging findings after systemic and loco-regional treatments vary greatly depending on baseline features of the treated tumour and treatment modality. conventional uni-dimensional and bi-dimensional criteria (such as recist 1.1 and who criteria) have been extensively validated in metastatic lesions treated with conventional chemotherapy. however, their prognostic value is limited in patients treated with new molecular targeted therapies and after locoregional treatments. in the setting of hepatocellular carcinoma (hcc), specific response criteria (such as easl and mrecist) have been proposed that take into account variation in the size of the viable tumour. these criteria have been extensively validated, although their interpretation could be troublesome after some specific treatments, such as molecular targeted agents and y90radioembolisation. on the other hand, there is no consensus regarding tumour response criteria for metastatic lesions after loco-regional treatments. the role of morphological criteria and several imaging biomarkers (such as those provided by diffusion and perfusion imaging, fdg activity, dual source ct) is under investigation, being able to provide additional information on tumour activity and biology. while new drugs with different mechanisms of action and new treatments are becoming available, the work of radiologists is changing and there is increasing evidence that tailored radiological response criteria are required for these new targeted and tailored treatments. learning objectives: 1. to understand the common imaging findings after chemotherapy for liver tumours. 2. to recognise common imaging findings after radiofrequency ablation of liver tumours. 3. to be aware of the common imaging findings following transarterial treatment of liver tumours. vessel size is practical, since it is related to the pathological changes as well as to the clinical and radiological presentation. the two main large vessel vasculitides are giant cell arteritis and takayasu arteritis. behcet disease may combine large and small vessel vasculitis. imaging plays an important role in primary vasculitis. chest radiographs are not especially useful in large vessel vasculitis. contrast ct and mri further detect and especially help in the characterisation of large vessel vasculitis. vessel wall changes are well detected with both techniques. contrast enhancement, distribution of vessel involvement and morphological vascular changes should be considered. today, pet/ct is the recommended imaging technique in the assessment of vessel wall inflammatory changes and in the evaluation of treatment response. although the clinical scenario differs usually between takayasu and giant cell arteritis, the radiologist should combine the imaging findings with clinical and laboratory data to suspect a specific vasculitis. therefore, this presentation will concentrate on the basic signs and associated findings in large vessel vasculitis, pathologic correlation, imaging protocols and the differential diagnosis. the term vasculitis refers to a variety of clinico-pathological entities. the most widely used chapel-hill classification divides the vasculitis syndromes into three groups based on the size of vessels primarily involved. small vessel vasculitis such as anca-associated granulomatous vasculitis (wegener's disease), churg-strauss granulomatosis and microscopic polyangitis are most often associated with pulmonary abnormalities. the spectrum of hrct findings is quite variable and differs by entity. the hrct findings will be discussed together with clinical and laboratory findings to be integrated into a multidisciplinary diagnostic approach. the typical findings in wegener's granulomatosis include solitary or multiple, often cavitary nodules or masses, or focal or diffuse consolidations, churg strauss is dominated by interlobular thickening or transient multifocal and nonsegmental consolidations frequently in subpleural distribution. all types of pulmonary vasculitis may present with focal or diffuse pulmonary haemorrhage that produces pulmonary ground glass or consolidations in various distributions. a number of collagen vascular diseases (e.g., lupus erythematosus) or other granulomatous diseases (e.g. sarcoidosis) may affect the small pulmonary vessels causing haemorrhage or pulmonary hypertension. per disease entity, the course will review typical and more rare hrct features and key features that allow for diagnosis and classification, discuss side-to-side overlapping of morphologic features important for differential diagnosis and illustrate the findings of other diseases that represent the most challenging differential diagnosis, e.g. oedema, infection or malignant diseases. learning objectives: 1. to learn when hrct is of value in investigating pulmonary vasculitis. 2. to appreciate the different appearances of pulmonary vasculitis on hrct. a-014 17:07 d. inflammation and remodeling a.a. bankier; boston, ma/us (abankier@bidmc.harvard.edu) the presentation will lay out the pathological and pathophysiological basis for the complex processes of inflammation and remodelling. the implications of these processes for imaging will be discussed and illustrated by selected pathologies. finally, the presentation will indicate how the imaging reflections of these processes could be used in the future as imaging biomarkers for the diagnosis, follow-up, and outcome evaluation of disease. at (marcus.hacker@meduniwien.ac.at) appropriate diagnosis and therapy of coronary artery disease (cad) frequently require information about both the morphological and functional status of the coronary artery tree. thus, combined imaging consisting of invasive coronary angiography (ica) plus spect myocardial perfusion imaging (mpi) is practiced in clinical routine diagnostic of patients with stable angina since many years and can therefore be accepted as the reference standard in the diagnosis of hemodynamically relevant coronary artery stenoses. both morphological and functional information are mandatory for the decision of performing an interventional therapy or initiating/maintaining medical treatment in numerous symptomatic patients. the hemodynamically relevance of coronary artery lesions is a major condition to decide whether an interventional therapy should be performed or not. a non-invasive concept providing both information could provide accurate allocation of perfusion defects to their determining coronary lesion and specific morphological and functional classification of patients with coronary artery disease. in symptomatic patients, a normal stress mpi confers a very low short-term risk for cardiac death and/or acute myocardial infarction. however, a normal mpi does not exclude the presence of underlying coronary atherosclerosis, which may be extensive although not yet flow-limiting. in this regard, ct will unmask a sizeable subgroup of patients with coronary atherosclerosis who should receive more intensive antiatherosclerotic intervention than would have been indicated by mpi results alone. knowledge regarding the presence and extent of subclinical coronary atherosclerosis in patients who do not have ischemia by mpi can be of importance in patient management. learning objectives: 1. to appreciate the scope of information a spect/ct cardiac study can deliver. 2. to become familiar with protocols of spect/ct studies. 3. to learn a structured approach to performing and reporting a spect/ct study. a-017 17:00 c. mr/pet: do we really need it? h.h. quick; erlangen/ de (harald.quick@imp.uni-erlangen.de) following pet/ct and spect/ct, mr/pet hybrid imaging is the most recent addition to the palette of hybrid imaging modalities. mr/pet synergistically combines the excellent soft tissue contrast and detailed image resolution of mr with metabolic information provided by pet. integrated mr/pet systems furthermore offer the ability to acquire hybrid imaging data simultaneously. this can be applied to mr-based motion correction of pet data. these features open up several cardiac applications, e.g. evaluation of cardiac function and viability, diagnosis of cardiac inflammatory diseases and tumorous diseases. to fully assess the diagnostic potential of mr/pet, however, several technical challenges have to be considered: attenuation correction (ac) of the patient tissues in mr/pet has to be based on mr-images and is currently hampered by a limited number of tissue classes and undercorrection of bone tissue. cardiac radiofrequency coils and ecg gating equipment are currently not considered in ac. consequently, quantification of pet data therefore might be biased. the clinical workflow is rather complex and needs to be tailored to cardiac examinations. few research groups currently explore this new hybrid imaging modality in selected cardiac applications. cardiac mr/pet: do we really need it? considering the sparse clinical experience that is available today, it is quite early to answer this question yet. however, once the remaining technical hurdles are overcome and the diagnostic potential can be fully exploited clinically, the answer is most likely positive. the majority of malignant bone tumours can be detected on plain radiography. the age of the patient, location of the tumour in a bone and history of a preexisting bone abnormality should be included in determining the likely diagnosis. careful analysis of the pattern of bone destruction, periosteal reaction and matrix mineralisation allow for characterisation of most cases of osteosarcoma, ewing's sarcoma, chondrosarcoma and adamantinoma. mri is the best imaging technique for staging by displaying 1. the extent of bone marrow involvement, including epiphyseal infiltration and skip lesions, 2. the presence and extent of extraosseous soft tissue mass, 3. involvement of the neurovascular bundle, muscle compartments and adjacent joint. this allows to find the best biopsy approach and establish the feasibility of limb salvage as opposed to amputation. longitudinal non-contrast t1 sequences are the most accurate for determining intraosseous extent. axial fat-suppressed pd or t2 sequences optimally demonstrate soft tissue extension, and dynamic contrastenhanced mri is useful for differentiation of extraosseous tumour from edema and for assessment of tumour response to chemotherapy. chest ct is the most sensitive modality for detection of pulmonary metastases, and technetium skeletal scintigraphy is still frequently used for detection of osseous metastases. the most valuable, readily available and easy-to-use techniques to assess response to radiation therapy and chemotherapy are dynamic contrast-enhanced mr imaging, diffusion mri and colour-doppler ultrasound. to evaluate local control of disease and for detection of local recurrence, mri is usually the best imaging technique. plain radiography may detect complications of prosthesis. learning objectives: 1. to consolidate knowledge on malignant primary bone tumors on plain radiography, ct and mri. 2. to understand the principles of tumour staging and monitoring chemotherapy. 3. to become familiar with imaging findings following chemotherapy and surgery. oncologic approach to malignant primary bone tumours c. dhooge; ghent/be (catharina.dhooge@ugent.be) the most common bone sarcomas are osteosarcoma (os) and ewing sarcoma. os occurs primarily in long bones, ewing sarcoma occurs also in the pelvis, spine or chest wall. localised disease confers a 65% cure rate, and initially metastatic disease 25%. a multidisciplinary approach which includes neo-adjuvant systemic chemotherapy and local control measures for primary and metastatic sites followed by adjuvant chemotherapy has become the standard of care. complete surgical excision is mandatory in os; in ewing, radiation can also be used. standard chemotherapy for os is based on a combination of cisplatin, doxorubicin and high-dose methotrexate. ifosfamide and etoposide will be further considered (euramos). systemic therapy for ewing includes vincristine, doxoribicin, cyclofosfamide, ifosfamide and etoposide. high-dose chemotherapy with autologous stem cell reinfusion is evaluated in intermediate prognosis and metastatic disease (euro-ewing). among the different prognostic factors, response to neo-adjuvant chemotherapy by measuring chemotherapy-induced necrosis is a powerful indicator of outcome in bone sarcomas. patients who achieve a good histological response to pre-operative chemotherapy, defined as < 10% viable tumour at the time of tumour resection, have a better survival than those who show poor response (>= 10% viable tumour). five-year survival for good responders is 7o-75% compared to 45-50% for poor responders. however, the outcome for malignant bone tumours has improved little in the last 25 years. large international studies exploring new drugs such as biologic agents (interferon) or mechanisms conferring drug resistance (topoisomerase inhibitors) in randomised controlled trials will hopefully lead to therapeutic innovation. learning objectives: 1. to become familiar with the principles of chemotherapy in malignant primary bone tumours. 2. to understand what the oncologist expects from the radiologist. 3 . to recognise the value and limits of chemotherapy in malignant primary bone tumours. thursday a-024 16:45 surgical approach of malignant primary bone tumours g.m.l. sys; ghent/be (gwen.sys@ugent.be) in primary malignant bone tumours, three surgical procedures are necessary: biopsy, resection and reconstruction. whether a biopsy is performed in an open or a percutaneous way is a matter of preference, but in each case it should provide sufficient and representative material for pathological investigation without compromising the following treatment. the area of interest and the trajectory should be determined preoperatively in a multidisciplinary meeting. as the biopsy tract has to be removed during the resection surgery, it should be close to the planned approach for the subsequent resection. if a biopsy is performed improperly, the diagnosis may be wrong or the following resection may be impaired because of extensive contamination of compartments, resulting in a severe functional deficit. surgery planning is based on clear imaging and a multidisciplinary discussion of tumour extension, aiming for a wide resection of the tumour with clear margins. correct perioperative measurements are based on predefined fixed bony landmarks that should preferably be visible on the same image as the tumour. an amputation is performed if a surgical limb-salvage procedure is expected to result in a non-functional limb. nowadays, several reconstruction techniques for bones (bone grafts or prostheses), tendons (artificial or human ligaments) and skin (skin flaps or grafts) are available. invasion of the soft tissues such as the neurovascular structures, muscles and skin, will determine which reconstruction technique (s) are necessary to restore the patient's function. each reconstruction technique bears inherent complications requiring a regular follow-up. we outline the current opportunities and threats in diagnostic radiology: traditional diagnostic radiology has been rapidly replaced by clinical radiology and the role of the radiologist is changing from image interpreter to clinical manager of imaging data. to care for the patient`s medical problem and not only his images is important. this contains great opportunities for radiology to develop and for the radiologist to become a central player in patient management. however, this requires not only clinical knowledge and involvement, but also visibility and sometimes even 24/7 availability. the need for " only" image reporting is declining as clinical subspecialisation easily brings image interpretation into the domain of non-radiologists. to understand the importance of identity, visibility is very important. visibility can be achieved by being part of mdt s and also in many other ways. clinical radiology is an idea which, after all these years, has not been very well embedded in current radiology and radiology training. to understand the importance of certified training, maybe the most important action we have to undertake now is to capitalise on our radiological expertise. image interpretation in a clinical context can only be done or franchised (to non-radiologist) under conditions of certification and accreditation by radiology. we should never let the primate of education and certification slip to non-radiologists. radiology certification should be a quality standard, recognised by international and national medical bodies, such as medical chambers and specialist societies. the latter should have high priority. session objectives: 1. to learn about the current opportunities and threats in diagnostic radiology. 2. to understand the importance of identity. 3. to acknowledge the importance of certified training. where are the turf battles in diagnostic imaging? g.m. bongartz; basle/ch (georg.bongartz@usb.ch) turf battles in radiology are a foreseeable development for most imaging techniques which evolve push-button methods and readily interpretable imaging results. we as radiologists must learn to accept competition. turfs should rather be seen as challenge than as threat. predominantly, nonirradiating techniques like ultrasound and mri have become progressively easier to apply (us) or to understand (mri), where the final image in some standardised areas (eg joints) can readily be interpreted by medical specialists in this field. but also x-ray diagnostics in dental medicine or orthopedic imaging is largely applied outside the radiologic department. ct today seems still relatively excluded because of its complexity. but with increasing resolution, optimal 3d reconstruction and fast accessibility, it is only a question of time when the added value of the radiologist will be under question. radiology has changed. we must become experts with respect to patho-anatomy and radiological differential diagnosis. this requires profound education, both initial training and ongoing education. radiology must be advertised internally and externally. in radiological publications, outcome studies are still underrepresented. demonstration of our dedicated skills, fostering our special expertise and offering this as support to our medical colleagues will preserve radiology for the future. cooperation with partners seems the only way out of a turf battle -we need to search for alliances and integrate our partners to create a win-win situation. a-027 16:23 beating threats in europe with radiological training a.k. dixon; cambridge/uk (akd15@radiol.cam.ac.uk) by introducing radiology to medical students, it is hoped that they will begin to appreciate how difficult it is! likewise, when teaching residents, they must come to understand the basic anatomy and principles better than their clinical colleagues; this is very much the tenet of subspecialty training. they should also appreciate that patient care is optimal when there is close collaboration between clinicians and radiologists. passing of an examination (national or edir) offers some proof that a radiologist has attained a certain standard, but the principle of testing oneself formally or informally at regular intervals again provides a measure of continuing competence. such certification can be of value in the case of litigation. radiology is one of the fastest growing specialties and the techniques that we learn during training are quickly outdated; hence, the need for life-long learning and effective continuing professional development. learning objectives: 1. to understand how to teach radiology to undergraduate medical students. 2. to become familiar with the principles of self-assessment. 3 . to appreciate the necessity for life-long learning. history of ultrasound in radiology: lessons learned l.e. derchi; genoa/ it (derchi@unige.it) the relationship between radiology and us has never been an easy love story, and still isn't. in the early 1970s this new imaging field was not readily covered by radiologists and many other colleagues established us sections within their departments. then, important fields of us (cardiology, obstetrics, gynecology) became almost exclusive domain of non-radiologists. in the 1980s, the increasing success of us initiated turf battles with other clinicians. nowadays, clinical specialists perform > 50% of us examinations wordwide. in europe, most in-hospital us examinations is still performed in radiology, but this is not the case in all countries. a strong practice in us is quite important since this is often the first approach to patients. if initial us referrals are kept, radiologists will continue to guide decisions in subsequent imaging workup. furthermore, us keeps close to patients; in europe the examination is usually done directly by radiologists or, if by sonographers, the radiologist usually checks the case with limited directed us imaging. this clearly shows our role as physicians. to maintain a key role in us radiologists need to: 1) have the best specialists in us; attention must be given to us in residency programs. 2) invest in us technology (as examples: ceus, elastography, 3d/4d). 3) invest in us research. 4) have high visibility in the us community, keeping close contact with all clinical colleagues. 5) present higher visibility of us within radiology, with leaders supporting us within the radiological community and each radiologist promoting us in his/her environment. learning objectives: 1. to understand why ultrasound has moved out of the hands of radiology in some subspecialties. 2. to learn what this means for daily radiology practice and the quality of work. 3 . to know about the threats and how we should deal with them. thursday a-029 16:59 interdisciplinary cooperation without losing identity m.f. reiser; munich/de recently, major shifts in the paradigms of patient care took place: interdisciplinary counseling and including the patient in the decision making process for diagnostic and therapeutic measures. the new concept is that the patient no longer comes to the specialist, but the specialists come jointly to the patient. this is reinforced by the competition among health care providers, political decision makers and the public. in many hospitals this general trend has resulted in the establishment of various centers and boards such as the breast cancer centers, vascular centers and tumor boards for several cancer entities to name only few. at the university hospital of munich 46 centers and boards have been implemented up to now. in almost all of them the participation of radiologists is required. this results in a major challenge in terms of personal resources. together with the regular clinical-radiological rounds the time necessary for these activities equals 2 full-time radiologist posts. the participation of radiologists has many beneficial aspects: acknowledgement of radiology as an important clinical discipline and of the radiologist as a clinical consultant; participation in and influence on the creations of sops and (internal) guidelines; opportunity to advocate appropriate radiological methods for diagnosis and interventions; increase of knowledge in clinical medicine and new concepts of therapy; close personal links with our clinical partners. in order to prevent radiologists from losing their identity as radiologists it is mandatory that they remain firmly integrated in the radiology department and to strengthen the position of radiology as the central institution for providing cost-effective imaging and interventional services. moreover it must be taken care to offer attractive career options within the field of radiology. at (michael.fuchsjaeger@medunigraz.at) ultrasound (us) is the adjunct method of choice to mammography in breast imaging. over the past two decades, us technology has undergone profound advancements and refinements. us has, therefore, become an assessment tool with a defined field of indications as well as a unique set of diagnostic descriptors for breast lesion differentiation. the acrin 6666 study has demonstrated the special benefit of us in patients at risk with dense breast tissue. the bi-rads lexicon for ultrasound, in its second edition, expanded the role of breast us. further enhancement of image quality as well as the recent advent of automated breast us has even fueled scientific discussions on the potential role of us for breast cancer screening. automated breast us, which is based on computed generation of a 3d imaging data set obtained from many parallel 2d images, offers a different approach with a variety of benefits. images are obtained by the sonographer in standardised fashion, whole breast data sets can be reviewed at any time after the examination, reducing operator dependence, and image fusion with, i.e. mri is easily possible. the basic physical background, the significance as well as important aspects of practical use of handheld and automated breast us will be explained and illustrated by the respective imaging examples. emphasis will be laid on strengths and potential weaknesses of both us technologies with regard to breast imaging. the terms "complicated cyst" and "complex-cystic lesion" are based on breast ultrasound (us) terminology. the simple cyst is a fluid-filled, clearly defined, anechoic lesion without any suspicion of a solid intracystic mass. if a simple cyst is complicated by echogenic fluid, it is called complicated cyst. this echogenic fluid can be caused, e. g., by cell debris. thin echogenic septa are common in complicated cysts. vascularisation can never be found in these echogenic components. a complicated cyst has no solid component and no thickened wall or thickened septa. the expected probability of malignancy is 2%. the us criteria of a complex-cystic lesion following berg et al. categorise it into 4 types: type 1, thick outer wall and thick internal septa (alone or in combination of both); type 2, one or more intracystic masses; type 3, mass of mixed cystic and solid components (at least 50% cystic); type 4, predominantly solid with eccentric cystic foci (at least 50% solid). complex means there is a suspicion of a tumour inside a cyst or a solid tumour with cystic components. a complicated cyst will usually be followed by us after 6 months. a complexcystic lesion needs a correlation with mammography. us-guided large core needle biopsy in combination with a us and mammography visible marker placement is useful in type 3 and in type 4 complex-cystic lesions. in type 1 and type 2 complex-cystic lesions, a preoperative hook wire placement and excision surgery is the typical procedure. learning objectives: 1. to learn about the us appearance of complicated cysts and complex-cystic lesions. 2. to consolidate knowledge on differential diagnosis for these respective lesions. 3. to understand the diagnostic algorithm for a work-up of these lesions. renal colic is the most frequent non-obstetric cause for abdominal pain and subsequent hospitalisation during pregnancy. intervention is necessary in patients who do not respond to conservative treatment. ultrasound (us) is widely used as the first-line diagnostic test in pregnant women with nephrolithiasis, despite that it is highly nonspecific and may be unable to differentiate between ureteral obstruction secondary to calculi and physiologic hydronephrosis. magnetic resonance imaging (mri) should be considered as a second-line test, when us fails to establish a diagnosis and there are continued symptoms despite conservative management. moreover, mri is able to differentiate physiologic from pathologic dilatation. in fact in the cases of obstruction secondary to calculi, there is renal enlargement and perinephric oedema, not seen with physiological dilatation. in the latter, there is smooth tapering of the middle third of the ureter because of the mass effect between the uterus and adjacent retroperitoneal musculature. when the stone is lodged in the lower ureter, a standing column of dilated ureter is seen below this physiological constriction. mri is also helpful in demonstrating complications such as pyelonephritis. in the unresolved cases, computed tomography remains a reliable technique for depicting obstructing urinary tract calculi in pregnant women, but it involves ionising radiation. nephrolithiasis during pregnancy requires a collaboration between urologists, obstetricians, and radiologists. learning objectives: 1. to list the us, mr and ct imaging findings of urolithiasis and urinary tract infections. 2. to discuss the role and the appropriate uses of us, mr and ct for imaging these suspected conditions in pregnancy. 3 . to discuss how imaging can influence the management of nephrolithiasis during pregnancy. oncology t.f. hany; zurich/ch (thomas.hany@gmail.com) in malignant tumours, pet/ct imaging using 18-fluoro-deoxyglucose (fdg) is widely used nowadays. fdg-uptake is an unspecific process and results in physiological as well as pathological malignant and non-malignant tissue uptake. to properly understand and interpret pet/ct imaging, knowledge of the mechanism and pathways of fdg in different tissue types like brain and the gastrointestinal tract is key. intrinsic as well as extrinsic factors influence uptake pattern not related to oncological disease like uptake in brown fat in patients exposed to cold ambient temperature and psychological stress or increased muscular uptake in nonfasting patient. typical treatment-related changes occur during and after treatment and must be recognised correctly so as not to overstage patient disease. a systematic analysis and knowledge of all these factors facilitate and improve the reading of oncological clinical cases. learning objectives: 1. to understand pattern of physiological fdg-uptake. 2. to learn about the pattern of non-pathological uptake in several tissue types. 3 . to understand the influence of chemotherapy and other agents on fdguptake in the body. radiologists mostly prefer to use the comparative technique while evaluating radiological images, especially when the anatomy is identical for both sides. comparative analysis mostly works if the anatomic details are not complex or the right resembles the left. however, the complex anatomy and relatively high incidence of individual variations in head and neck may hinder this way of interpretation. variable pneumatisation of paranasal sinuses and temporal bone may cause difficulty. vascular system, especially venous structures may be sources for pseudolesions. for example, asymmetrically enlarged jugular vein or venous plexuses at any location may be misinterpreted as mass of any origin. veins may also become problematic on mr imaging due to entry slice phenomenon, in-plane flow, and flow turbulence effects and can have variable enhancement. normal anatomical structures such as facial nerve may enhance and can be mistaken to be pathologic on mri. technical issues can be considered as a group that may cause pseudolesions. images of the improperly positioned patient may become problematic while evaluating tiny structures. pet and pet-ct carry their own risks for pitfalls. normal structures may confound interpretation and result in false-positive findings. the situation may become much more complicated when there is asymmetry. similarly, atrophy and unilateral absence of a structure may be misread as a mass on the contralateral side. because of the complex anatomy and relatively high incidence of individual variations, head and neck imaging demands much more attention and careful analysis. the appropriate imaging technique and detailed knowledge of anatomy are essential to recognise pseudolesions. as a general rule, detailed knowledge of the patient's clinical history is essential before any imaging study is performed, to evaluate the appropriateness of the indication, tailor the acquisition protocol and correctly interpret the study. in head and neck imaging, this rule particularly fits in the emergency setting. in certain circumstances, the swelling and enhancement of soft tissues produced by infectious lesions may mimic a neoplasm. even more so, in patients already treated with surgery or chemoradiation. in these patients, the challenge is double: to identify any abnormality in the new anatomy produced by treatment and to discriminate between inflammation, complication and relapse. these can be very difficult without knowledge, for example, of the reconstructive procedure after surgery. previous images are extremely useful, not only because they help detect abnormalities, but also because through indirect information on the growth rate of the lesion they are crucial for correct interpretation of findings. tablets in radiology represent a novelty. since the introduction of the tablets on the market, the radiological field has been probably the first medical discipline to discover the many advantages of these devices. in fact, many applications for image management have been made available on the app stores (apple and android), and allow radiologists and non-radiologists to handle dicom images on the tablet, as part of the patient's record. however, the emerging applications are driving the process from the simple dicom image viewing to the full integration of the tablet with the pacs, allowing the handling of a patient's full record and presumably the possibility to report. in view of this rapid technological development, again radiology falls in the middle of a storm and is asked to find a solution to problem: are tablets suitable to read and report dicom images? and if so, which kinds of images (ct, mri, x-ray, etc) .? how can we manage the portability of patients' data (security issues, data loss, etc).? what will be the impact on teleradiology? these issues will be addressed by the panel of experts who will speak in the refresher course. session objectives: 1. to appreciate the current state of tablet technology and its practical use in radiology. 2. to understand the pros and cons of the use of tablets. 3 . to learn about specific critical areas of utilisation (dicom images reading and teleradiology). a. tablet-computers: a technical overview j. fernandez-bayo; sabadell/es (jfernandezb@cspt.es) since their introduction in 2001, tablet pcs have evolved extensively. they have become very popular, filling the gap between laptop computers and smart mobile phones. we will review technical aspects like the processors, storage space and memory, size and weight, connectivity and networking, software, autonomy, and battery life in different devices. special focus will be on the displays and different possible uses in radiology. for diagnostic purposes, different technical aspects must be taken into consideration, like the display size, resolution, pixel size (pixel pitch or pixels per inch), luminance, and contrast. displays in radiology normally have sizes between 20" and 24" and resolutions up to 5 mpx, with luminance that ranges from 250 cd/m 2 to 600 cd/m 2 . by contrast, tablets have screen sizes between 9" and 10" and resolutions up to 3 mpx, with luminance that ranges from 370 cd/m 2 to 480 cd/m 2 . due to their screen size, tablets score better in pixel pitch, with around 250 ppi versus 150 ppi in medical displays. the two systems have similar contrast ratios. other technical aspects of display that we should take into consideration are the number of distinguishable grays that can be represented, which in tablets correlates with the number of colours that can be displayed (color gamut) and colour accuracy (delta-e). additionally, we should take into consideration that displays should be calibrated for medical diagnostic purposes and tools to calibrate tablets have recently become available. learning objectives: 1. to learn about the pc evolution: from desktops, to laptops and tablets. 2. to appreciate the versatility features of a tablet. 3 . to understand the hardware features with a specific focus on display. 4. to understand the hardware features with a specific focus on networking. a-046 16:28 b. reading dicom images on the tablet o. ratib; geneva/ch touch screen tablets are becoming widely available, providing convenient mobile solutions for physicians and health-care providers. this is particularly attractive in medicine to "nomad" physicians, who need to be able to access relevant patient data and images anywhere-anytime in their daily practice where they are rarely at a single location. while they may not always be adequate for routine diagnostic tasks, they provide a convenient mobile solution for on-call and remote consultations. there are different types of software architecture that can be implemented for such tasks. two different major designs are: (1) online web-based applications where the device serves as a "thin-client" to display images rendered and manipulated on a remote computer and (2) local applications that reside on the mobile device and can run independently after images have been downloaded on the device. the first solution requires the user to be constantly connected to the network, while the second solution can continue to function after being disconnected from the network. most pacs vendors are starting to provide web access to their imaging solutions that can be accessed from mobile devices. web access can however be slow and dependent on reliable access to wireless network. we chose to develop a stand-alone companion application to our open source imaging platform osirix. with the increasing capacity and computing power of mobile devices, users will soon be able to perform most of the processing and image manipulation functions that are today only feasible on desktop or laptop computers. learning objectives: 1. to learn which dicom readers are available for tablets. 2. to appreciate the different approaches to dicom reading (local vs remote) and the pacs/tablets integration. 3. to understand the pros and cons of dicom image reading with the tablet in regards to image quality and displays. the optimisation of clinical breast cancer care comprises the prevention of over-diagnosis, reduction of over-treatment, and avoiding unsuccessful treatments. these goals are targeted in the vph-prism project by seven european and two us partner institutions. from the prospectively collected data, we will derive optimised imaging protocols that comprehensively take a woman's history and risk factors into account. the tight integration of radiological and histopathological images enables joint assessment of quantitative tissue parameters from microscopic and macroscopic imaging. more informed therapy decisions can be taken by such enhanced multidisciplinary data, backed by a powerful case database. the reduction of overtreatment, and highly individualised diagnosis and therapy decisions are closely related. we ultimately aim at deriving predictive parameters from the multi-modal and multi-disciplinary database to select the treatment option with the best chance of enduring recurrence-free survival. prospectively collected data, personal risk factors, and corresponding imaging data fed into the database from three large cohort studies are expected to provide insights into the individual preconditions and factors affecting disease progression. to optimise therapy, the decision between therapy options is key. this will be addressed by a decision support system using the project database. for surgical excision planning, vph-prism will aim at providing better estimates of tumour size, and with visual planning aids supporting radiologists and surgeons. for chemotherapy, quantitative lesion parameters, tracked over time during therapy, may help to detect success or failure of the treatment early on, such that a chemotherapy regime can for a non-responder be switched to a different regime in due time. quantitative imaging biomarkers in dementia; the fp7 vph-dare@it project w.j. niessen; rotterdam/nl (w.niessen@erasmusmc.nl) the number of individuals suffering from dementia today is roughly 36 million. due to ageing societies, this number is predicted to increase to 115 million by 2050. worldwide annual costs are estimated to be â�¬450 billion. in 2012, the who declared dementia a global health priority, highlighting the urgent need for improvements in this area. vph-dare@it's aim is to enable more objective, earlier, predictive and individualised diagnoses and prognoses of dementias to cope with the challenge of an ageing european society. the expected impact of vph-dare@it will influence the scientific, clinical and industrial communities across europe and internationally to improve health care of dementia patients. in this presentation we will introduce the vph-dare@it project. we will then focus on the development, validation and implementation of quantitative imaging biomarkers for the early detection and differential diagnosis, which will take place as part of the project. author disclosure: w.j. niessen: advisory board; part-time detached to quantib bv as scientific director. shareholder; co-founder and shareholder of quantib bv. horizon 2020: improving diagnosis and medical interventions and support to medical imaging j.-l. sanne; brussels/be (jean-luc.sanne@ec.europa.eu) research and innovation contribute to increasing europe's competitiveness. at the same time, research and innovation help make people's lives better by improving things like healthcare. in january 2014 the european union launches horizon 2020, the biggest eu research and innovation programme ever, with a budget of â�¬ 79 billion (current prices) over seven years (2014) (2015) (2016) (2017) (2018) (2019) (2020) . eu support for research and innovation helps drive international projects across the european union and beyond, and promotes the progress of knowledge and technology. one of the three key pillars of horizon 2020 will be tackling societal challenges (priority 3) such "health, demographic change and well-being". one feature is the development of new and more effective diagnostics. relevant tools and technology innovations will be supported in view to improve disease outcomes through earlier, more accurate diagnosis and by allowing for more patient-adapted treatment. support will be provided through the work programme 2014 -2015 of societal challenge 1 "health, demographic change and wellbeing". additional opportunities are offered in the work programme 2014 -2015 of priority 2 (industrial leadership) "leit -information and communication technologies". practically, all imaging modalities have been used in space research since a long time ago. first of all, radiology is targeted in research activities, because by definition all cosmonauts and astronauts are healthy persons. the biggest volume of examinations had been performed on crew members for studies of organs and functions of the human body before and after long-term flights. health effects of zero gravity were of special interest. for example, multiple studies with involvement of both russian and international specialists were done on bone mineralisation (bone densitometry), muscle volume (mri) and metabolism (mr-spectroscopy) both in astronauts and healthy control subjects. first, ultrasound (us) examinations were conducted in space onboard russian orbital stations in 1982. complex us studies were done by the author himself during his flight as a crew member of "salut-7" orbital station in 1984. the author had found some complex changes in blood and fluid dynamics under weightlessness. teleradiology was used for data transfer to medical specialists on the earth. today, we are continuing to use radiology for research on astronauts. for example, applications of sophisticated brain mri and fmri methods are of special interest for studies of subtle brain changes in space travellers. among our targets are flights to the moon, mars and large asteroids. to be better prepared for that task, we need better diagnostic tools. new versions of mobile us systems, miniature x-ray and ct machines suitable for use inside spaceships are under development. there are several mri pitfalls that should be recognised when imaging the female pelvis. mri appearances of uterus and ovaries are dependent on the phase of menstrual cycle/use of exogenous hormone therapy. normal postsurgical and post-radiation appearances of the pelvis can sometimes mimic tumour recurrence. it is important to become familiar with these appearances to avoid potential pitfalls. one very common pitfall is differentiation of transient myometrial contraction from adenomyosis. interrogation of all imaging planes over the duration of the entire mri examination can be useful to distinguish between the two, although myometrial contractions can last up to 45 min. the choice of the correct imaging plane is crucial for the precise classification of uterine anomalies (coronal oblique) and accurate evaluation of parametrial invasion (axial oblique) in patients with cervical cancer. both dynamic contrast-enhanced mri and diffusion-weighted mri improve the accuracy of mri in the evaluation of malignant pelvic conditions. however, certain pitfalls related to each technique should be recognised to avoid misinterpretation. it is crucial to be familiar with the anatomy of the uterovesical (uv) ligament, as it is often the site of pelvic lymphoma (such as bladder or cervix lymphoma). however, some benign conditions such as endometriosis can involve the uv fold and invade both bladder and uterine wall. certain mri features can be helpful in making the correct diagnosis. learning objectives: 1. to become familiar with normal variations in mri appearances of female pelvis resulting from physiological conditions (e.g. different phases of menstrual cycle) and treatments (including exogenous hormone therapy, surgery and radiation) potentially mimicking disease. 2. to consolidate knowledge on the role of the correct mr imaging plane in avoiding potential mis-classification of uterine anomalies and parametrial invasion in patients with cervical cancer. 3 . to learn about certain pitfalls related to dynamic contrast-enhanced mri and diffusion-weighted mri. a-057 09:15 b. pitfalls in ultrasound k. kinkel; chãªne-bougeries/ch (karen.kinkel-trugli@wanadoo.fr) pitfalls of sonographic findings in the pelvis can be related to technical issues, interpretation errors or to the patient's specific condition or pathology. common problems consist of insufficient bladder filling, misinterpretation of posterior enhancement or shadowing according to the anatomical structure and pathology of a size that goes beyond the field of view of the probe. organspecific problems will be illustrated in interactive questions, particularly for the uterus and the ovaries. identification of diseases can be difficult in many areas of abdominal imaging and therefore misses are easily made, also by the more experienced radiologist. it is difficult in the mesentery and peritoneum, covering a large area but being a very thin structure where abnormalities are easily missed. therefore, knowledge of the peritoneal anatomy and pathophysiology of peritoneal diseases is not widespread and differential diagnosis can be difficult. hence, special attention should be paid to prevent misses. another difficult area is diagnosing occult gastrointestinal bleeding. here, the choice of the proper imaging method is crucial as well as understanding the pros and cons of the method. the technique used should be optimised, as otherwise sometimes subtle signs of bleeding are missed. the presence of bowel dilatation itself is often correctly diagnosed, but the extent of the obstruction, the cause of the obstruction and especially complications (ischaemia) might be misdiagnosed. ct is the preferred technique for evaluation of bowel dilatation. care should be taken to scrutinise the examination for principal findings in patients with bowel obstruction. a. mesentery and peritoneum d. akata; ankara/tr (dakata@hacettepe.edu.tr) imaging findings of neoplastic or inflammatory diseases within the peritoneal cavity and the mesentery sometimes overlap and cause difficulties in interpretation. even disease processes in the peritoneum, mesentery or omentum may not be recognised on radiological examination, causing major difficulties in the management. peritoneal anatomy and physiopathology of peritoneal diseases must be well understood for better evaluation. ct is the best modality to assess the whole cavity. mr is equally sensitive with better contrast resolution; however, both modalities have advantages and limitations. ultrasound has a complementary role in evaluating the peritoneal fluid content. the presence of lacelike mobile thin septa is highly significant for tuberculosis. for better diagnosing the pathology, systematic approach is needed such as assessing the presence or absence of fluid in the peritoneal cavity, its character and location, accompanying soft tissue densities and their location. some inflammatory or infectious causes, such as acute pancreatitis and tuberculosis, involve typically parietal peritoneum and certain peritoneal reflections. peritoneal carcinomatosis involves typically both visceral and parietal peritoneum as well as subdiaphragmatic space. contrast enhancement patterns of the peritoneal membranes and the mesentery also have a complementary role in differentiating a variety of diseases. learning objectives: 1. to learn about the imaging characteristics of peritoneal and mesenteric masses and their differentials. 2. to appreciate the potential and limitations of imaging techniques in the detection of such lesions. 3. to understand the common pitfalls in diagnosis. a-060 08:58 a. filippone; chieti/ it (a.filippone@rad.unich.it) patients with persistent, recurrent, or intermittent bleeding from the gastrointestinal tract for which no definite cause has been identified by initial oesophagogastroduodenoscopy, colonoscopy, or conventional radiologic evaluation are considered to have an occult gastrointestinal bleeding (ogib). the management of ogib is clinically challenging, since the causes of such a bleeding frequently arise in the small bowel (sb), until now considered as the ''dark continent''. conventional barium contrast studies allow only a limited evaluation of sb, whereas angiographic diagnosis is strictly related to active bleeding. the introduction of capsule endoscopy (ce) as well as of crosssectional imaging dedicated to the sb visualisation, such as multidetector-row computed tomography enteroclysis (cte) and magnetic resonance enteroclysis (mre), represents significant technological advances that have overcome the limitations of older diagnostic tests. although ce is recommended as a first-line investigation in ogib patients, cte or mre are alternative diagnostic tools when ce is contraindicated due to suspected/known obstruction or stricture. moreover, in patients in whom a tumour is suspected, cte or mre may be the preferred initial test. therefore, radiologists have to be familiar with cte and mre techniques, in terms of bowel distension, scanning parameter selection, contrast administration as well as with specific imaging findings. similarly, they have to be aware of the potential pitfalls such as suboptimal bowel distension, artefacts due to peristalsis or breathing, intraluminal food debris and previous surgery. learning objectives: 1. to understand the causes of gi bleeding and underlying pathophysiology. 2. to appreciate the strengths and limitations of the imaging techniques used in diagnosis. 3 . to learn about common pitfalls in diagnosis. dilatation. presently, ct takes a major place in this setting with a reduced role for plain films. sonography is an alternative method when ct is not recommended. the questions of mondor in 1947 were pointed before the advent of cross-sectional imaging; these are still valid and have to be answered: 1) is this a true occlusion (how to differentiate it from adynamic ileus)? 2) does the obstruction concern the small bowel or the colon (impacting on the decision to operate or not)? 3) what is the cause of the obstruction? 4) are there signs of bowel ischaemia? the key points to avoid missing imaging diagnoses in bowel dilatation are to make the distinction between true mechanical obstruction and adynamic ileus (an early sign of mesenteric infarct) and to detect signs of strangulation leading to ischaemia (such imaging findings are present despite normal blood tests). in this setting, ct is the preferred technique; if it is not available, plain films and sonography can help in an optimal medical decision. the national lung screening trial (nlst) found a 20% reduction in lung cancer mortality with three annual screens using helical ct relative to chest xray. the us preventive services task force has issued draft recommendations to provide annual ct screening to high risk individuals defined by age and smoking criteria. questions remain regarding the implementation of ct screening: the determination of risk to identify those who should be screened, the frequency and duration of screening, definitions of screen positivity based on detected nodule characteristics, diagnostic algorithms for the follow-up of positive screens, overall societal costs of screening, and methods to adequately diffuse this technology across all socioeconomic groups at risk. answers to these questions are being addressed by several groups through ongoing research and secondary analyses of trial data. several models exist to identify individuals at highest risk of lung cancer (and lung cancer mortality), which may be enhanced if validated molecular markers are included. ongoing analyses of nodule features and likelihood of lung cancer will better inform screening interpretation guidelines and diagnostic algorithms. estimates from the nlst suggest that screening as performed in the nlst will be cost effective: the base case estimates $67,000 per quality adjusted life year gained (qaly). subset analyses suggest that screening is much more cost-effective in women than men, in higher versus lower risk groups, and in current versus prior smokers. while several variables influence cost-effectiveness, major drivers of cost are the cost of ct screening exams as well as the number of follow-up ct scans per positive screen (1.26 in nlst). while the national lung screening trial (nlst) had shown a significantly reduced lung cancer-specific mortality and all-cause mortality, the current results from the various european trials do not show such positive results. the dutch-belgian nelson trial, the german lusi trial and the british ukls have not yet published their results. so far, more cancers were detected in the screening arm of published danish and italian trials, but the positive effect on cancer mortality could not yet be shown. the italian mild trial even showed higher mortality in the yearly screening arm, and no difference between 2yearly screening and the control arm. this presentation discusses the implications of these findings and the consequences on implementation on screening in clinical practice. while limited in number of participants, european trials used advanced approaches that are most likely to be used if screening will ever be implemented. this presentation will discuss issues such as growth assessment and volumetry as critical factors for nodule assessment, handling of sub-solid lesions, computer aided detection and evaluation, and use of nonradiologists for reading and standardised follow-up. the goal is to provide an insight into how the european trials have affected our idea on practical implementation of lung cancer screening. the discussion will address the following issues: 1. are there sufficient data to support the implementation of individual lung cancer screening in clinical practice? 2. if yes, how to move from efficacy to effectiveness: what are the most optimised risk profiles for screening? what is the minimum level of infrastructure support and organisation required? how should subjects be informed about screening? what are the optimal follow-up duration and screening interval? what are the technical and positive screen management requirements? 3. what about the alternatives of waiting for additional data from ongoing trials or the validation of new biomarkers of lung cancer, permitting better selection of screened population before implementing individual lung cancer screening? attendees' opinions will be collected interactively. the speakers will be asked to comment and debate. treatment of prostate cancer depends strongly on the stage of the disease at the time of detection. however, treatment is controversial, even in prostate cancers found through early detection. this presentation will be based on a careful recent literature review. early detection of prostate cancer by use of psa testing leads to a significant reduction of at least 30% of disease-related mortality in screened men. this is however at the price of 40-50% of overdiagnosis, usually resulting in overtreatment. diagnostic developments which reduce overdiagnosis and the proper identification of cases which may not require treatment are central issues of current research and will be addressed by referring to available evidence. active observation of potentially nonaggressive cancers is an option in the management of this disease until, preferably, the diagnosis of such cases can be avoided all together. radical prostatectomy and radiotherapy are the options for treating those cancers which are judged to be aggressive. treatment recommendations for prostate cancer continue to evolve and are affected by technological advances in surgery, new discoveries in tumour biology, and the development of predictive and prognostic biomarkers. with the increased complexity of treatment decision-making, the role of mri is also evolving. the more individualised and targeted the treatment approach, the greater is the role of imaging in treatment selection, planning and follow-up. mri is especially crucial for planning technologically sophisticated treatment approaches such as robotic surgery, igrt, or focal therapy and in assessing patients' eligibility for active surveillance. though needs for uniform interpretation and standardised reporting remain unresolved, the value of mri in pretreatment staging of prostate cancer, particularly for evaluating extracapsular extension and seminal vesicle invasion, has been documented. not only the tumour stage, but also its size, volume and grade (aggressiveness) are important factors that influence treatment selection. therefore, the introduction of functional mr is essential. when added to t2weighted mri, diffusion-weighted mri, dynamic-contrast-enhanced mri, and mr spectroscopy, in addition to improving tumour detection, can provide an indication of tumour aggressiveness. mri performance on all sequences is dependent on lesion size/volume and grade, and this should be considered when applying mri results to treatment selection and planning. while it has been shown that multiparametric mri is generally more accurate and informative than anatomic mri alone, evidence-based guidelines specifying which combinations of sequences are essential for specific indications in patients with prostate cancer are yet to be developed and validated in welldesigned studies with robust outcome measures. in major trauma, it is essential to immediately recognise life-threatening conditions and to initiate early treatment. the majority of these patients succumb at the site of the injury to severe injuries of the central nervous system, heart and great vessels. however, there is another peak of early deaths within the first four hours after the injury. in the majority, these patients are at risk due to haemorrhage which is basically controllable by early minimally invasive treatment. consequently, this means that the vast majority of internal injuries can be survived as long as bleeding control is achieved within the first four hours after an injury. minimally invasive interventional techniques are already in use at a very early stage of the clinical decisionmaking process. particularly, we have witnessed a major paradigm shift in the treatment of blunt aortic injuries. endovascular repair has replaced open repair in many trauma centres. in appropriately selected patients, this adoption of endovascular stent grafts has resulted in a reduction in perioperative mortality, stroke and paraplegia, as compared to open repair. this entire session will provide knowledge about indications, requirements, standard procedures, and outcome of vascular emergencies, pardon me, urgencies. a. aortic emergencies m. cejna; feldkirch/ at (manfred.cejna@lkhf.at) aortic emergencies can be classified into several categories. "acute aortic syndrome": acute aortic syndrome is an entity of changes of the aortic wall. these include aortic dissection, intramural thrombus, and penetrating atherosclerotic aortic ulcer. besides coronary malperfusion and aortic valve insufficiency (type a dissection), emergency presentation is often due to visceral/limb ischaemia. sequelae of aortic syndromes are pseudoaneurysm formation and potentially aortic rupture. endovascular treatment has been established as the treatment option in at least type b dissections and penetrating aortic ulcers. aortic aneurysm rupture: with increasing diameter, aneurysms in the thoracic, thoraco-abdominal and abdominal aorta are prone to rupture. signs of impending aortic rupture are pain and imaging signs are sometimes subtle just like blurred contours of the aorta and (blister like) vascular wall deformation. endovascular treatment is an alternative to vascular surgery. aortic trauma: in severe thoracic trauma (mostly deceleration trauma), pseudoaneurysm formation and aortic rupture occur at the level of the aortic isthmus. endovascular treatment is considered the treatment of choice. inflammation, mycotic aneurysms and aorto-enteric fistulae: with acute and chronic inflammation, aneurysm and pseudoaneurysm formation and fistulae to enteric structures can occur. endovascular treatment is more often considered as bridging to vascular surgery instead of being a definitive cure. iatrogenic aortic injuries: besides accidental aortic injury during operations or interventional procedures, transaortic valve replacement and placement of aortic balloon pumps can result in iatrogenic trauma. endovascular treatment may be a minimally invasive approach. the focus will be on systematic presentation of aortic emergencies and the role of endovascular treatment. there are a number of vascular visceral emergencies that may be traumatic or nontraumatic in origin. the degree of urgency or potential for urgency varies with each condition and the subsequent management and intervention techniques will vary accordingly. an understanding of the natural history, pathophysiology, diagnostic tests and interventional techniques for these conditions will aid the diagnostic and interventional radiologist in identifying the pathology and knowing when to refer or initiate definitive treatment. i talk about embryonal development and anatomical differentiation of cardiovascular system, with special attention to the peripheral vascular system. the goal of this part of presentation would be to understand the anatomical structure and architecture of arteries and capillaries. we will discuss the casual classification of different kinds of peripheral arterial emegencies; e.g. congenital, posttrauma, arteriosclerotic and iatrogenic. the audience will learn about different therapy approaches, interventional and non-interventional, with accent on pad (classification, pathophysiology, risk factors, statistical facts and therapy). at the end, we will review different studies about combination therapy (conventional and interventional) with different possibilities and outcomes. modern cancer research and increasing therapy are mechanism based with the development of disease-modifying therapies that target the hallmarks of cancer. modern imaging tools enable the visualisation and quantitative assessment of the expression of molecular targets, of their interaction with potential ligands, as well as of the functional consequences of interactions at a molecular, cellular, metabolic, physiological, and morphological levels in a temporo-spatially resolved manner. the ability to gather such information from the intact organism renders imaging highly attractive for biomedical research and drug development. the determination of cell proliferation with radiolabelled thymidine is a wellestablished method in various life science branches where [3h]thymidine has been used for more than 40 years and still represents the gold standard for the assessment of tumour cell proliferation. since non-invasive determination of this parameter is required in clinical studies, considerable efforts have been made in radiopharmaceutical research. the synthesis of a large series of proliferation markers resulted therefrom mostly focussing on pyrimidine nucleosides. the labels used were gamma as well as positron emitting radionuclides. here, [18 f]flt (3'-deoxy-3'-fluorothymidine) is examined and discussed with respect to its preclinical and clinical application. since apoptosis is an important mechanism of cell death in tumours responding to treatment, the non-invasive assessment of apoptosis with tracers for the detection of phosphytidyl-serine presentation and/or caspase activation could be used as surrogate marker for therapeutic efficacy. several approaches have been followed during the last years; their potential and limitations will be presented. angiogenesis is one of the hallmarks of cancer that is considerably easy to characterise with many different imaging modalities and methods. it is not only crucial for invasive and metastatic tumour growth, but is also a prerequisite for the accumulation of anticancer drugs and highly impacts the success of radiotherapy. this talk summarises our experiences in microstructural, functional, and molecular imaging of tumour angiogenesis. the microarchitecture of vessels can longitudinally be studied using high-resolution ( )ct. dce mri and hf-us are introduced as favourable tools to characterise perfusion, vessel permeability and vessel maturation during antiangiogenic treatments. using targeted probes, it is shown that "fluorescence molecular tomography (fmt)", mri and us are capable of estimating the expression of angiogenic marker molecules on tumour vessels and of matrix-associated enzymes in the interstitial space during vascular remodelling. additionally, examples are also given for epr-based nano-sized theranostics and it is shown how us can aid in better accumulating them at the target site by inducing vascular permeation. many of these novel imaging concepts and tools can relatively easily be translated into clinics. thus, one can expect them to play a major role in the clinical management of tumour treatments soon. mammography technique from the point of view of radiographic compression and positioning is no different from film screening and radiologists ignore this at our peril. we will discuss the danger areas at the edges and the back of the breast and help you to find lesions only seen on one view. with digital capture the technologist can view images immediately, but the temptation is for them to repeat exposures to obtain radiographic perfection on otherwise clinically acceptable images. however, the task of assessing quality cannot be left to them, as viewing conditions on the 'lower resolution' acquisition monitor in a bright x-ray room is not enough. there is now evidence from 2 population screening programmes that poor image quality can reduce cancer detection from between 15% in france to 24% in ontario. 'quality' can be lost at 3 keys points in the imaging chain: the x-ray beam and dose, the detector and finally display. in flanders, poor detector performance was compensated for by increasing the x-ray dose by 60% and by meticulous quality control. postprocessing is less well understood, but reader studies now show different algorithms will affect performance particularly for the detection and classification of micro-calcification. finally, it does not matter how good all the equipment is if we try and read the images with the lights on full. mammography is the most important breast imaging technique allowing the visualisation of masses and micro-calcifications. however, in conventional mammography the three-dimensional breast tissue is reduced to a twodimensional image. therefore, small lesions may be undetectable due to superimposed glandular tissue. digital breast tomosynthesis (dbt) has emerged as a new imaging modality to overcome this limitation. several lowdose mammographic projections are performed over a limited angle of up to 50 degree using a standard mammography system. the average glandular dose of a tomosynthesis scan is somewhat higher compared to one-view mammography, but lower compared to a standard mammography in two projections. based on the low-dose projections, a stack of cross-sectional images covering the entire breast is reconstructed with an interslice distance of about 1 mm. several studies have shown that tomosynthesis improves both tumour detection and the characterisation of focal masses. due to the crosssectional nature of dbt, the techniques allow on the one hand the reliable differentiation of true focal masses from summation artefacts. on the other hand, tomosynthesis improves the detailed analysis of the lesions' border to differentiate benign lesions and carcinomas. additionally, contrast-enhanced spectral tomosynthesis may allow analysing signal-intensity time curves. in conclusion, dbt adds important information to standard two-projection mammography and can replace spot compression and rolled views as problem solver for difficult cases. however, the impact of tomosynthesis on breast cancer screening has to be investigated in larger clinical trials. reading screening mammograms is not the same as reading diagnostic mammograms. the vast majority of women attending a screening programme are usually asymptomatic and do not have abnormalities associated with a malignancy. the task of a mammogram reader is to scan a mammogram and perceive any possible abnormalities that could be associated with a malignancy. in other words, we are talking about perception and not diagnosis of a finding. examples will be shown about this crucial step. in modern population-based screening programmes, we use computerised reading and recording systems. since the work flow is rather quick, we have to ensure basic steps such as identity control and see that both ris and pacs are synchronised so that decisions of screening readings are recorded in both the systems of one and the same patient. in computerised screening programmes, we use standard reports informing a woman that no signs of malignancy have been detected on her screening mammograms. in case of findings that need further assessment, there are several ways to deal with this situation. the most common way is via a phone call, but this can also be done with a letter. a screening report should be short and concise and should only inform whether we see signs of a possible abnormality that can be associated with a malignancy. extensive reports describing the contents of a breast or findings of no clinical relevance should not be part of a screening report. emergency radiology services are very much on the rise in the last decade. medical emergencies and trauma are of enormous importance and a leading cause of death in all age groups. the use of radiological imaging in emergency departments showed an exponential increase since the 1990s. the annual growth rate in ct is 5-15% per year depending on the institution. even for advanced level 3â° medical centres running an own emergency radiology unit, it is a challenge to integrate advanced radiology services in an interdisciplinary team treating patients with acute traumatic and non-traumatic emergencies. general principles: radiology and radiological imaging procedures should be integrated in an interdisciplinary team. imaging should be guided by interdisciplinary clinical algorithms or guidelines (e.g. nexus or canadian cspine rule). many clinical diagnoses relay today on a early and thorough initial radiological diagnostic workup -mostly based on mdct. emergency radiology (er) is still a relatively young subspecialty in european radiology -it deserves specific training. the lecture will cover: the development of emergency radiology and its future perspectives; the use of conventional radiography, ultrasound and mdct; logistics and management of the patient; clinical guidelines and mdct in the primary patient survey (e.g. using atls for trauma) and advanced scanning protocols for mdct. infants and children with abdominal emergencies present special diagnostic challenges because of similarities in clinical findings between various paediatric conditions. imaging is frequently a critical part of the diagnostic process, but the choice of the best imaging modality can be controversial. patient age and safety issues such as radiation exposure must be taken into consideration when planning imaging. because certain pathologies are more likely to occur in specific age groups, patient age is a primary determinant of the imaging approach. this presentation will illustrate the differences in pathology between several paediatric age groups and discuss effective imaging algorithms for congenital and developmental, inflammatory, and obstructive conditions. the optimal use of radiographs, ultrasound, ct, and mri will be discussed. pitfalls that should be avoided in ultrasound and ct will be emphasised. in diagnostic imaging, we tend to focus on radiation protection, justification and optimisation, as the primary opportunity for radiographers and radiologists to ensure the safety of patients, both adults and children; however, this ignores some other important issues. this session aims to raise awareness amongst medical imaging professionals of some key considerations in relation to a number of child protection issues. when imaging a child in case of suspected non-accidental injury, every detail of that examination from conversations with the child and their parents or guardians, technical aspects of the examination, observations during the examination and the language used following the examination need to be carefully considered. another area of medical imaging requiring attention is how we communicate any radiation risks associated with examinations or procedures with children and their parents. there is evidence that while consent processes for invasive procedures are usually in place, these often lack focus on the risks associated with a high exposure to ionising radiation. these two medico-legal areas, suspected non-accidental injury and risk communication, are commonly encountered by radiographers and radiologists and as such it is important to make sure that we operate at the highest possible professional standards and in keeping with both regulations and best practice including the production of witness statements/contemporaneous notes. on rare occasions, we may find ourselves involved in legal proceedings as a witness or expert witness and it is thus important that we are all aware of the key considerations in this regard. session objectives: 1. to appreciate the need for radiographers to focus on more than just the imaging procedure in paediatric examinations. 2. to understand the extremely vulnerable nature of paediatric patients and the need for all health professionals to pay particular attention to this. a. professional responsibilities: an international perspective m. davis; dublin/ie (michaela.davis@ucd.ie) radiographers play a vital role in imaging children with suspected nonaccidental injuries. this session will also explore the wider role that radiographers have in child protection. current legislation and its implications will be explored from a variety of countries including those outside europe. in addition, case studies will be presented focussing upon child protection issues that have arisen in the x-ray department during imaging procedures. several of the barriers to radiographers becoming involved in child protection will be explored. radiographers and their contribution to child protection will be discussed and practical examples given. learning objectives: 1. to become familiar with current legislation and guidelines which have particular relevance to radiographers from an international perspective. 2. to appreciate best practice in child protection and the need for all radiographers to be aware of this. 3. to learn about child protection case reports involving imaging, radiologists and radiographers. a-085 08:58 b. risk communication in paediatric examinations j.l. portelli; msida/ mt (jonathan.portelli@um.edu.mt) medical imaging plays a vital role in the diagnosis and treatment of numerous medical conditions for millions of patients worldwide. however since most medical imaging examinations utilise ionising radiation, the associated risks of radiation exposure also need to be acknowledged, especially since high doses of radiation are known to cause adverse biological effects. medical imaging professionals should have a good understanding of the benefits and risks associated with the imaging examinations they perform, so as to ensure a high benefit-risk ratio for all patients undergoing diagnostic imaging procedures, and to be able to appropriately communicate such information to patients, their families and other healthcare professionals. this may be particularly more important when imaging paediatric patients, who are relatively more susceptible to the effects of radiation and receive a higher effective dose per unit of radiation when compared with adults undergoing the same medical imaging examination. indeed, following worldwide media attention about radiation incidents and their adverse effects, some parents/legal guardians may be concerned and reluctant to pursue important medical imaging examinations requested for their child, as they may have a misconception of the risks involved. in this regard, this lecture will seek to enhance awareness about the radiation doses associated with common paediatric imaging examinations; highlight the importance of medical imaging professionals having an appropriate understanding of benefits and risks associated with these examinations; and encourage such professionals to improve patient care by making use of this knowledge to have better discussions with referring clinicians, patients and their families. learning objectives: 1. to appreciate the frequency and radiation dose associated with certain paediatric imaging examinations. 2. to become familiar with the current status quo in the communication of radiation dose-related risks. 3. to understand best practice and potential considerations in providing accurate information to referring clinicians, patients and their families. c. what to do if you find yourself being called to give evidence m.d. viner; london/uk radiology is a powerful tool in the investigation of cases of suspected nonaccidental injury and suspicious death in children. the evidence obtained can be pivotal in bringing successful prosecutions against suspects and protecting the child and others from further harm. it is essential that evidence is obtained, recorded and presented in accordance with applicable rules of evidence in order to be admissible in court. it is thus important that those undertaking such examinations are appropriately trained, conversant with standards of evidence and maintain continuity of evidence throughout the investigation. this presentation will review rules of evidence for cases of suspected child abuse and their application to imaging examinations. it will examine the role of the radiographer and the importance of training and familiarity with legislation and guidelines that underpin forensic practice, highlighting the pitfalls that lawyers may exploit if procedures have not been followed. drawing on examples, it will discuss best practice from the radiographer's perspective, detailing the importance of continuity of evidence and maintenance of contemporaneous notes and witness statements. it will address key considerations for radiographers and others who provide evidence or act as an expert witness. imaging professionals play a pivotal role in the investigation of suspected child abuse. it is essential that this evidence is obtained, recorded and presented with regard to the applicable standards of evidence. for those called to give evidence, the importance of appropriate imaging protocols and procedures, detailed documentation and thorough preparation cannot be understated. learning objectives: 1. to understand the importance of contemporaneous notes and witness statements if involved in any forensic or suspected non-accidental injury examination. 2. to become familiar with the importance of continuity of evidence in forensic examinations. 3. to appreciate the key considerations if you are asked to provide evidence or act as an expert witness in court. brain tumours are the second most common neoplasms in children after leukaemia. as "paediatric brain is not just a small brain", paediatric brain tumours are not the same as tumours in adults. mri is a method of choice in their diagnosis in accordance with the principle alara in the paediatric population. by the age of approximately 3 years, supratentorial tumours dominate; later (4-10 years of age), the majority of children show infratentorial neoplasms which are pilocytic astrocytomas, most often found in the hemispheres, and medulloblastomas or ependymomas -in the fourth ventricle. after the age of 10, both groups are diagnosed with equal frequency. cerebral hemispheric tumours include astrocytoma which is the most frequent, teratoma in neonates, and in older children atypical teratoid/rhabdoid tumour, ependymoma, pnet, ganglioglioma and dnet. in the midline, we deal with chiasmatic or hypothalamic glioma, craniopharyngioma and germ cell tumours of the pineal region. extraparenchymal tumours are uncommon in the paediatric population. apart from the location, imaging pattern in various sequences, and contrast enhancement of the tumour, advanced mri techniques are helpful in establishing the diagnosis. dwi helps to differentiate between tumours of high and low cellularity showing low adc values in case of medulloblastoma and high in astrocytoma. mrs, pwi and dti also add important information to the diagnosis. mri of the spinal canal is obligatory in case of these primary brain neoplasms that have a high propensity to metastasise to other parts of the central nervous system such as medulloblastomas, ependymomas, high-grade gliomas, cerebral neuroblastomas, and pineal region neoplasms. learning objectives: 1. to learn about the difference between paediatric and adult brain tumours. 2. to understand the imaging strategy for the paediatric population. 3. to become familiar with the most common paediatric brain tumours. pancreatic endocrine tumours (p-nets) include both pancreatic neuroendocrine tumours associated with a functional syndrome (functional p-nets) and those associated with no distinct clinical syndrome (non-functional p-nets). non-functional p-nets may show immunohistochemical positivity for hormones which may be produced, but not secreted, which are clinically inert and whose serum concentrations are insufficient to induce symptoms. among functional p-net, the most common are gastrinomas and insulinomas, whereas those secreting vasoactive intestinal peptide, glucagon, somatostatin and other hormones are considered together as a group called rare functional p-nets. non-functional p-nets are classified, according to the who 2010 classification, in well-differentiated neuroendocrine tumours and poorly differentiated neuroendocrine carcinomas (necs) of small or large cell type. well-differentiated neuroendocrine tumours are then divided according to a grading scheme based on mitotic count or ki67 index in nets-g1 (with a mitotic count < 2 per 10 high-power fields (hpf) and/or 2% ki67 index), and nets-g2 (with a mitotic count 2-20 per 10 hpf and/or 3-20% ki67 index). all poorly differentiated neuroendocrine carcinomas are graded g3 (with a mitotic count > 20 per 10 hpf and/or > 20% ki67 index). most pancreatic nonfunctional p-nets are well-differentiated tumours, whereas poorly differentiated neuroendocrine carcinomas are uncommon. pancreatic endocrine tumours (p-net) are divided into functional p-nets and non-functional p-nets. diagnostic imaging of these tumours includes detection, characterisation and staging. there are significant differences when dealing with functional p-nets and non-functional p-nets. in fact, in the first case the main aim of diagnostic imaging modalities is the detection of the tumour, while for non-functional p-nets the main aim is the characterisation and the differential diagnosis with other tumours of the pancreas, mainly with pancreatic adenocarcinoma. staging is also important for both tumours, but mainly for non-functional p-nets. a large number of imaging modalities are available, both "morphological" and "functional". we can arbitrarily divide the imaging modalities for the diagnosis of p-nets into three levels: the first level includes us (with contrast-enhanced us), mdct, mri and nuclear medicine techniques; the second, endoscopic us, angiography and venous sampling; the third, intra-operative us. functional p-nets are represented mainly by insulinomas and gastrinomas which are small in size in most cases. their detection is still difficult, but significant improvements have been made with us, mdct and mri, so that these tumours are detected in most cases if appropriate imaging techniques are performed. however, still, no single modality is 100% effective. non-functional p-nets can be differentiated from pancreatic adenocarcinoma, since they are hypervascular and usually large in size. since they are potentially malignant, they require accurate staging by imaging modalities, both morphological (mdct, mri) and functional (pet/ct) to plan surgery and chemotherapy. there is worldwide consensus about surgical treatment of resectable p-nets in the following clinical situations: proven malignancy, whenever it is possible to remove the primary tumour and at least 90% of liver metastases (debulking); p-nets associated with a clinical syndrome caused by hormonal hypersecretion (insulinomas and gastrinomas mainly); non-functional p-nets with a size larger than 2 cm. vice versa, there are different expert opinions about the surgical treatment of functional and non-functional p-nets in men1 syndromes and in sporadic non-functional p-nets less than 2 cm in size. in men1 all insulinomas should be resected, while for gastrinomas the extent of resection is patient tailored, deserving standard whipple for selected cases. in the most common sporadic small incidentalomas, where long-term prognosis is favourable, surgical treatment has to be weighted with co-morbidities and morbidities of the patient and the procedure planned. these tumours have a risk of node metastases at the time of diagnosis in less than 10 % of patients. whenever possible, mini-invasive approach with pancreas-sparing operations should be recommended. in elderly patients, a first period of follow-up should be preferable and surgery should be offered only if the size of the tumour demonstrates increasing trends. the "acute aortic syndrome" includes three closely related emergency entities of the thoracic aorta: aortic dissection, intramural hematoma and penetrating atherosclerotic ulcer. as these conditions present with similar symptoms, cross-sectional aortic imaging is essential for diagnosis, triage and treatment planning. initial imaging features of these pathologies including typical early complications as well as their differential diagnosis will be reviewed. as nowadays several of these patients will undergo early endovascular thoracic aortic repair, an update on its indication, the different technical options and their clinical results will follow. finally, the focus will be on repair-related late complications and progression of aortic disease. imaging follow-up protocols, features of chronic complications and their interventional repair will be discussed. a. pre-therapeutic radiological evaluation j. ferda; plzen/cz (ferda@fnplzen.cz) the acute thoracic aorta syndrome covers patients suffering from acute chest pain and those injured during high-energy trauma. despite the similar symptoms, the aortic pathologies are heterogeneous, including acute aortic injury, intramural haematoma, aortic dissection, and ruptured thoracic aortic aneurysm and mycotic aneurysms. the diagnostic approaches could include the whole pallete of the imaging modalities: chest x-ray, transesopheageal echocardiography (tee), multidetector ct angiography (mdcta), mri and pet/ct. because of some disadvantages of tee, like problems with intubation in injured patients or problems of mri with seriously ill patient monitoring, mdcta has become the most used modality due to its ability of discrimination between aortic and non-aortic pathologies, and also due to its high sensitivity, specificity, availability and especially superior geometrical resolution and potential of 3d imaging. the proper pre-therapeutic mdcta protocol is using sub-millimeter isotropic resolution covering the entire aorta with pelvic arteries. when the pathology of thoracic aorta is found during the triple rule-out triage protocol, additional mdcta of the rest of the aorta and pelvic arteries has to be completed. ecg triggering could be an important advantage in the reduction of pulsation-derived artefact. the volume of applied contrast material used should be as small as possible to plan applications during endovascular treatment. 3d reconstruction of the thoracic aorta with its side branches and advanced vessel analysis have a crucial role in the measurement of the aortic diameter, diameter profile and lengths in the selection of proper stent graft type and size. they can be accommodated even in patients with small vessels and tortuous anatomy. calcified arteries can be no longer considered absolute exclusion criteria. some devices are designed to reduce the incidence of endoleaks, improving sealing capabilities by the use of a polymer to better adjust to the variable morphology of the proximal neck or to fill the aneurysmatic sac completely. more importantly, the introduction of fenestrated devices has resolved the problem of facing difficult anatomies when the aneurismatic pathology involves renal or visceral arteries. obviously, the use of these new devices requires a learning curve. beyond an increase of cost, they permit treating those patients who in the past were considered unfit candidates for evar. the evar new frontier requires performing the procedure in an outpatient fashion. a multicentre study was conducted on 100 patients who were discharged 4/6 hours after uncomplicated stent-graft implantation. cases (4%) with access vessel complications required additional procedures and patients were hospitalised overnight. the 30-day readmission rate was 4% for access vessel stenosis or false aneurysm. from the time of the first evar procedure, significant improvements have been achieved but there is still room for further progress. the standard imaging modality after endovascular treatment for thoracic aortic pathology (tevr) is ct angiography (cta). cta enables the radiologist to assess for the patency of the endografts, the presence of any complications after tevr, and the development of any new pathology related not only to the aorta, but elsewhere above and below the diaphragm. the role of mr is reduced compared with cta, particularly in the presence of stainless steel endografts. however, good images can be obtained by mri and mra if nitinol endografts have been inserted. mr is a useful modality for follow-up in young patients who require lifelong follow-up and, therefore, limited exposure to ionising radiation. ultrasound has no practical role in the follow-up after tevr, and although plain thoracic radiographs are routinely performed by some centres post-tevr, in practice almost equivalent information can be obtained by ct. the main complications after tevr are endoleaks, type a dissection, paraplegia and stroke. the classification of endoleaks is similar to the classification for evar. type 1 and type 3 endoleaks require treatment by additional endograft coverage with or without supraaortic or visceral artery bypass. other treatment options include the use of branched, fenestrated endografts or the use of chimneys and snorkels. type 2 endoleaks are less common than post-evar. similar to the evar population, intervention is mandated for an enlarging aortic diameter and involves embolisation in most cases. interventional oncology is a discipline that uses imaging-guided procedures in the treatment of cancer patients. when the malignant disease in not curable, interventional techniques such as biliary and oesophageal stenting can provide useful palliation and improve the patient's quality of life. in patients with potentially curable tumours, thermal ablation, cryotherapy and radioembolisation provide useful alternatives to radiotherapy and surgery in carefully selected patients. interventional radiologists who treat patients with cancer should practise as clinicians, participating in multidisciplinary meetings where treatment choices can be discussed with specialists from other oncological disciplines. they should involve themselves in all stages of clinical practice, including pre-treatment consultations, ward rounds and patient follow-up. radiation oncology and interventional oncology have much in common, including the potential for curing cancer using minimally invasive techniques. interventional oncologists can usefully adopt many of the principles and methods of practice in radiation oncology, including quality assurance and the collection of robust outcome measures. an alliance between these disciplines would be beneficial to clinical practice and research in both disciplines. session objectives: 1. to understand the contribution of interventional radiology to oncology. 2. to appreciate the areas of overlap between radiation oncology and interventional oncology. 3. to understand the need for a clinical pattern of practice in interventional radiology in oncology. the current scope and future challenges j.i. bilbao; pamplona/es (jibilbao@unav.es) together with chemotherapy, surgery and radiotherapy, interventional radiology (ir) is the fourth pillar in oncology. transcutaneous and endovascular procedures, guided by imaging, constitute a fundamental knowledge essential for the multidisciplinary management of oncologic patients. the range is wide and covers most of the needs in patientâ´s care. in short: obtaining samples for making an accurate diagnosis and also to know more about its specific biology (biomarkers); ir covers any possibility needed for vascular access; percutaneous needle ablation is the best alternative in selected patients; endovascular embolisation with "vehiculisation" of therapies is an outstanding method for selective treatment, and sometimes precise ablation, of different tumors; ir is a unique way to offer palliation in a wide range of tumoral complications, such as embolisation for bleeding, stenting for vein obstructions or drainage of fluid collections. there is an obvious need of continuous technical refinement. image-guided therapy is a continuous process that implies many disciplines and that includes every step, from staging through guidance of the procedure to the evaluation of the outcomes, both immediately, during and in the follow-up. future developments in ir may be focused towards the personalisation of therapies to each patient and to a better understanding of the biological mechanisms of tumour response or progression and their image expression. finally, radiologists must be actively involved in the whole process of clinical trials, from the creation of new lines to the performance of therapy until the evaluation and diffusion of the data. radiation treatment has a fundamental role in the multidisciplinary management of people with cancer. the evidence base for radiation therapy is robust and approximately 50% of people diagnosed with cancer will benefit from radiation treatment. most of this benefit comes from an increase in cure. the technical quality of delivery of radiation treatment is of great importance in avoiding a geographic miss and also in reducing the amount of normal tissue being irradiated unnecessarily. as well as the excellent technical delivery of any treatment offered, of paramount importance is the intelligent integration of care with attention to evidence base choices for both local and systemic treatment. multidisciplinary teams are in the best position to integrate surgery, radiation treatment, interventional oncology and systemic therapy in a planned and deliberate fashion. best practice: how to organise an interventional oncology unit a. gangi, j. garnon, g. tsoumakidou; strasbourg/fr (gangi@unistra.fr) interventional oncology is a fast growing field. interventional oncology is a clinical and technical speciality. solid clinical knowledge associated with the technical skills is mandatory for a successful practice. the technical skills should be associated to the clinical part. the knowledge of all treatment modalities and the participation of a multidisciplinary team is vital for the best practice. every single patient should be seen by the interventional oncologist and followed-up. the interventional oncologist is part of a multidisciplinary team, taking care of the patient. the team includes oncologists, radiotherapists, pain specialists, psychologists, surgeons, and anesthesiologists. the interventional oncology unit should include specialised nurses, technician, anesthesiologist, anesthesiologist nurses, and the interventional radiologist. the team should be able to take care of the patient's follow-up and eventual complications. to summarise, high-quality interventional oncology services are essential for safe and effective patient care. the technical skills of the interventional oncologist should be associated with an excellent clinical knowledge of the disease. a multidisciplinary team work is mandatory for a successful interventional team. harmonisation of training and appropriate credentialing is required for clinical services of the best quality. interventional radiologists continuously improving their skills and knowledge, patient access to safe and effective minimally invasive treatment options is increasing. whereas cardiac ct and mri are routine examinations for specialised radiologists, it has been necessary to wait for the introduction of fast scanning techniques to modify the behavior of nonspecialised radiologists regarding the interpretation of cardiac cavities. the objective of this session is twofold. first, cardiac radiologists will underline the role of these imaging modalities in the assessment of congenital heart disease but also in ischaemic and nonischaemic cardiomyopathies. in the second part of this session, chest radiologists will focus on the diagnostic information accessible at the level of the right ventricle, known to be the target of numerous respiratory disorders. two practical situations will illustrate this approach: pulmonary thromboembolic and chronic respiratory diseases. accurate assessment of the right ventricle (rv) is crucial for the management of congenital heart disease. echocardiography can provide some information, but as the rv sits directly behind the sternum and as many patients have undergone multiple operations, visualisation can be difficult. furthermore, for long-term follow-up and treatment planning, accurate measurement of ventricular size and mass, and valvular flow (tricuspid and pulmonary), and assessment of anatomy in 3d and 4d are vital. this presentation will outline the role of cross-sectional mri and ct for assessing the rv, and describing the indications, imaging protocols, technical pitfalls and relevant information for treatment planning. right heart failure in ischaemic and non-ischaemic cardiomyopathies m. grothoff; leipzig/de (matthias. grothoff@herzzentrum-leipzig.de) the role of the right ventricle (rv) has been underestimated for many years. today, we know that the rv is of importance for keeping up a sufficient circulation and that right heart failure in both ischemic and non-ischemic cardiomyopathies can result in hemodynamic compromise. rv ischemia has a higher in-hospital morbidity and mortality but post-infarction chronic right heart failure is a rare finding. as the rv has a different physiology from the left ventricle (lv), also the pathophysiology of ischemia is different here. using our standard cmr tools t2 weighted imaging for detection of edema and late gadolinium enhancement imaging for detection of necrosis/scar we can find that the rate of myocardial salvage is much higher in the rv than in the lv and that rv failure in the acute phase is basically caused by reversible ischemic effects. in non-ischemic cardiomyopathies like hcm and dcm changes in the rv myocardium mostly resemble changes of the lv. in arrhythmogenic right ventricular cardiomyopathy/dysplasia (arvc/d) however, there are specific findings in the rv and the role of imaging in diagnosing arvc has been strengthened by the revised task force criteria published in 2010. cine imaging should be performed carefully for detection of rv akinesia, dyskinesia or small aneurysms as well as the planimetry of the rv. findings like the detection of fibrosis in lge imaging and the detection of fat in t1 imaging can provide additional information, but are not diagnostic for arvc. learning objectives: 1. to learn about the different ct and mri techniques for evaluating right heart morphology and function. 2. to understand the prognostic impact of right heart involvement in ischaemic heart disease. 3 . to learn about the basic morphological and functional features of different non-ischaemic cardiomyopathies. right heart and chronic respiratory diseases: can ct be used as a onestop-shop? m. remy-jardin; lille/fr (martine.remy@chru-lille.fr) over the last decade, ct technology has evolved towards fast scanning capabilities and high temporal resolution, enabling improved evaluation of the heart and surrounding structures in the course of routine thoracic ct imaging. this has progressively modified the radiologist's implication in the interpretation of chest ct examinations. firstly, it is more and more common to integrate the physiological interactions between heart and lung when analysing the ct features depicted on a given examination. secondly, it is now possible to integrate cardiac functional information into a diagnostic ct examination of the chest, providing prognostic information in the management of patients with a wide variety of chronic respiratory disorders. the purpose of this presentation is to provide non-specialised radiologists with some practical guidelines in the choice of the scanning protocols and range of functional information that can be deducted from chest ct examinations. right ventricular dysfunction and levels of pressure within the pulmonary circulation are the key points of such approaches. learning objectives: 1. to appreciate the clinical impact of a cardiothoracic evaluation from the same ct examination. 2. to learn about the scanning protocols enabling such a combined analysis. 3. to understand its compatibility with other non-invasive modalities. rv and prognosis in pulmonary thromboembolic disease n.j. screaton; cambridge/uk (nicholas.screaton@papworth.nhs.uk) right ventricular failure is the most common cause of early death following acute pulmonary embolism and in patients with chronic thromboembolic pulmonary hypertension. echocardiography is sensitive in diagnosing and quantifying rv dysfunction. ct is the reference standard for the diagnosis of acute pe diagnosis and has the potential to provide comprehensive evaluation of the pulmonary arteries, heart and lung parenchyma. ct signs of right ventricular dysfunction which have shown predictive value for adverse outcome include: flattening of the inter-ventricular septum or bowing towards the left ventricle, reflux of contrast medium into the ivc, relative rv/lv diameter ratios on transverse and 4-chamber reconstructions, and ventricular volumetry as assessed both on routine non-gated ctpa and ecg-gated ct. in patients with cteph, mri permits imaging of the pulmonary vasculature and functional evaluation of the right ventricle and pulmonary circulation, enabling both morphological assessment and prognostic evaluation. learning objectives: 1. to learn about clinical and imaging factors associated with prognosis of thromboembolic disease. 2. to understand the benefits and weaknesses of different imaging modalities in predicting prognosis in thromboembolism. 3. to discuss the merits of comprehensive imaging evaluation in the routine diagnostic workup of suspected thromboembolic disease. multimodality imaging including ultrasound has within recent years been introduced in several anatomical regions. pet, ct and mri datasets can after an initial co-registration be fused and shown either side by side or using overlay on screen while doing real-time ultrasound; thus, the pet, ct or mri dataset is reformatted in a projection to fit the real-time ultrasound images. several methods of aligning the images are available and have been shown to have a high accuracy. image fusion involving ultrasound has been tested in phantoms, animals and in patient studies, mainly in abdominal imaging. by combining several imaging modalities, it is possible to benefit from the strengths of each modality. it is useful for characterisation of and intervention on liver lesions, abscesses containing air and lesions in areas with poor overview by ultrasound. also, the method is useful for characterisation and biopsy of pet-positive lesions, especially in patients with a history of cancer. the background of the method and clinical examples, mainly from abdominal applications, will be covered. also, perspectives and future research topics will be highlighted. contrast-enhanced ultrasound (ceus) has proved to improve the detection and characterisation of pathologies compared to conventional ultrasound, ct and mri in a number of indications. ultrasound contrast agents (uca), which are purely intravascular, do not show any interstitial diffusion or glomerular filtration like iodinated complexes or gadolinium chelates. dynamic contrastenhanced ultrasound (dce-us) allows to display the enhancement of a lesion with a high frame rate after bolus or infusion administration of uca, and to compare enhancement profiles between normal and abnormal tissue. quantification of dce-us is useful to quantify tumour enhancement and to limit intra-and interobserver variability. mathematical models with several perfusion parameters can be used. dce-us has shown to be of interest after antiangiogenic therapies as it allows an earlier evaluation of tumour response than usually done with ct and mri, which remain mainly based on the recist criteria. the common perception of 3d ultrasound (us) is of surface-rendered images, especially of the foetus. the same approach, enhanced by new transducer technology and software, can be used to take ultrasonography to another level in general body imaging, providing different image presentations and working practices similar to those of ct and mr. the technology involved in a us volume acquisition was represented initially by mechanical 3d transducers, and more recently by purely electronic, matrix probes. this latest technology allows bi-plane real-time acquisitions, fast switch to volume acquisition up to 100 degrees, and 4d acquisitions with acceptable frame rates. protocols have been described for major abdominal and retroperitoneal organs, with fast optimisation of acquisition settings. the technology supports contrastenhanced ultrasound (ceus). after volume acquisition, interpretation for volume us datasets requires a post-treatment phase, including multi-planar reconstruction, multislice imaging, and volumetric analysis. virtual cystoscopy and volume ceus quantification are new options. the implementation of this new, efficient us modality in a radiology department supposes deep changes in the daily practice with delayed post-treatment reporting times. it should represent a more effective way for comparison between different examinations and a better communication tool with clinicians. the proven and potential benefits, in terms of clinical accuracy, training, workflow and overall efficiency, will be discussed. the purpose of this lecture is to emphasise some pitfalls in liver imaging. morphologic changes in the liver are usually attributed to chronic liver disease where liver cirrhosis represents the most important cause. however, noncirrhotic diseases may also induce atrophy-hypertrophic changes of the liver. the most common mechanisms are related to venous obstruction (either portal or hepatic venous) and biliary obstruction. multidetector ct and mr imaging are essential to highlight these abnormalities. when dealing with liver tumours, the most important question that has to be solved is tumour characterisation. yet, it is often difficult to assess whether a large tumour is intra-or extrahepatic. imaging findings that might be helpful will be shown. last, some liver lesions can mimic liver tumors. vascular disorders and focal fatty changes or focal fatty sparing are the most common causes. some other conditions can be also mimickers and such cases will be shown. the technique and the anatomy of the bile duct and pancreatic duct will be described. the anatomical variants of the biliary duct and the pancreatic duct system will be analysed and their possible role in generating diagnostic imaging pitfalls described. strategies to avoid pitfalls in diagnostic imaging of the bile duct and the pancreatic duct system will be illustrated, considering the possible source of pitfalls. diagnostic imaging findings of different diseases involving the biliary ducts and pancreatic duct system will be illustrated, as well as the diagnostic imaging criteria useful for the differential diagnosis. over the last two years, the number of ct and mri units has increased by 30%, and modern pet centers and leading centers for radiotherapy have been built. we can identify an approximately 20% increase in the number of radiological research projects--mainly ultrasound, ct, and mri investigations. during the last ten years the total number of vascular interventions and mr studies has increased by ten times, four times for ct, and the annual growth of us and x-ray investigations is about 10%. unfortunately, these technical innovations are not always accompanied with pacs and ris installations; this is a reason why all advantages of digital equipment are not achieved. we see rapid development of private medicine; new private hospitals and ambulances have grown by more than 10% and investment companies are looking for new projects in this field. however, the professional education of radiologists is not enough to work with new diagnostic equipment. this is a reason why in 2014 we will start a pilot project to create a new system of continuing medical education in clinical medicine, including diagnostic radiology. we hope, this pilot project will increase the efficiency of clinical practise. differential diagnosis (dd) including tumour and non-tumour brain pathologies is an integral part of neuroradiological diagnostics and in some cases is a challenge to experienced neuroradiologists. more than 5000 patients with different cns pathologies have been investigated in the department of neuroradiology, burdenko neurosurgical institute since 2002. in the vast majority of the cases, there were tumours. we used deconvolution method for bv, bf, mtt and ps maps reconstruction on commercially available software (perfusion 1.2.0, 4.0 protocols, adw, ge). ct perfusion has demonstrated high level of information in determining the degree of malignancy in glial brain tumours. a strong correlation between bv and ps and tumour degree has been demonstrated. the use of ct-pwi makes it possible to successfully carry out dd between radiation necrosis and tumour progression. some histological types of brain lesions are characterised by unique haemodynamic properties which enable using this method as non-invasive "biopsy". ct-pwi has been especially useful in dd of the skull base region, bone and extracranial pathologies. the absence of artefacts created by the skull base bones makes this method especially valuable as compared to the mri t2*-and asl-perfusions. ct-pwi makes it possible to successfully differentiate tumours and a number of non-tumour cns lesions including demyelinating diseases, infectious and non-infectious granulomas, etc. ct-pwi is a powerful method for differential diagnosis of brain pathology. t-pwi can provide unique functional information regarding tumour pathophysiology and haemodynamics, which are not available with routine ct and mri. learning objectives: 1. to become familiar with the technique of brain perfusion ct. 2. to understand the added diagnostic value of perfusion ct. 3 . to learn about input of ct perfusion for assessment of treatment. interlude: development and use of web-based teleradiology in russia o.s. pianykh; newton highlands, ma/us (opiany@gmail.com) the largest territory in the world, russia, presents a perfect teleradiology use case of extremely unevenly distributed health care, concentrated in moscow and spread thin outside over an enormous area and sparse population. this unevenness deeply affects the quality and availability of radiological services, and cries out for efficient and practical teleradiology solutions. however, the same unevenness in medical expertise, financing and it infrastructure frequently acts against the advancement of teleradiology projects, blocking their natural progress. as a result, technical, financial, educational and clinical matters, interleaved into the nascent russian teleradiology ventures, require serious and predictable solutions, based on analysis and adaptation of already developed, internationally proven strategies. currently, russian teleradiology simply takes advantage of whatever is available to make its progress better, but needs to develop itself up to the tasks it faces. tuberculosis in russia: a challenge for a national radiological service i.e. tyurin; moscow/ ru (igortyurin@gmail.com) approximately, 1.7 billion people worldwide are infected with mycobacterium tuberculosis, of which 20 million are active cases. the reasons for resurgence of tb infection include the hiv epidemic, a rise in reactivation disease in the elderly, a growing migrant population and spread of drug-resistant strains. the incidence of atypical tb infection is also on the rise, of which mycobacterium avium intracellulare is the most important human pathogen. the pathologic form of the pulmonary infection depends on the sensitivity of the infected host and is classified as primary or postprimary. primary tb pattern represents infection resulting from recent contact with the pathogen. postprimary tb pattern results from reactivation of a dormant focus within the lungs. thoracic tuberculosis produces a broad spectrum of radiographic abnormalities. the radiological patterns had been described as parenchymal, airway, vascular, mediastinal, pleural, and chest wall lesions. common causes of a missed diagnosis of thoracic tuberculosis are failure to recognise hilar and mediastinal lymphadenopathy as a manifestation of primary disease in adults, overlooking of minimal productive lesions or reporting them as inactive, and failure to recognise that an upper lobe or superior segment of lower lobe mass might be tuberculosis. in aids patients, the imaging features depend on the degree of immune suppression. a pattern of postprimary tb is also usually seen among patients with decreased immunity due to alcoholism, renal failure, diabetes mellitus, ageing, malignancy, and renal and cardiac transplantation. learning objectives: 1. to understand the scope of the problem with tuberculosis screening in the russian federation. 2. to learn about the changing imaging patterns of thoracic tuberculosis. 3. to appreciate the current role of imaging in the differential diagnosis and follow-up of this pathology. interlude: mystery of denisov's cave and paleoradiology m. mednikova; moscow/ ru (medma_pa@mail.ru) this study focuses on the anatomical identification of fossil bones from altai highland in southern siberia, their radiological description, and parallels among other hominin fossils. methods describe the small and isolated tubular bones. we used microct versaxrm-500 by xradia inc. and digital microfocus x-ray. denisova cave is the best studied paleolithic cave in north asia. archaeological data suggest that about 300 thousand years before the present, a group of humans migrated to southern siberia from the west. their descendants had lived in the altai mountains in relative isolation for 250 thousand years. the taxonomic status of the early inhabitants of southern siberia was clarified thanks to palaeogenetic studies. it was concluded that the altai hominin was genetically twice further from modern humans than were neanderthals. phylogenetic analysis suggests that this clade diverged from that ancestral to humans and neanderthals very early -about 1 billion years ago. descendants of this clade apparently survived in the altai refugium until the period 50 -40 thousand years ago. due to structural patterns of preserved pedal and manual phalanxes, humans from denisova cave could be expected to be the bearer of "archaic" traits. the extraordinarily thick walls of tubular bones in adults reflect a high level of occupational stress. radiological volumetric microscopy of the denisovan girl phalanx gave evidence for the histological estimation of the developmental age. radiological methods seem to be the perspective approach in the study of rare and fragmentary fossil human remains, differentiating between archaic and modern humans. advances in imaging of pancreatic masses g.g. karmazanovsky; moscow/ru (karmazanovsky@ixv.ru) modern diagnostic radiology allows not only to detect pancreatic tumours, but also to carry out their differential diagnosis with high accuracy. this is especially important because many benign tumours of the pancreas do not require immediate surgery. at the same time, many benign tumours may become malignant. the differential diagnosis of the pancreatic cystic lesions using endoscopic ultrasound and magnetic resonance pancreaticocholangiography has now become particularly accurate. contrast enhancement allows detecting signs of tumor invasion into the main blood vessels and adjacent organs. modern developments of radiology help to use extended operations for malignant tumours and sparing surgery with minimal removal of intact functioning pancreatic tissue in benign tumours. learning objectives: 1. to become familiar with major types of pancreatic masses and their radiological manifestations. 2. to understand approaches to the selection of diagnostic pathways in pancreatic tumours. 3. to become acquainted with new developments in diagnostic imaging of pancreatic tumours. interlude: an artistic view of ct a.l. yudin; moscow/ ru (prof_yudin@mail.ru) radiology is a specialty based largely on figurative perception of diagnostic imaging. the radiological picture of many symptoms reminds one of objects and environmental phenomena (for example, vanishing lung, draped aorta, geographic liver, porcelain gallbladder, dirty fat and others). training of creative mentation promotes lasting assimilation of educational material at the associative level. metaphorical thinking skills can also be improved by searching for amusing fragments in radiological images similar to the objects in everyday life; animals, cartoon characters, and others. the essential help in the study of the physical foundations of radiology and functional capabilities of workstations provide the execution and study of x-ray films, ct or mri of fruits and vegetables, flowers, various artifacts and other objects in the environment. eventually, it is just beautiful. ultrasound of the breast is an established imaging technique with several advantages. it has been used to differentiate solid from cystic breast lesions for a long time. it has also been increasingly used to visualise small lesions in mammographically dense breasts and is the initial imaging method of the breast in young women. the features of the lesions that need to be analysed are: shape, relation to anteroposterior to laterolateral diameter, margins, internal structure and absorption of sound (distal acoustic phenomena). color doppler enables the thorough assessment of flow within the breast lesions. elastography is established as a useful method to differentiate breast lesions on the basis of their stiffness, which can be quantified. the accurate staging of axillary disease is an important aspect in the management of patients with breast cancer. it is recognised, however, that underlying malignancy can be found in lymph nodes that appear morphologically normal. a variety of morphological features that may be seen in pathological nodes have been described (cortical thickness of > 3.5 mm and absence of a fatty hilum). the automated breast ultrasound technique has been known for a long time, but with recent improvements now may play an important role. the automated breast volume scanner (avbs) employs frequencies of 5-14 mhz. avbs has various major advantages, such as being independent of the experience of the operator as well as supplying consistent and reproducible results. additionally, for the first time it has become possible to obtain coronal images of the complete breast, which greatly assists in the planning of surgical interventions. to study the technical basics in breast ultrasound (us), a breast scanning phantom helps to understand different us settings of greyscale imaging. typically, breast us work has a linear array transducer with a minimum field of view of 3.8 cm and a high frequency of minimum 7 mhz. a broadband transducer (e.g. 6-16 mhz) with different bands is preferred. in the central axillary area, a lower frequency band offers a deeper penetration depth. high frequencies improve the tissue contrast and optimise the axial and lateral resolution. the transmitter focus is adapted to the region of interest. highly sensitive color doppler detects slow flow rates (1 cm/s and less). for frequencies and power settings used in diagnostic greyscale and color doppler studies, no safety limitations have to be considered. breast us is mainly used as a second-line imaging tool to mammography (mg). a correlation between both imaging modalities is crucial. skin markers and additional mgs may help to solve the correlation problem. in bi-rads 4 or 5 us lesions with unclear correlation in mg, a marker placement after us-guided large-core needle biopsy helps to clear the problem. the pathomorphological growth pattern of a lesion is the basis to understand different imaging aspects with different modalities. second-look us after mri is an important correlation of lesions, which were first visible with mri. understanding the complementary imaging criteria will help to reduce the number of false-positive results. a practical imaging approach to brain and neurovascular trauma will be reviewed, with an emphasis on understanding the correlation between pathophysiology and imaging signs. guidelines on when to order acute neurovascular studies will be presented. special technical considerations to help optimise ct and mr imaging protocols for suspected brain injury, cns haemorrhage, and arterial dissection will be discussed. neurological emergencies are often associated with high morbidity and mortality, and thus require prompt diagnostic and therapeutic action. nontraumatic emergencies may however have a subacute onset, and radiological signs may be subtle, which can lead to delay in diagnosis and treatment. since clinical features are often nonspecific, the radiologist may be the first to point the clinician in the direction of the correct diagnosis. it is therefore of great importance that the radiologist is aware of and familiar with the various imaging findings, on both computed tomography (ct) and magnetic resonance imaging (mri), of non-traumatic neurological emergencies. these include vascular, infectious and inflammatory diseases. commonly encountered emergencies are ischaemic and haemorrhage stroke, venous thrombosis, arterial dissection, abscess, acute disseminated encephalomyelitis (adem), and encephalitis. radiological findings in rarer diseases may mimic those in the more commonly occurring diseases, but need to be correctly interpreted as therapeutic strategies and prognosis may be entirely different. such entities include for instance posterior reversible encephalopathy syndrome (pres), reversible cerebral vasoconstriction syndrome, susac's syndrome, and status epilepticus. furthermore, initial findings of (impending) complications of brain disease, such as hydrocephalus and herniation of brain structures, may be subtle, while early recognition allows for prompt and adequate intervention. finally, diagnostic and therapeutic interventions performed in an emergency setting may interfere with the diagnosis and interpretation of clinical and imaging findings. associated limitations and pitfalls therefore need to be recognised to avoid false-negative or false-positive diagnosis, respectively. learning objectives: 1. to learn about the modalities (ct/mri) and protocols for non-traumatic neurological emergencies. 2. to learn how to diagnose the main non-traumatic neurological vascular and non-vascular emergencies. 3. to become aware of the pitfalls and limitations of clinical presentation and imaging findings in non-traumatic neurological emergencies. the current century has brought with it new challenges in radiation protection, many of which follow the development of mdct which greatly enhanced diagnostic capabilities and substantially reduced scanning time to just a single breath-hold for chest ct, making ct scanning both patient-friendly and the physician's preferred tool. ct has also been added to nuclear imaging systems to create hybrid scanners (pet/ct; spect/ct image gently 5 years later: lessons learned in radiation protection for children. the alliance for radiation safety in pediatric imaging was founded in 2007 to promote radiation protection for children worldwide through awareness, education and advocacy. comprising over 75 medical professional societies and agencies, the alliance seeks to change practice locally for improved paediatric patient safety in medical imaging. since its inception, the alliance has had 6 campaigns in ct, diagnostic and interventional radiology, nuclear medicine, digital radiography and an outreach campaign to parents and 3 educational summits. yet, there is still work to be done. there is a need for parents and patients to receive information about their imaging test prior to the performance of imaging procedures, particularly those involving ionising radiation. the paediatric medical imaging community should work tirelessly with the manufacturers of imaging equipment to tailor equipment for children to optimise the study and ensure that the users of the equipment are knowledgeable in its safe use in children. the routine display of size-specific dose estimate on ct scanners will better estimate patient dose for quality improvement within facilities and in dose registries. finally, there is a need for diagnostic reference levels in paediatric radiology. this presentation will update the audience in progress to date regarding these challenges. the image wisely programme continues to move forward, guided largely by its steering committee, composed of two representatives each from acr and rsna and one representative each from aapm and asrt. the image wisely website (www.imagewisely.org) has educational content for imaging professionals (radiologists, medical physicists, and technologists) and referring physicians. a patient tab features links to radiologyinfo.org and the image gently website. a tab for "my equipment" links visitors to radiation dose-related 'microsites' developed by ge, hitachi, philips, siemens and toshiba. as of august 29, 2013, 18,646 individuals, facilities and associations have taken the image wisely pledge. to attract traffic to its website, image wisely has recently instituted 'news' and 'top reads' sections on the splash page highlighting recent articles and announcement, highlighting breaking news coverage and journal publications on relevant topics. in 2012, content on nuclear medicine procedures was finalised, completing two of the three targeted foci of the initial action plan_ct and nuclear medicine. in october 2013, a launch meeting will initiate the process of developing content for the third target area, fluoroscopy. in 2012 and 2013, image wisely has concentrated on efforts to engage referring physician communities, with particular interest in paediatricians and emergency medicine physicians. progress has been slow, but has recently gained traction with emergency medicine in the form of radiologist participation in a 2015 symposium, diagnostic imaging in the emergency department: a research agenda to optimise utilisation, organised by the society of academic emergency medicine. learning objectives: 1. to learn about the image wisely campaign for radiation protection of adults. 2. to understand the lessons learnt while communicating messages. lessons from a national approach to patient safety in radiation protection p. cavanagh; taunton/uk (petecavanagh@gmail.com) in considering a european campaign on radiation awareness, it is useful to gain information from similar campaigns in health care. there have been a number of national patient safety campaigns based on the institute for healthcare improvement (ihi) 100,000 lives campaign initiated in the usa in 2006. following the success of this, a similar campaign was launched in england. part of this process included an analysis of the success of the programme and the key interventions and drivers that were considered essential at both the national and local level. these included strong leadership, 1. bone (pseudo)-tumours: the majority of bone tumours can be detected on plain radiography. the age of the patient, location of the tumour in a bone and history of pre-existing bone abnormality should be included in determining the likely diagnosis. careful analysis of pattern of bone destruction, periosteal reaction and matrix mineralisation allow for characterisation of most bone tumours and differentiation from pseudotumours. ct may be useful for osteoid osteoma and mri is the best imaging technique for further diagnosis and staging by displaying tumour composition and extent of bone marrow involvement, including skip lesions, presence and extent of extraosseous soft tissue mass, and involvement of neurovascular bundle, muscle compartments and adjacent joint. this allows to find the best biopsy and surgical approach. to evaluate local control of disease and for detection of local recurrence, mri is usually the best imaging technique. 2. soft tissue (pseudo)-tumours: the majority of soft tissue tumours can be detected on ultrasound. except for cysts and subcutaneous lipoma, mr will be the next imaging technique for diagnosis, local staging, and eventually to find the best biopsy and surgical approach. the age of the patient, location of the tumour and careful analysis of the signal characteristics on mri allow for characterisation of many soft tissue tumours and differentiation from pseudotumours. plain radiography and ct may be useful for detection of calcifications and myositis ossificans. to evaluate local control of disease and for detection of local recurrence, ultrasound and mri are the best imaging techniques. in this honorary lecture, i will review a number of personal impressions that may contribute to the successful performance of research projects in cardiovascular radiology. also, issues and obstacles in performing successful research in the field of radiology will be considered. key factors for success include guidance by inspiring mentor, genuine interest and motivation, some creativity and serendipity. radiology has developed tremendously with many innovative modalities over the last 25 years, providing ample opportunity to participate in clinical research. potential issues that should be addressed are subspecialisation, turf battles, competition from other clinicians/ imaging specialists and adequate training in radiology research. the field of imaging research includes traditionally more clinically oriented research by focussing on developing and testing of new modalities and applications, now becoming more basic by including molecular imaging, population imaging, outcome studies and alike. silicone-filled implants (single or double lumen) require a dedicated sequence where silicone exhibits a high signal intensity, whereas signals from fatty and fibro-glandular tissues are cancelled. diagnosis of intracapsular rupture relies on the detection of a linguine sign (direct sign) or multiple "key-hole" and/or " teardrop" images (indirect signs). extracapsular rupture is defined as the presence of silicone outside the capsule (breast, soft tissues, lymph nodes). breast reconstruction after mastectomy may involve autologous tissue flaps (skin, fatty tissue, muscle and fascia). the transferred muscle is inserted in front of the major pectoralis muscle and enhances after contrast medium injection. the most common benign findings seen in such reconstructed breasts and also after a breast-conserving treatment are oedema, seroma, haematoma, fat necrosis and fibrosis. diffuse thickening of the skin and trabeculae is usually observed the first year after completion of radiation therapy. small focal areas (less than 5 mm) of non-mass-like enhancement and thin linear or rim enhancement at the lumpectomy site can all be expected findings. these benign findings decrease progressively, but residual enhancement may be observed in 15% of women at 5 or more years. in patients who were switched from tamoxifen to aromatase inhibitors, a stronger or re-appearance of a background enhancement may be observed. before classifying such findings as benign or probably benign, clinical examination and standard imaging data must be taken into account. highly suspicious lesions in such patients are similar to bi-rads 5 lesions in the nontreated breast. prevention strategies for women at high lifetime risk of breast cancer are usually adapted to the individual woman's risk of breast cancer. women at high risk (brca mutation carriers or women with a 30% likelihood of brca-heterzygosity) are offered primary prevention, which includes chemoprevention by tamoxifen or surgery (risk-reducing mastectomy and/or salpingooopherectomy, where the latter also helps reduce the risk of subsequent breast cancer by 30%). if women opt for secondary prevention (active surveillance/screening), this has to start at 30 at the latest. mri is considered a compulsory component of all programs worldwide. due to the very limited added cancer yield of mammography in this subset of women, and because of the still unsettled issue of possibly increased radiosensitivity of brca-mutation carriers, mammographic screening is not recommended until the age of 40. there is broad agreement that (at least) an annual screening is important; especially for brca1 mutation carriers, screening every 6 months may be more appropriate. we recommend interleaved screening, with annual mri and annual ultrasound (â± mammography) phase-shifted by 6 months. there are important differences between brca1-and brca2-associated cancers in terms of age distribution and incidence rates, histologic features, but also specific imaging features which must be known by radiologists. mri screening protocols must be adjusted to the specific needs of this (usually very young) screening population. this presentation will review the current evidence with respect to screening of women at high familial risk of breast cancer and will provide information on all aspects mentioned above. chest trauma is directly responsible for 25% of all trauma deaths and is a major contributor in another 50% of all trauma mortality. blunt trauma, accounting for 90% of chest injuries, is the third most common site of injury in polytrauma patients. plain radiographs still have a role in recognition of some acute thoracic pathology that requires immediate further management, either diagnostically and/or therapeutically, such as tension pneumothorax, major transdiaphragmatic herniation, large hemothorax or obvious mediastinal hematoma. mdct of the chest is now typically included in a whole body scan with iv contrast to facilitate rapid diagnosis on polytrauma cases using less radiation than selected segmental scans. mdct is the well-proven diagnostic gold standard for chest injury evaluation. the major advantages of mdct over other modalities include identification of active bleeding, direct signs of trachea or esophageal injury, direct evidence of major arterial vascular injury, such as pseudoanurysms, pneumo and hemopericardium, location and extent of lung contusion and laceration, and assessment for thoracic spine, shoulder girdle and rib fractures. diaphragm injuries are well depicted by mdct, especially on the left by identifying both the torn diaphragm edges, herniation and constriction of abdominal contents at the level of the torn diaphragm (collar sign), and direct contact of herniated structures with the posterior chest wall (dependent viscera). tracheal injuries are suggested by diffuse and progressive pneumomediastinum, dilated tracheostomy cuff, ectopic endotracheal tube, and direct connection of mediastinal air with the trachea lumen. ct-angiography eliminates the majority of indications for diagnostic catheter angiography. pulmonary symptoms such as chest pain, shortness of breath or wheezing are common non-traumatic symptoms prompting er visits. because clinical symptoms are very non-specific, imaging plays a major role in differentiating life-threatening from less severe diseases and forming a diagnosis. the chest radiograph remains the first imaging despite its limited sensitivity for certain diseases and being prone to inter-observer variability. comprehensive cardiothoracic ct examinations using most modern ct equipment are well evaluated in their diagnostic accuracy to determine the presence of vascular life-threatening events such as aortic dissection, acute coronary disease or pulmonary embolism. protocols and literature evidence will be discussed. the main focus of the course, however, will lie on the analysis of pulmonary ct findings and its contribution to the differential diagnosis of pulmonary emergencies (e.g. pneumonia, oedema, pneumothorax, exacerbation of fibrotic or obstructive lung diseases) and how to further integrate imaging findings, laboratory findings, patient history and clinical information to tackle the differential diagnosis. imaging findings will be discussed by clinical case studies, key findings and also overlapping morphological features of other differential diagnosis will be discussed side by side, illustrating the options and also limitations of imaging findings. mentor was first introduced in greek mythology, and in its modern usage first recorded by a french writer, franã§ois fã©nelon, in 1699. since then, this concept has been widely used in the development of mentoring, mentorship and more recently of mentees, with an overarching principle based on accompanying, sowing, catalysing, showing and harvesting. this concept remains today as a fundamental one in all teaching activities and implies generally a close contact between the mentor and the mentee. however, the development of internet with concomitant e-learning capabilities, which are hugely increasing, raises the very challenging necessity to re-think this concept and to adapt it to this new era. the esr is very concerned by this endeavour in the context of the striking development of esor, on one hand, and with the launching of its e-library, on the other. n. gourtsoyiannis; athens/gr (gournick@gmail.com) the presentation "esor in action" gives an overview on all esor activities in 2013 and 2014. a detailed report on the esor courses and teaching programmes in 2013 is presented, containing statistics about the number of course participants and of scholarship and fellowship grants. additionally, all educational activities in 2014, including dates, venues, topics and local organisers, are announced. evidence-based radiology: the basics evidence-based medicine (ebm) was derived from clinical epidemiology during the last century. it "is the conscientious, explicit, and judicious use of current best evidence in making decision about the care of individual patients" (dave l. sackett, 1996) . this means integrating (1) individual clinical expertise with (2) the best available external evidence from systematic research and (3) patient's values and preferences. when considering evidence-based radiology (ebr), the needed expertise is not only clinical, but also technical, while (4) radioprotection issues assume a relevant value according to the "as low as reasonably achievable" (alara) principle. ebm (and ebr) can be practised according to the "top-down" model, when using guidelines issued by governmental, professional, or academic bodies, or the "bottom-up" model, when local physicians (1) formulate an answerable question, (2) search for the best evidence; (3) appraise critically; (4) apply findings to practice; and (5) evaluate the performance. a hierarchy of radiological studies has been established according to the investigated matter: 1. technical performance; 2. diagnostic performance; 3. diagnostic impact; 4. therapeutic impact; 5. patient outcome; 6. societal impact. different degrees of recommendations are based on different levels of evidence, with experts' opinion as the lowest level and meta-analyses of high-quality homogeneous studies and multicenter studies being the best level of evidence. to practise ebr, radiologists should be familiar at least with basic statistics and epidemiology as well as of methods for study design, thus recognising the principal types of bias which can limit the value of published studies. learning objectives: 1. to understand the historical development and general principles of evidence-based medicine (ebm) with its top-down and bottom-up approaches. 2. to learn how to apply ebm principles to radiology (evidence-based radiology, ebr) and to illustrate the main reasons for the relative delay in developing ebr, including the challenges of fast technological innovation in medical imaging. 3 . to learn about the relationship between levels of evidence and the strength of recommendations for diagnostic imaging and interventional radiology. 4. to learn how radiologists could play a stronger role in building the evidence in favour of diagnostic imaging and interventional radiology, taking the patient's interest as the primary aim of clinical practice and science. education in research: action plan j. hodler; zurich/ch a survey regarding education in research has been commissioned by the esr and published in insights imaging (2012) 3: 535-542. the results indicate that education in research, associated with career models, needs promotion. the research committee of the esr is working on possible future steps to promote research through education. several problems will have to be addressed, most notably inhomogeneity within europe, motivation issues, illdefined career paths as well as funding issues. several stakeholders will play an important role, including scientific societies, although this is the core business of academic radiology chairmen. most young professionals starting a career in academic institutions are eager to expand their professional and personal aptitudes. an effective way to support young professionals in this regard is by mentoring. mentorship is a relationship where the mentor supports a junior faculty member (mentee) in personal and professional development. the mentee benefits from early determination and initiation of career-relevant steps, greater productivity in research and publishing activity and developing techniques in networking and collaboration. moreover, the mentee gains perspectives on how his/her discipline operates academically, socially and politically, improves self-efficacy and deals more confidently with challenging intellectual work. the mentor, a knowledgeable, experienced and regarded person, benefits from fresh ideas, energy and curiosity of mentees, as well as through acceptance as a mentor an enhanced status in the department. it is a trusted relationship of dialogue, learning and challenges, based on mutual interests. however, the mentor is not automatically the best friend or the sole exclusive advisor of the mentee. more and more academic medical institutions offer facilitated mentoring programmes, which help the mentoring pairs to create an effective mentoring relationship to accomplish the desired skills. evaluation of faculty mentoring programmes in academic medical institutions demonstrates the importance of mentoring in research and academic development as well as in patient care. especially in radiology where over many years there have been challenges in recruiting and retaining talented young professionals, mentoring is considered as an essential way for preparing the next generation of scientific and intellectual leaders. pitfall: "a hidden or unexpected danger or difficulty". imaging methods can provide an extraordinary amount of useful data to specialists treating head and neck (cancer) patients. it is crucial that these data are used to full advantage of individual patients. the most important factor in this process is mutual cooperation between the physicians in charge of patient care and the diagnostic imaging specialist. pitfalls in the head and neck may present in various ways: normal variants may look like disease, incidental findings are frequently encountered and suboptimal technique may obscure important findings. moreover, many pitfalls are directly related to technical errors. the presentation aims to familiarise general radiologists, who have an interest in head and neck imaging, with common pitfalls encountered on ct and mr studies focussing on the neck. in an interactive setting, examples from daily practice will be discussed. imaging of the skull base and maxillofacial skeleton requires a meticulous imaging technique and a good knowledge of normal anatomy and possible anatomical variants. asymmetry in the pneumatisation of the paranasal sinuses, skull base or temporal bone is a common reason for misinterpretation. for example, hypoplasia of the maxillary sinus may be misinterpreted on conventional radiography as maxillary sinusitis or orbital blowout fracture, depending on the context; asymmetric pneumatisation of the petrous apex or mastoid bone may mimic, respectively, a cholesterol granuloma and fluid effusion in the non-pneumatised side on mri. vascular variants may also cause interpretation problems. for example, turbulent flow in a large jugular bulb may mimic a jugular foramen tumour on mri. variants in the vascular plexus surrounding the trigeminal or facial nerve may occur, and cause asymmetric findings on mri, possibly mimicking neuritis or perineural tumour spread. incomplete maturation or arrested development of skull base structures may also cause confusion. examples are the cochlear cleft, not to be confused with otosclerosis, or arrested pneumatisation of the sphenoid sinus, possibly mimicking a tumoural lesion in the central skull base. to avoid problems, one should keep in mind the existence of such variants, while correlating the imaging findings with the clinical problem; in some cases, an additional imaging study may be needed to exclude a pathological process more confidently. this short 5-min introduction by the session chairman will give an overview of the current state of cardiac computed tomography (ct) for diagnosis and prognosis. in addition, the introduction will provide the basis for the subsequent dedicated lectures covering low radiation dose, diagnostic accuracy, and incidental findings in cardiac ct. what are the protocols with the lowest radiation dose in clinical practice? j.-f. paul; le plessis robinson/fr (pauljf@ccml.fr) the radiation dose delivered for coronary ct angiography using retrospective gating is high, because only a small part of the total radiation delivered is used for the reconstruction of the image in the retrospective mode. on average, 20% of the radiation burden is used to reconstruct one phase of the cardiac cycle. ecg-triggered tube current modulation allows reducing the nominal dose by up to 96% in the systolic phase. another approach for reducing radiation exposure is to use prospective, sequential acquisition, with this approach being associated with 75% dose reduction compared to the spiral retrospective acquisition. exposure time may be also shortened by an increase of pitch, in particular on the dual-source ct. however, applicability to each dose-sparing technique depends on the heart rate and its regularity. dose-sparing strategies should be modified in case of high or irregular heart rate and radiation dose reduction may be less effective. for coronary ct angiography, individually weight-adapted protocols have been successfully applied, by adjusting mas to patient's weight. more recently, settings of 100 kv and even 80 kv have been successfully used for cardiac studies, especially in slim patients or children. reduction of exposure time and individual adaptation have an additive effect on dose reduction: it has thus been possible to scan down under 1 msv in selected, slim patients, using this combined approach. in many cases, using the latest technology, radiation dose may be lower than the mean radiation dose associated with conventional angiography. learning objectives: 1. to understand various protocols to lower radiation dose in cardiac ct with regard to the clinical situation and the risk of image quality impairment. 2. to learn how to tailor the radiation dose level to each patient in terms of morphology. 3. to become familiar with modulating exposure windows in regards to a patient's ecg. how accurate and prognostically valid is coronary ct angiography? f. cademartiri, e. maffei; monastier di treviso/it (filippocademartiri@gmail.com) the role of cardiac computed tomography in cardiovascular diseases is becoming increasingly important. cct is a robust and reliable investigation for the detection and exclusion of significant coronary artery disease. in addition, cct provides reliable noninvasive information concerning coronary plaque burden (severity, distribution, type), morphology and function of left and right ventricle, valves, aorta, and so forth. in the past 5 years, the prognostic role of cct has been established. the prognostic information that can be extrapolated from cct is very diverse and most of it is still under investigation. there are converging evidences that cct can stratify cardiovascular risk better than conventional clinical methods, especially in symptomatic patients. for asymptomatic individuals, the role is still controversial since coronary calcium score alone has a very important role already. several aspects of cct information seem to have importance for prognostic stratification: plaque presence, obstruction, plaque type and distribution. more recent studies have started showing the relationship between cct and pharmacological treatment. this is a very new and appealing topic, since the evidence is towards the fact that the most effective pharmacological treatment (e.g. statin) should be restricted to patients with at least some nonobstructive cad as detected by cct. this might become a revolutionary concept in cardiovascular medicine with several implications. learning objectives: 1. to learn about and integrate the prognostic information from coronary ct angiography into conventional methods. 2. to learn about coronary ct angiography and conventional methods. 3. to appreciate the prognostic impact of coronary ct angiography and conventional methods. incidental findings in cardiac ct: how to report and proceed s. leschka; st. gallen/ch (sebastian.leschka@kssg.ch) rapid advances in computed tomographic (ct) technology have facilitated the widespread use of ct for cardiac imaging worldwide, and can be considered nowadays an essential part of the clinical workup of patients with suspected coronary artery disease. albeit that the performed ct study is focussed on the cardiac structures and the coronary arteries, adjacent noncardiac structures are in the field of view whenever a patient undergoes cardiac ct to quantify coronary calcium or to perform a noninvasive coronary angiogram. in addition, the location of the heart near other anatomic regions, including the lungs, mediastinum, upper abdomen, and bones, necessitate that these structures are included when acquiring coronary ct angiographic images. several publications have demonstrated a high frequency of incidental findings on coronary ct angiography. the availability of this information is part of an ongoing clinical debate. while some radiologists believe that every image should be interpreted completely, others believe that examining noncardiac structures reveal too many incidental findings of uncertain clinical significance, which may harm because additional testing increases risk, cost, and patient anxiety. the aim of this lecture is to separate solid facts from opinions and beliefs. the diagnosis of pulmonary embolism (pe) is usually established by a combination of clinical assessment, d-dimer testing, and imaging with either pulmonary ventilation-perfusion (v/q) scintigraphy or pulmonary multidetector ct angiography (ctpa). v/q scintigraphy is a functional imaging method using isotopes for the visualisation of ventilation and perfusion distribution in the lungs. in recent years, the imaging techniques for diagnosing pe have improved. many nuclear medicine centres have adopted the single photon emission computed tomography (spect) technique as opposed to the planar technique when diagnosing pe. the introduction of 3-dimensional v/q spect technology instead of 2-dimensional planar v/q scintigraphy has resulted in fewer indeterminate results and a higher diagnostic value. the latest improvement is the addition and combination of a low-dose ct without contrast to the v/p spect (spect/ct) technique. the spect/ct in combination has been compared to ctpa, planar scintigraphy and spect alone, and one study has shown that spect/ct in combination had the highest diagnostic accuracy for pe diagnosis. spect in combination with low-dose ct without contrast enhancement is superior, especially for small subsegmental emboli; however, consensus is lacking regarding the clinical impact and treatment. spect and spect/ct may provide alternative diagnosis if pe is refuted and are feasible in almost all patients, because there are no definitive contraindications. in the present lecture, spect and spect in combination with low-dose ct are discussed in the context of diagnosing pe. over the last few years, emergency radiology (er) has been a subspeciality with growing interest. because of rapid developments in technology, ct has become the most useful tool in evaluating trauma and other emergency patients. in this lecture, the basics of planning and organising an er department are presented and discussed. besides optimising technical equipment and protocols for imaging, different logistic concepts have to be considered in planning and organising er departments. first of all, logistic concepts have to be considered for obtaining an optimal workflow: the radiology department has to be in close proximity to the emergency department and the admitting area, in particular. the whole workflow must be optimised for speed and accuracy. this also mandates having dedicated and standardised examination and viewing protocols for ct. in contrast to the usa where dedicated emergency radiology departments are well established, nonspecialised radiologists still frequently do the reading of emergency radiology cases in european countries. the radiologic staff involved has to be trained for interpretation of trauma and other emergent cases. this does not only account for residents, but also for consultants and attending radiologists. since a large number of cases will arrive during after hours and on weekends, staffing has to be adjusted to this fact, which includes attending radiologists to be available during these hours on call or, preferably, on-site. this lecture will give an overview of logistic concepts and organisation of an emergency department and will also discuss critical issues in polytrauma imaging. at least during the radiological training in hospitals, every radiologist will personally be confronted with the treatment of polytraumatised patients. it is a fact that standardised whole body mdct (wb-ct) as an independent predictor is able to save around 20% of patient lives. thus, wb-ct is the major diagnostic tool and should be performed as fast as possible. some institutions bypass the emergency room and directly start patient stabilisation in the ct cabinet. however, radiographs and focused ultrasound remain important in general settings as long as they are performed in a way which does not delay ct diagnostics. after scanning, specially trained radiologists support the whole interdisciplinary team with correct, appropriate and prioritised diagnoses. besides optimisation of parameters like logistics, patient positioning preferably 'feet first', reading and communication, 'choosing the right protocol' is a crucial factor for ideal radiological patient care. four types of protocols should be differentiated: there is a wide agreement that for patients with polytrauma, integrating whole body computed tomography (ct) scan into early trauma care significantly increases the probability of survival. therefore, ct is today considered the most important imaging technique in the diagnostic workup of polytrauma patients. the downside of whole body ct represents the relatively high radiation exposure. to overcome this handicap, the following measures can be taken: 1. positioning of the arms during whole body ct above the head results in reduction of radiation dose; 2. adaption of scan parameters, especially reduction of tube voltage to 100 kv reduces radiation dose; 3. installation of recent technical improvements like iterative reconstruction algorithm reduces noise in the image, allowing a downward adjustment in radiation dose to obtain standard diagnostic quality images; 4. installation of dose control software enables optimisation and improved dose management over time. another disadvantage of high-resolution whole body ct is the amount of acquired data. to optimise the workflow in the evaluation of a couple of thousand submillimetre images it is necessary to connect the mdct scanner with a dedicated workstation for volume image reading, which offers the possibility of quick multiplanar online evaluation. in this introduction i will define the connectome (a comprehensive map of neural connections in the brain) and related concepts such as scaling, structural and functional connectivity as well as the integration-segregation paradigm. the development of mri-based techniques such as white matter tractography and segmentation of white and gray matter has played a crucial role in the emergence of connectomics by providing tools to map in vivo the entire human structural connectivity at a macroscopic scale. i will explain these methods and how from mr imaging a human connectome can be mapped and represented as a network (set of nodes and edges). finally, i will also review the validation work related to those techniques and mention the foreseen technical advancements in the field. session objectives: 1. to learn what the human connectome is and how it is affected by brain disease. 2. to understand how the human connectome can be imaged and characterised with mri. 3. to become familiar with the network formalism and its interpretation. 4. to understand the relationship between brain function and underlying structural connectivity. 5. to understand the conceptual ideas behind connectomics. 6. to learn about the general workflow, from diffusion imaging to mapping a structural brain network. 7. to become familiar with the robustness of the technique by reviewing validation studies and getting a glimpse of the technical challenges. the economics of brain networks e. bullmore; cambridge/ uk (etb23@cam.ac.uk) we review the methods and recent results of network analysis of human neuroimaging data. human functional mri and structural mri data can be analysed using mathematical tools drawn from graph theory to quantify the complex (non-random) topological properties of brain networks. these results can be substantiated by meta-analysis of prior neuroimaging results and analysis of non-human nervous systems. brain networks consistently express complex topological features, such as small-worldness, hubs, modules and rich clubs. some of these features entail disproportionate biological cost, but may be "worth it" by supporting integrative information processing and adaptive behaviours. highly connected hub nodes are high cost/high value network components that likely also represent special points of vulnerability for diverse brain disorders. these economical principles of brain network organisation are expressed at the microscopic scale, e.g., in the nervous system of the nematode worm c. elegans, and may therefore provide a new axis for translation between macro and micro systems neuroscience. neuroimaging can be used to elucidate the economical principles of human brain network organisation in health and disease. connectomics in brain pathology m.p. van den heuvel; utrecht/nl (m.p.vandenheuvel@umcutrecht.nl) healthy brain function depends on efficient functional communication within a complex network of structural neural connections, a network known as the connectome. conversely, damage to the brain's network, disrupting local neuronal processes and/or global communication between remote functional systems may lead to brain dysfunction. in the last few years, emerging evidence from a wide variety of studies suggests that connectome abnormalities may indeed play an important role in the aetiology of several brain disorders. in my talk, i will discuss the results of recent studies suggesting an important role for affected connectome organisation in a number of neurological and psychiatric disorders. in particular, i will highlight the findings of affected functional and structural brain network in neurodegenerative disorders such as alzheimer's and als, as well as discuss how the application of network science and connectomics may aid our understanding of the biological basis of psychiatric disorders such as autism and schizophrenia. learning objectives: 1. to understand the role of connectome architecture in (cognitive) brain function and dysfunction using diffusion mri/functional mri. 2. to become familiar with connectomics as a tool for examining disease pathology in a wide range of neurological and psychiatric brain disorders. linking structure and function: the role of modeling in understanding the pathophysiology the interplay of the brain's intrinsic activity and the external world has seen a revival in the last decade, especially in neuroimaging. a long-held assumption in many of these studies has been that ongoing brain activity is sufficiently random that it averages out in statistical analysis. hence, imaging studies are termed 'activation' paradigms, where experimental manipulation results in the activation of cerebral circuits that are necessary for performing the task. nevertheless, a large amount of recent literature reports a body of observations that there are consistently distributed patterns of activity during rest. this fact has led to the suggestion that it might be possible to characterise network dynamics without needing an explicit task to drive brain activity. indeed, numerous neuroimaging experiments have evidenced the solid existence of spontaneous long-range correlations, i.e. functional connectivity (fc), by fmri, meg, and eeg techniques. the functional connectivity is defined as the statistical dependence between remote neurophysiological dynamics. the emergence of resting functional connectivity is intrinsically linked with the underlying anatomical connections between those areas, i.e. the structural connectivity. whole brain modeling can indeed establish a direct link between structure and function. furthermore, the modeling can shed light on the origin of pathological functional disfunction by making the link with the underlying anatomy explicit. we will show how, structural dti tractography, functional imaging and modelling studies can be combined for reaching this goal. traumas to the paediatric pelvis and hip include traumatic dislocations of the hip, fractures of the femoral neck, fractures of the pelvic ring, acetabular fractures and apophyseal avulsion fractures. traumatic dislocations of the hip, fractures of the femoral neck, fractures of the pelvic ring and acetabular fractures are rare in children (less than 5% of paediatric fractures), as compared to adults. these fractures are commonly the result of high-energy trauma. imaging is based on plain radiographs, but ct and mri are very useful to precisely assess bone (ct) and cartilage and soft tissue (mri) lesions. imaging enables accurate diagnosis, appropriate treatment and detection of potential complications (femoral head osteonecrosis, premature physeal closure â�¦). in contrast with the previous injuries, apophyseal avulsion fractures of the hip and pelvis are common in children and adolescents, usually associated with athletic activities. in most cases, these fractures are of good prognosis and can be treated conservatively when minimally displaced. plain radiographs confirm avulsion injuries to ossified apophyses, but mri and ultrasound are the modalities of choice to demonstrate injuries to nonossified apophyses and to assess apophyseal displacement. the elbow is a very common site for fractures in a child. the challenge for the radiologist is to differentiate normal variants of growth from possible injury and this is usually achieved by having good-quality radiographs and an understanding of normal growth. it is important to recognise those fractures which require surgical intra-operative treatment. in a small number of cases when assessing for vascular integrity, intra-articular extent and injury to cartilaginous structures, ultrasound and mr imaging have a valuable role. this lecture will give an overview of the radiographic appearance of fractures, highlight the features which require orthopaedic intervention and illustrate the use of additional imaging modalities. learning objectives: 1. to become familiar with the types of injuries seen in the paediatric elbow. 2. to understand the strengths and weaknesses of different imaging modalities. a-162 17:00 the diagnosis of c-spine injury is more complex in children than in adults. early diagnosis is crucial since delayed diagnosis results in high morbidity and mortality. leading mechanisms of pediatric c-spine trauma are motor vehicle accidents, sports and pedestrian injuries. due to their anatomy, children are prone to different types and locations of injuries. children < 10 yeas of age are more likely to injure the spinal cord itself and are prone to dislocations and high (c1-c4) bony injuries. children > 10 years of age more often sustain c-spine fractures. in children under the age of 2 years, radiographs are rarely helpful. ap and lateral radiographs are helpful in children aged between 2 and 8 years. in children aged > 8 years, additional lateral and odontoid views are obtained. anatomical variants such as pseudosubluxation of c2-c3, widening of the atlantodental interval and ossification centres may appear to be of concern on imaging, but are normal. abnormal radiographic findings require additional imaging to differentiate them further with ct on the area of concern. mri is mandatory if signs of atlantorotary subluxation and spinal cord injury without radiologic abnormality (sciwora) are present. mri identifies injuries to the spinal cord that are not apparent with other modalities, and should be used when a child presents with a neurologic deficit but normal radiographs on ct scan. nowadays, ultrasound (us) has become the first choice for performing most breast biopsies. the main advantages of this technique are non-ionising radiation, full control of the needle position in real time and widespread use of us equipments at all centres. us allows access to difficult places (such as the axilla or near the nipple), multiple lesions can be safely biopsied in one single session, the breast is not compressed, there is excellent comfort for patients and radiologists, local anaesthesia and haematoma do not hide the lesion and it is a cost-effective technique. however, the main limitation is that the lesion must be visible on us. us-guided fine-needle cytology was widely used in the past, but today its use has decreased. us-guided core-needle biopsy has proven to be a reliable technique to perform a biopsy for breast lesions, showing a sensitivity value of about 98%. furthermore, it can be safely used for performing biopsies of axillary lymph nodes. vacuum-assisted devices can be used not only for diagnostic purposes, but also for therapeutic ones, because small palpable benign lesions (such as fibroadenomas), papillomas and radial scars can be completely removed. stereotactic breast biopsy is the performance of tissue sampling under mammographic guidance. as with any imaging technique, some lesions are only seen with mammography. when these lesions are suspicious (e.g. birads 3 or higher), there are no imaging techniques that can downgrade this suspiciousness directly, although for birads 3 lesions follow-up might be a viable alternative. in mammography, most lesions that are only visible on the mammogram consist of clusters of microcalcifications. these harbour a likelihood of around 25% being malignant and should thus be classified as birads 4. this implies that tissue sampling is mandatory. different from ultrasound-guided biopsy, it is not possible to perform a real-time biopsy under mammographic guidance. rather, stereotactic biopsy uses triangulation to assess the depth of a lesion within the breast, while the lesion location in the xand y-plane is assessed on a scout view. the needle is positioned using the coordinates thus obtained. since there is no real-time feedback of the accuracy of needle positioning, it is necessary to obtain substantially more tissue than under ultrasound guidance. therefore, vacuum-assisted systems are essential. in case of calcified lesions, the biopsy result is controlled by x-ray. calcifications should be present in the sample. biopsy complications that occur under stereotactic guidance are usually limited. most common is the formation of large haematomas. scarring may also occur. breast magnetic resonance (mr) imaging is the most sensitive modality available to evaluate the breast for cancer. it can detect lesions that are occult at mammography and ultrasound. it has a limited sensitivity and the positive predictive value ranges between 15 and 40%. histopathological assessment of mr-detected lesions is therefore mandatory. some of these lesions will be visible at second-look ultrasound and can be biopsied sonographically. a significant number however will only be discernable on mr, and mr-guided biopsy is therefore the sampling technique of choice. mr biopsy has become an essential component of any breast imaging practice. several mr-biopsy techniques are available including the grid-localising, pillar and post and the freehand techniques. the technique for preparing and performing a mr-guided vacuum-assisted biopsy using the grid-localising technique is reviewed. potential complications, limitations of mr breast biopsy and actions to prevent failure are discussed. imaging-histologic correlation is essential to ensure accurate sampling. clip placement and follow-up imaging should be performed to ensure sampling, including ultrasound correlates. finally, new developments in mr-guided therapeutic interventions are discussed. abdominal injuries require a timely and reliable diagnosis to prevent potentially lethal outcomes. the armoury of clinical tools (physical examination, lab tests) does not fulfil these criteria, since they are either not fast or not reliable. imaging diagnostic modalities help the clinician to acquire the necessary amount of information to initiate focused and effective treatment. however, the selection of the appropriate imaging algorithm, modality and technique, as well as the precise detection and interpretation of essential imaging findings are frequently challenging, especially because the circumstances, under which these examinations are performed (open wounds, bandages, non-removable life-supporting equipment, lack of patient cooperation, etc)., are frequently less than optimal. knowledge of critical imaging signs, symptoms and the role they play in the evaluation of the patient's condition, as well as fast decision-making and ability to closely cooperate with the clinicians are skills of key importance for radiologist members of the trauma team. this presentation will describe the technique and important findings for ct stone studies as well as the accuracy of this study. an explanation of when iv contrast should be given to augment a ct stone study and findings of gu and non-gu diseases that can mimic symptoms of stone disease will be provided. examples and descriptions of acute mesenteric vascular abnormalities, bowel obstruction and infectious conditions will be included. ways to differentiate and categorise emphysematous infections for proper treatment will be described. lower tract emergencies will also be illustrated and described. a systematic approach to evaluating abdominal cts will be described to avoid mistakes. using cases and an audience response system, this segment of the course will go over the optimal imaging approach for patients presenting with acute abdominal pain and abdominal injuries. ct findings will be emphasised. key imaging findings of traumatic and nontraumatic causes of acute abdominal pain including gastrointestinal tract and urinary tract pathology will be explained. a systematic approach for the imaging evaluation of patients with abdominal emergencies will be illustrated and explained including proper scan protocols and analysis of imaging findings. imaging diagnosis of blunt and penetrating abdominal injuries, urinary tract obstruction, infection, bowel obstruction, and ischemia will be emphasised. transcatheter renal denervation represents a novel therapy for treating patients with treatment-resistant hypertension, leading to higher risk of major cardiovascular events. an overview of sympathetic nervous system anatomy, physiology and physiopathology will be followed by a description of the technical aspects of renal denervation. first, results in patients with therapyresistant hypertension look very promising. however, these data need to be confirmed. importantly, long-term efficacy and safety need to be assessed. as a consequence, the treatment cannot be considered, at the moment, standard therapy. future studies need to address other disease conditions characterised by sympathetic hyperactivity, including heart failure, chronic kidney failure and others. it is a general opinion that in the near future the treatment will also be applied to lesser severe hypertensive patients. future studies should also include formal cost-effectiveness analyses. renal denervation can be achieved by a number of different techniques that include radiofrequency ablation, intraluminal and high-intensity focussed ultrasound ablation, chemical ablation and radiation ablation. radiofrequency and ultrasound ablation are currently the most commonly used techniques. most of the evidence to date is derived from studies and trials based on devices that use radiofrequency ablation technology. there are a number of currently ce-marked devices available and each device differs in the catheter design, generator design and energy delivery. these device types include single-point ablation, multi-point ablation, balloon-mounted systems and irrigated technology. the indications for renal artery denervation have been formulated by various international and european societies based on the various clinical trials and studies. these indications include patients with true resistant hypertension, age 18-85 years, egfr > 45 ml/min/1.73 m 2 (mdrd formula), single renal arteries with diameter > 3-4 mm with a landing zone of 20-21 mm depending on the device, no significant renal artery stenosis > 30%, no renal artery aneurysm, no previous renal artery angioplasty or stenting and the absence of significant valvular heart disease where lowering blood pressure will be dangerous. renal denervation of the sympatic nerves around the renal arteries is a new catheter technique to treat patients with resistant hypertension. resistant hypertension is seen in about 10%-20% of all patients with hypertension. the mechanism of sympatic nerve driven resistant hypertension will be explained. the available techniques for rdn will be discussed, focusing on the pros and cons of each technique. currently, rf ablation, hifu and cryo-ablation are the techniques under investigation. the technique and physics of renal denervation with radiofrequency ablation will be explained in more detail, focusing on available devices in the market. patient selection and nonresponders will be discussed. the current evidence from the available trials will be reviewed. the future of rdn and the role of radiology and the radiologist will be illuminated. the adrenal glands are composite endocrine organs consisting of the steroid hormone-producing cortex and the catecholamine-synthesising medulla. the increased use of imaging modalities has demonstrated the presence of varying sized mass lesions in up to 5% of individuals subjected to ct studies for reasons unrelated to adrenal dysfunction. most of these incidentally discovered lesions are non-functioning benign lesions of cortical origin. however, incidentalomas may also represent functioning lesions and malignant masses. clinical diagnostic and biochemical evaluation is used to further subdivide functional and non-functional adrenal lesions. f-dopa has been found to be of high sensitivity and specificity in pet imaging of pheochromocytoma. ct and mr imaging are first choice in characterisation of adrenal lesions. techniques of dual energy ct and histogram analysis may offer additional information. pet-ct has been shown to contribute to the diagnostic power, especially in oncologic patients. knowledge of the physiologic appearance of adrenal glands in 18-fdg pet is necessary to correctly identify pathologic processes. fdg-pet also has the ability to detect metastatic lesions in non-enlarged adrenal glands. in addition, fdg-pet has the advantage of simultaneously detecting metastases at other sites. the role of mr-dwi and mr-spectroscopy in characterising adrenal masses has to be defined by further studies. differentiating benign from malignant adrenal masses using non-invasive imaging methods can reduce the need for percutaneous adrenal biopsy in patients with underlying malignant disease and the follow-up imaging of incidentally detected adrenal adenomas. renal cell carcinoma (rcc) is the most common malignant tumour of the kidney. as response rates to radiation and nonantiangiogenic chemotherapy are low, surgical excision, i.e. radical nephrectomy has been the treatment of choice. however novel treatment options have emerged, so that imaging of rcc is of increasing interest. nephron sparing partial nephrectomy has become an accepted operative option and antiangiogenic agents such as inhibitors of tyrosine kinase (tk) and mammalian target of rapamycin (mtor) have been approved for treatment of advanced rcc. thus, it has become important to perform correct local staging and identify patients suitable for partial nephrectomy using standardised scoring systems such as renal or padua. furthermore, optimal imaging strategies for monitoring of advanced and metastatic rcc are discussed, as current antiangiogenic therapy evaluation in clinical routine is based only on morphological imaging information, but changes in tumour size may lag behind functional changes. finally, common side effects, i.e. pneumonitis, of vascular disruptive agents are addressed. characterisation of renal masses can be performed using three categories with respect to the lesion size and gross architecture: the indeterminate very small masses, the cystic, and solid renal masses. lesions with diameters below 10 mm are usually difficult to classify due to partial volume effect that prevents accurate ct attenuation measurement. in the general population, these lesions are likely to be microcysts and do not require further workup. better characterisation remains needed in selected patient populations such as patients with hereditary renal tumour disease and previous history of renal carcinoma. in this case, mri combining t2w, diffusion-weighted imaging and dynamic contrast enhanced sequences or contrast-enhanced us may help differentiate very small cysts from solid neoplasms. cystic renal mass characterisation still relies on bosniak's classification with 5 categories: benign (i) and minimally complicated (ii) cysts, indeterminate cystic lesions (iif and iii) and malignant cystic masses (iv). some cystic masses remain unclassified at ct because of atypical attenuation characteristics or enhancement properties. us, contrast-enhanced us, and mri are now playing a key role by providing additional diagnostic information that help distinguish between atypical fluid filled masses and atypical solid neoplasms, especially poorly enhancing solid papillary rcc. the characterisation of small solid renal tumours starts at ct with the identification of macroscopic fat, a typical feature of angiomyolipoma. in the case of non-fatty indeterminate renal neoploasms, percutaneous-guided biopsy can be performed when accurate characterisation is needed before surgery or when renal metastases or lymphoma are suspected. drug development being a complex and costly process, there is an increasing need for imaging biomarkers to take go/no go decisions in the early clinical phases. the recist criteria based on tumour size measurements at ct are currently used for this purpose. however, additional functional and molecular biomarkers have been developed to assess the early biological effect of drugs on tumours. development of imaging biomarkers is a structured process in which new biomarkers are discovered, validated and qualified against biological processes and clinical end points. the validation not only concerns the determination of the sensitivity and specificity, but also the measurement of reproducibility. reproducibility assessments, standardisation of the acquisition and data analysis methods and quality control are crucial when imaging biomarkers are used in multi-centre trials. functional and molecular parameters obtained at perfusion imaging, diffusion-weighted mr imaging and pet are being developed and validated. the perspectives (earlier assessment of response to treatment) and limitations (limited validation and standardisation) of these imaging biomarkers in cancer drug development will be presented. more recently, pharmacodynamic imaging biomarkers such as fdg-suv and k trans have been introduced. drug developers are reluctant to use more exploratory unvalidated imaging biomarkers (i.e. cannot distinguish a true negative from a false negative). the extensive literature on biomarker validation mostly refers to biochemical biomarkers extracted as analytes from biospecimens and is unhelpful to radiologists. unlike biospecimen biomarkers, the quality and validity of imaging measurements as biomarkers depend crucially on the use of a diagnostic imaging device, in the presence of the patient, in a manner for which the device (a) was not designed, (b) has not received regulatory approval and (c) may be unfamiliar to the user in the trial site. technical validation and biological validation are orthogonal activities. ''technical validity'' is confidence that the imaging biomarker can be measured reliably anywhere in the world. ''biological validity'' is confidence that the biomarker correctly reports some underlying biology that is important to the patient's future clinical outcome. since the physician always has access to the patient's clinical status and history, the biomarker is only useful if it provides a better forecast than clinical data alone. (if the forecast is near perfect, the biomarker might be a surrogate end point). technical and biological validations are massive undertakings best achieved by consortia, and in particular publicprivate partnerships, of which the innovative medicines initiative in europe and the biomarkers the standard imaging assessment of tumour response relies on size measurements, which, with predominantly cytostatic targeted agents, may not reflect the drug effect. functional imaging biomarkers have the potential to quantify the biological characteristics of tumours and measure on-target and off-target effects that indicate early likelihood of response to a specific therapy, which can then be used to guide the optimal biological dose and drug schedule. serial, non-invasive assessments of whole tumour are possible. this is particularly important in the context of inter and intra-patient tumour heterogeneity, as different parts of the tumour and primary vs metastatic lesions may be biologically different and these characteristics may change with treatment. however, functional imaging end points suffer from variability, which can be very significant in a multicentre setting. strict quality assurance and quality control measures need to be implemented at the start of a trial and the variability across centres documented. data acquisition protocols need to take account of equipment variations. data analysis methodology needs standardisation of software, central review and preferably double reading of scans. automation may not always prove the most robust and reliable option. this presentation will focus on the factors that are crucial in determining the compatibility of data in multicentre trials with functional imaging end points. learning objectives: 1. to learn about the potential role of quantitative imaging in processes related to tumour growth such as cell metabolism, cell death, and vascular function in the assessment of tumour response. 2. to become familiar with the issues of accuracy, reproducibility and standardisation for using functional imaging biomarkers in drug development. quantitative nuclear medicine in drug development w. weber; new york, ny/us nuclear medicine techniques can detect and quantify very low concentrations of radiolabelled pharmaceuticals in the human body. this allows investigators to use nuclear imaging for various purposes during drug development. nuclear imaging can visualise drug targets that are only present in nanomolar concentrations and can thus identify patients most likely for therapies directed against these targets. a recent example is folate receptor spect imaging for the selection of patients for treatment with a folate-targeted drug conjugate. in addition, nuclear imaging and specifically pet can measure the concentration of pharmaceuticals within tumour and normal organs over time. nuclear imaging can also be used to monitor target inhibition, for example the blocking of oestrogen receptors by anti-oestrogens. finally, nuclear imaging can assess tumour response to therapy by measuring changes in tumour metabolism or proliferation, e.g. with fdg-and flt pet/ct. this allows an earlier and more sensitive detection of tumour response than morphologic techniques. since pet is a whole body imaging technology, pet imaging can also be used to study the heterogeneity of target expression, tissue pharmacokinetics, target inhibition and response. pet imaging is now widely available in many countries and has become internationally standardised. it is therefore a robust clinical technique that will increasingly be used during drug development. there are about 80.000 patients per year in europe who lose their leg. about 70% are due to diabetic ischaemic and ulcerative leg problems. in diabetic patients the prevalence of foot ulcerations is about 20% and the risk for developing foot ulcerations is increased four times. diabetic foot problems may be due to neuropathy and malperfusion or a combination of both. the neuropathic ulcer and the neuroischaemic ulcer are usually at the plantar pedis, have a punched-out appearance and are painless. bone deformities (charcot foot) may be associated. the arterial ulcer is usually at the toe, forefoot and ankle, with pale, cold skin and it may be painful. patients need a multimodality approach involving a diabetologist, vascular specialist (angiologist, vascular surgeon, interventional radiologist) and podiatrist. pain control, antibiotic and antithrombotic treatment and the treatment of cardiovascular risk factors and other co-morbid disease have to be done first. in case of ischaemic pain and ulceration imaging such as mra and cta is the next step. patients should be referred to a team of vascular specialist early in the course of their disease to plan for revascularisation options. revascularisation is the optimal treatment for patients with an ischaemic and neuroischaemic diabetic foot. a. pathophysiology of the diabetic foot v. bã©rczi; budapest/hu (berczi@hotmail.com) the incidence of diabetes mellitus, associated with both predisposing genetic and environmental factors, is increasing globally. several major clinical trials have proved that complications may occur many years following proper glycaemic control. besides peripheral arterial disease, sensory and motor neuropathy along with an altered response to infection is of crucial importance. recent studies have showed that microvascular occlusive arterial disease is not a major factor affecting the diabetic foot; infrapopliteal macrovascular disease and microvascular dysfunction (e.g. arteriovenous shunting, precapillary sphincter malfunction, capillary leakage, venous pooling) are major components of impaired perfusion of diabetic foot. there are no randomised controlled trials analysing the major outcome following endovacular or open bypass surgery. the major outcomes, however, were similar in the case series: 1-year limb salvage showed a median of 85% (interquartile range 80-90%) and 78% (interquartile range 70.5-85.5%) following open surgery and endovascular treatment, respectively. limb salvage rate, however, was considerably higher with either type of revascularisation compared to medical therapy. negative pressure wound therapy, hyperbaric oxygen therapy, effective off-loading or nonweight-bearing therapies (total contact casts rather than removable devices) have also shown promising results in recent publications. endovascular arterial revascularisation is today a solid option in the management of cli with low complication rates and limb salvage rates comparable with surgery. the restoration of adequate blood flow to the foot is crucial to facilitate wound healing, provide pain relief, and avoid whatever amputations. the angiosome concept was first introduced in 1987 by taylor and further developed by attinger for planning treatment of ischaemic lesions of the foot. they divided the foot into six distinct angiosomes, arising from tibial and peroneal arteries. planning the procedure on the basis of this concept will yield the best local results of wound healing, compared with the indirect intervention. a proper pre-procedure assessment through colour doppler us and dsa of lower limbs is mandatory for guiding the procedure through the vessels of the foot. several studies have evaluated the efficacy of pta in the btk and the reliability of the angiosome model, approaching 100 % with a limb salvage rate of up to 87% at 12 months. on the basis of these data, we can conclude that pta in diabetic patients with btk disease is a safe and effective technique. the first endovascular treatment option is related to the angiosome model, but when not feasible the indirect technique is also a valid and similarly effective procedure. to face technical failures, up to 20% in crural chronic total occlusion a decade ago, different approaches and dedicated devices and technologies have been developed in the last few years. furthermore, percutaneous revascularisations are gaining more interest, particularly in patients with critical limb ischaemia not only as first-line treatment, but also as the only possible treatment for complex lesions and high-risk patients. special techniques for crural endovascular revascularisations are by design techniques rarely used in routine practice, but could offer wide possibilities for the interventional radiologist to solve challenging situations and manage complex lesions. these techniques include options for arterial access (trans-popliteal, trans-tibial, trans-pedal), approaches for crossing chronic total occlusion (assisted endoluminal, lambda technique, re-entry technologies) and uncommon routes for angioplasty/recanalisation (trans-metatarsal loop technique, trans-collateral techniques). combined antegrade and retrograde approaches have also been developed as well as related methods for successful re-entry. deciding when the patient/lesion is a potential candidate for special techniques is also a crucial issue. the interventional radiologist should be able to convert at any time if necessary the strategy of treatment to another one. he should also be able to select the most appropriate technique for the patient in planning revascularisation. continuous medical education and training is however mandatory and for some techniques the learning curve is relatively long. pathology of the eye and orbit is rare in the radiologist's practice. however, differential diagnosis is not too difficult if the compartment model is applied. in the orbit, different anatomical structures like the optic nerve as part of the cns, muscles for moving the globe, vascular structures and glandular tissue are present in a very small space. each anatomical structure is found in a special compartment; each compartment may give rise to a different group of pathologies, and only to these pathologies: glioma in the optic nerve, rhabdomyosarcoma in the eye muscles, varix in the venous vessels (intraconal compartment) and pleomorphic adenoma in the lachrymal gland. understanding the compartments in the orbit is therefore the key to differentiating different pathological entities. this presentation explains the orbital anatomy, how the compartments are differentiated, and what changes in anatomy treatment may induce. orbital congenital lesions are uncommon. they can be diagnosed prenatally, at birth or later during childhood. several orbital components can be involved. we will focus on congenital globe lesions (such as staphyloma, coloboma, persistent hyperplastic primary vitreous, coats disease), the developmental cysts such as epidermoids and dermoids, and vascular malformations such as lymphangioma and vascular tumours, e.g. capillary haemangioma. orbital inflammatory and infectious lesions are on the other hand common. orbital pseudotumour can involve any area of orbit, being one of the great mimickers in the orbit. if located in the orbital apex and/or cavernous sinus, it will be called tolosa-hunt syndrome. other inflammatory processes in the orbit are sarcoidosis and wegener and sjogren syndrome. among infections the most common is the orbital cellulitis, mostly secondary to a sinusitis and frequent in the urgency setting. the role of the radiologist is to assess whether it is preseptal or already postseptal or complicated by a subperiosteal phlegmon or abscess. also of importance is to know and evaluate the possible intracranial complications. finally, we will focus on inflammatory and infectious lesions of some specific regions such as the globe and lachrymal gland and give some clues for their differentiation. as more than 100 pathologies can be seen in the orbit, a systematic approach is very important to come to the right diagnosis. the main and most helpful criteria of differential diagnosis of any orbital pathology is the definition of the affected orbital compartment, as some tumours may only or preferentially involve specific orbital structures. the criteria of the most frequent masses of the globe, malignant melanoma and retinoblastoma are presented as well as those of cavernoma and lymphoma, the main representatives of intraconal tumours. there are numerous extraconal neoplasms, only few arising from the nasal sinuses, and only a little number of tumours of the optic nerve. the presentation will include the most frequent as well as rare, but important tumours. the routine practice of oncologic imaging requires standardisation, which means that we need to harmonise technical protocols and agree on the meaning of selected words for the radiological report. the words "response, "progression" and "stable disease" are precisely defined according to internationally accepted thresholds and criteria. although the rules are quite simple and rather easy to apply, they are very efficient in the classification of the response to treatment, and therefore for the medical decisions. however, the role of the radiologist is not limited to measurements and calculation. the detection of new lesions may be challenging and requires experience. the differential between cancer progression and complications of the treatment might be very difficult and requires an adequate communication with the referring clinician. overall, most of the decisions taken by the clinician will be related to imaging results, stressing the importance of adequate protocols and reports. in solid as well as non-solid tumours, pet/ct imaging using 18-fluorodeoxyglucose (fdg) has demonstrated the ability to a) correctly stage disease, b) demonstrate therapy response and c) predict therapy outcome. fdg uptake can be measured objectively; however several factors in the standardisation processes of tracer application, image acquisition and post-processing are needed for reproducibility. the term standard uptake value (suv) measurement is used for compensating the influence of injected dose, decay time and body mass and represents fdg uptake in any selected pixel of the image. for therapy assessment, drop in fdg uptake represents tumour cell kill, notably a negative pet scan does not exclude viable tumour cells but overall has a better outcome. pet response criteria in solid tumours (percist 1.0) have been introduced to refine previously established pet response criteria by eortc. major changes concern the use of lean body mass-based suv (sul), sulpeak measurement in a fixed roi, use of only a single target lesion and normalization to liver uptake. metric measurements in ct component of the pet/ct as an intrinsic asset like in recist 1. 1 have not yet been introduced, but might be crucial in the future. the proposed percist 1.0 criteria are not yet standard, since several limitations hamper its general use but may improve metabolic tumour response assessment. malignant gliomas (who grade iii and iv) are the most common primary tumours of the brain. according to consensus guidelines, the standard of care of these tumours includes maximal safe surgical resection followed by combined treatment with chemoradiotherapy. radiological assessment is critical in the follow-up and should be performed at four different times: 1. within 72 hours after surgery, an early post-operative mri must be done to evaluate residual tumour and to be used as baseline for follow-up. 2. two to six weeks after completing radiotherapy, a new mri examination is recommended to evaluate the response to treatment. four possibilities are envisaged according to the rano criteria: complete response, partial response, stable disease or progressive disease. the evaluation of this first mri examination after rt is challenging and the pseudoprogression phenomenon can appear. advanced mr techniques may be of help in this respect. 3. additional follow-up should then be performed by mri every 2 to 4 months to rule out clinically silent progression. 4. in any case, an mri examination must be completed when there is a clinical suspicion of progressive disease. several options for treatment can be offered when progressive disease is detected, including antiangiogenic drugs. evaluation of response to these drugs is challenging too, and the pseudoresponse phenomenon can then appear. due its complexity, it is recommended that the management of malignant gliomas be performed in the context of multidisciplinary teams and that the radiologists are strongly involved in these teams. we are facing complex times with no parallel in human history. the worldwide economic crisis, in combination with a non-regulated process of globalisation, is pressuring countries to change their social and political model. these changes are affecting academic institutions and the health-care sector. higher education was always more internationally open than most sectors because of its immersion in knowledge, which was never worried about country juridical boundaries. it is well recognised that it was the knowledge created by universities research that contributed to the development of societies. we, as european citizens, must be able to transmit the message that having more knowledge and being capable of understanding better the world we live in will make us stronger, more successful and more competitive. european academic institutions must be prepared for this shift of paradigm and understand that they are no longer educating only for their country but for the globalised world. it is also important to bear in mind that developed health-care systems are suffering several pressures and a call for a new inter-professional collaboration concept is needed, based on each one's roles and responsibilities, towards a better and more efficient health-care delivery for the patients. in this session, the invited speakers will give us an overview about the challenges that academic institutions will face in the near future and the way they must adapt to become more attractive and at the same time guarantee that radiographers and radiologists are educated and trained according to the highest professional standards. session objectives: 1. to appreciate the challenges that academic institutions must face in order to educate graduates with the ability to work internationally and to actively contribute to the healthcare sector of the future. 2. to explore innovative approaches in education and assessment. 3. to highlight the importance of inter-professional collaboration in order to ensure that graduates are ready to meet the demands of the modern healthcare sector. challenges in undergraduate education l.j.o.c. lanca; lisbon/pt (luis.lanca@estesl.ipl.pt) radiographers operate a wide range of sophisticated equipment and perform a range of techniques in several radiological procedures. they are responsible for the radiation delivered to the patient while assuring safety and image quality at an acceptable level for an accurate diagnosis. education and training in radiography, in line with the constant technological developments, is a requirement to be fulfilled by higher education institutions (hei). this is of major importance in undergraduate education where radiographers learn to play an effective role as healthcare providers in planning, preparing and performing accurate and safe radiological procedures within the diagnostic or therapeutic field. the european qualifications framework (eqf) for radiography, in terms of the development of knowledge, skills and competences, provides a european standard for the development of radiography learning outcomes at eqf level 6. this constitutes an opportunity to develop, tune, advance and promote standards of radiographic practice, education and research throughout europe. the eqf provides guidance to increase the educational and professional recognition of radiography in europe. at a european level, the cooperation between hei in undergraduate radiography education would be an opportunity to provide discussions of mutual concern, explore new perspectives and views of different cultures, and also share learning and teaching methods. international cooperation is an opportunity to improve and provide the harmonisation of education regarding a professional group that plays an effective role in healthcare in their field of competence and expertise. there is a vast amount of evidence available from the published literature that higher education institutions continue to explore innovation in both teaching and assessment practices. this is especially true of health professional programmes as evidenced by the abundance of literature relating to medicine, nursing, radiography and other allied health professions. such higher education, health professional programmes would appear to be more innovative than many other disciplines often as a direct attempt to mirror the dynamic clinical environment in which most graduates will work. there are, however, challenges associated with any such educational innovations and novel approaches to delivery and assessment. these specific challenges must be carefully considered in parallel with the larger challenges facing higher education institutions, both nationally and internationally, along with the professions which they contribute to. through a case study approach, supported by published peer-reviewed literature, institutional reports and research, this presentation will consider international best practice in education along with the value of collaborative, inter-professional approaches to teaching and assessment. haemodialysis accesses have become the most commonly performed type of vascular surgical procedure. however, only 50% of all haemodialysis accesses remain patent at 3 years. autogenous fistulas have a higher rate of primary failure compared to prosthetic grafts (50% vs. 15%), but the long-term patency of fistulas is superior to that of grafts. autogenous fistulas fail after a median of 3 to 7 years, whereas prosthetic arteriovenous grafts fail after a median lifetime of only 12 to 18 months. the pathogenic stenoses causing access failure occur in various locations, but the most common site in prosthetic arteriovenous grafts is at the anastomosis between the graft and outflow vein, as identified in 47% (23,246) to 60% of cases, or in the outflow vein itself in autogenous arteriovenous fistulas. clinical assessment alone will detect a large number of failing fistulas. by assessment of the thrill, pulse character, palpation of the fistula itself, excessive bleeding and difficulty needling a fistula may all indicate a failing fistula. if the venous pressures during haemodialysis exceed 120 mm hg, fistula flow falls to< 500 ml/min, graft flow decreases to< 650 ml/min, or access blood flow falls by more than 25%. a fistulogram is recommended if monitoring or surveillance suggests that thrombosis is either imminent or has already occurred. duplex can be used to assess the fistula, but cannot visualise the central veins. mr and ct venography has also been used in many patients successfully. treatment of symptomatic stenosis of vascular access is essential as it can lead to thrombosis and loss of vascular access. but treatment can lead to restenosis. the treatment of stenosis remains a challenge which requires a good knowledge of different materials (guidewire, catheters, balloons and stents). though the pathophysiological mechanism of stenosis is different for native fistulas, grafts or restenosis, the treatment technique remains the same. the basic principle is the use of high inflation pressure balloon angioplasty. whatever the material used, the key is to have no residual stenosis greater than 30%. so far, no study has demonstrated the superiority of the "new" tools (cutting balloon, drug-eluting balloon, cryotherapy) regarding restenosis. except perhaps for anastomotic grafts stenosis, stents should be reserved to treat complications or failure of balloon angioplasty. the stents indications are residual elastic stenosis, wall obstructive damage, acute rupture during angioplasty, aneurysm or restenosis. complications of stenosis treatment are rare, but can lead to the loss of vascular access. the main complications are thrombosis and acute rupture. as with any treatment, there have been contraindications: infection, distal ischaemia, high flow, newly created or surgically revised access (< 6 weeks). when dealing with a vascular stenosis access, never compromise on the future, but think about the surgical alternative. so, the management of stenosis vascular access must also be multidisciplinary. percutaneous treatment of a thrombosed dialysis access can be extremely challenging. the major concern does not stem from the fact that the procedure can be complexly long, but arises rather from the management of its complications, which can be serious particularly when the access is branched onto the brachial artery. access infection is an absolute contraindication. temporary contraindications include fluid overload and severe hyperkalaemia. percutaneous thrombectomy of grafts is very well standardised and predictable: size of 6 mm, well palpable wall which is easy to needle, small average clot burden, and an underlining stenosis almost always found at the venous anastomosis. thrombectomy of avfs is subject to variations in approach and technical difficulties depending on their anatomical particularities. all techniques employed follow 2 rules: first, the removal of thrombi and, second, dilation of the stenosis responsible for the thrombosis. heparin and antibiotics must be injected. the basic principle is to place in the arterialized vein or graft 2 introducer sheaths in opposite directions to work on both the venous outflow and arterial inflow. thrombus lysis or removal can be achieved by mechanical, pharmacological and pharmaco-mechanical methods. all techniques may work in grafts given that the modest amount of thrombus (3.2 ml on average) can be simply pushed into the lungs. prosthetic grafts are thus easier to declot than native fistulas, but they are much more prone to early rethrombosis. thrombi located at the arteriovenous anastomosis form a firm and rubbery plug, frequently and notoriously resistant to thrombolysis. drug-induced lung disease is an increasingly common cause of morbidity and mortality. the diagnosis is based on clinical history and consistent radiologic findings. lung biopsy is performed in a small percentage of cases. highresolution ct may demonstrate different parenchymal patterns including diffuse alveolar damage, acute or chronic alveolar haemorrhage, nonspecific interstitial pneumonia (nsip), hypersensitivity pneumonitis, organising pneumonia, and eosinophilic pneumonia. the imaging and histologic manifestations are often nonspecific. a systematic approach to the radiological evaluation of drug-related lung diseases is essential and includes not only chest imaging pattern recognition, but also integration of available clinical information. in this interactive session, we will present and discuss several cases illustrating thoracic changes after instrumental procedures in the thorax such as surgery, radiofrequency ablation, interventional endoscopy, and intensive care. radiologists have an important role in assessing the results of these procedures as well as in depicting the complications. however, knowledge of the normal appearance after those procedures has to be presented. the initial imaging workup of polytrauma patients remains challenging. besides hardware requirements, workflow issues continue to evolve, with the current focus on the introduction of whole body ct into the early resuscitation phase of severely injured patients as a standard and basic diagnostic imaging method. this session is aimed at a thorough discussion on the requirements for advanced imaging in the early clinical situation in emergency radiology. focus is directed on the issues of radiation dose as well as on ct and contrast media protocols. a. chest and abdomen m. scaglione; castel volturno/it (mscaglione@tiscali.it) thoraco-abdominal injuries are a significant cause of death in the polytraumatised patients. early recognition and communication of lifethreatening thoraco-abdominal injuries is the major task of the radiologists involved in the emergency room. although most of these patients reach the hospital prior to dying, lethality continues to remain high. heart, thoracic great vessels, trachea, bronchus, pleura, lung, diaphragm, abdominal/retroperitoneal, vascular and solid organ injuries are potential cause of death. any appropriate surgical/interventional management approach must be carried out "around the clock", before thoraco-abdominal injuries reach the level of clinical evidence. on the other hand, non-operative management has actually become the standard of care for the most serious thoraco-abdominal injuries. these goals become feasible if a correct contrast-enhanced mdct diagnosis, in a dedicated facility in which the trauma team works effectively 24 h a day, 7 days a week, is performed. thus, in this lecture, the most serious thoraco-abdominal injuries will be illustrated, with special emphasis on vascular/injuries as well as the value of post-processing techniques, protocols, pitfalls, tips and tricks. furthermore, the importance of a rational and integrated imaging approach will be pointed out and, finally, the role of the radiologist in the emergency room will be emphasised. spinal and musculoskeletal trauma account for significant morbidity in severely traumatised patients. traumatic injuries to the spine encompass a variety of frequently occurring disorders and primarily result in stable injury. although rare, unstable disorders comprise injuries to the bone, the discs, and the ligaments. in the majority of cases, spinal cord injuries result in devastating medical and social consequences. severe musculoskeletal disorders usually are the result of high-impact accidents, such as motor vehicle accidents and falls from a height. for instance, the injured pelvic ring causes one of the most life-threatening conditions that the trauma team must handle. pelvic injuries are often associated with severe arterial, venous, and/or osseous bleeding. radiography is no longer recommended as the primary screening modality in spinal and pelvic trauma for adults. despite the radiation dose burden of ct, patients with a high risk of spine injury receive mdct imaging, as it is the method of choice. mr imaging is indicated primarily when patients present with myelopathy, and to search for spinal cord pathology. interventional radiology plays a major role in the therapy of complex traumatic pelvic disorders. extremity injuries in patients after polytrauma can be complex and are initially often difficult to be fully diagnosed. emergency radiology diagnosis is today mostly based on a standardised whole body ct (wbct), which can be extended with cta and adapted to cover extremity injuries. extremity injuries comprise: fractures of (1) long bones, (2) articular joints, (3) complex fractures of hands and feet, (4) vascular, (5) soft tissue, (6) nerve and plexus injuries and (7) amputations. imaging protocol: *mdct is indicated in all major and complex bony fractures and is carried out early or integrated with wbct. cta using mips and mprs enables a thorough workup. * the role of us and cr is limited. * the role of mr and mra (in stable patients only) is to evaluate unstable articular injuries, injuries of tendons or major ligaments and nerve and plexus injuries). * the role of dsa is mostly for intervention. clinical findings and findings from wbct determine how to proceed, "first things are done first" in a priority-oriented clinical algorithm. treatment of extremity injuries must therefore be priority oriented and carefully planned in the context of possible concurrent injuries and a possible risk of multi-organ failure (mof). systemic drugs can be used for the treatment of cns and non-cns diseases. both classes can affect the brain inadvertently. common general drugs that affect the brain in a bystander manner are steroids (~1% brain volume reduction), recreational drugs (alcohol, cocaine, heroin, xtc), metronidazole and anti-epileptic drugs (corpus callosum demyelination) and immunosuppressants like cyclosporine/tacrolimus (pres/rpls) and methotrexate. mechanisms of action include neurovascular compromise, fluid/metabolite shifts and toxic effects to myelin of other tissue components. among cns-targeted drugs, especially immunomodulating agents may cause specific side effects. cytokine-release syndromes may occur with broad-acting agents such as general t cell antibodies. specific side effects may occur in multiple sclerosis, where treatment with natalizmumab may cause reactivation of jc virus leading to progressive multifocal leukencephalopathy (pml). upon withdrawal of therapy, this may then evolve into an immune reconstitution inflammatory syndrome (iris). in alzheimer disease, novel antibodies or vaccinations against amyloid may cause amyloid related imaging abnormalities (aria), which may present with microhaemorrhage on t2* images, or with edema and effusion on flair. the objective of this session will be to review the diagnostic value of conventional sequences as well as the use of contrast in the monitoring of brain tumours, with special attention to gliomas. also, we will address the advantages and limitations of advanced techniques: perfusion, diffusion, and spectroscopy. immediately after surgery, the main objective of neuroimaging is the detection of the remaining tumour. it may also be necessary to rule out complications such as haemorrhage, ischaemia or infection. the fundamental technique is mri with contrast in the first 48 hours and also diffusion sequences. in late follow-up, the goal is to differentiate the changes secondary to treatment of those related to tumour progression or recurrence. in these cases, conventional sequences present important constraints and are useful studies of diffusion, perfusion and spectroscopy. during follow-up after chemoradiotherapy, the objective is to assess tumour response. the response according to the new rano criteria will be revised. the combination of chemotherapy and radiotherapy, as well as the use of anti-angiogenic drugs causes changes that complicate the assessment of the response to treatment, with cases of pseudoprogression and pseudoresponse. in these cases, perfusion techniques, diffusion and spectroscopy can provide relevant information, although it is necessary to standardise the quantification to make its wide use possible. the speakers in this course will update the audience on contrast media safety such as steps to be taken before contrast administration and present the newest safety guidelines. the first speaker will cover new concepts of non-renal reactions to contrast media explaining which hypersensitivity reactions are allergic and non-allergic. the audience may learn assessing symptoms according to the ring and messmer classification and understand the importance of tryptase sampling and skin testing in the follow-up. the second speaker will address nsf. the presentation will review the pathophysiology, risk factors, recent recommendations and prevention of nsf. patients with gfr less than 30 ml/min/1.73 m 2 have increased risk of developing nsf. lowstability gadolinium contrast media show the strongest association with nsf. following existing guidelines on the use of gadolinium contrast agents minimises the risk of nsf. potential long-term harm from gadolinium accumulation in the body and legal issues are discussed. the last speakers will cover contrast medium-induced nephropathy with more recently published guidelines related to that issue. the presentation will include the definition of cin and the choice of contrast medium and prophylactic measures. recent changes in esur guidelines will be explained. the risk of cin is considered significantly lower following iv. cm administration and patients referred for enhanced ct are genuinely at risk if they have an egfr < 45 ml/min/1.73 m 2 . volume expansion with isotonic saline or sodium bicarbonate may be used for preventing cin in at-risk patients. acute immediate hypersensitivity reactions occur within the hour following the administration of contrast media. they can be seen with iodinated and gadolinium-based contrast agents. over the last ten years, new concepts have emerged in the way of understanding, managing and exploring hypersensitivity reactions. the clinical appearance is best classified by the ring and messmer scoring, from grade 1 (cutaneous and subcutaneous signs) to grade 4 (cardiovascular arrest). the mechanisms involve either true ige-mediated hypersensitivity or non-allergic hypersensitivity. the differential diagnosis in favour of allergy is made on a triad: clinical signs (the more severe, the more are the chances to be allergic), elevated tryptase levels in the plasma (indicating mastocyte triggering) and positive skin tests performed one month after the reaction. these new concepts induce important consequences in managing hypersensitivity reactions: be prepared to treat the patient adequately, be prepared to draw blood after the reaction to dose tryptase levels, send the patient to a dedicated allergologist, and forget about the preventive role of premedication against severe reactions. the authorities have introduced several restrictions on the use of high-risk agents, which will be followed by every physician in the eu. the agents are contraindicated in 1) patients with severely reduced renal function including dialysis, 2) acute renal insufficiency, 3) neonates and 4) pregnant women. they may only be used with caution in patients with moderately reduced renal function and children less than 1 year old. there must be at least 7 days between 2 injections in those patients. renal function must always be determined by laboratory methods before use of high-risk agents. women should stop lactation for 24 hours. these agents should never be given at doses higher than 0.1 mmol/kg per examination in any patient. for the intermediate and low-risk agents, the restrictions are significantly less; they should only be used with caution in patients with severely reduced renal function including dialysis. if a physician does not follow these rules, he or she will have legal problems as they have been introduced into the spc by the authorities. the contrast media safety committee (cmsc) of the esur has updated its guidelines on contrast medium-induced nephropathy (cin). the acr recently updated its guidelines as well. new guidelines were produced by nephrological societies. the topics reviewed include the definition of cin, the choice of contrast medium, and the prophylactic measures used to reduce the incidence of cin. the cmsc considered it appropriate to keep the definition of cin that was agreed in 1999. however, nephrologists have recently agreed on a new definition. in the previous guideline, a number of risk factors were listed (raised s-creatinine levels, particularly secondary to diabetic nephropathy, dehydration, congestive heart failure, age over 70 years, concurrent administration of nephrotoxic drugs). the significance of these risk factors has been confirmed and new risk factors were added. the cmsc agreed that the risk of cin was significantly lower following intravenous cm administration and concluded that patients referred for enhanced ct were genuinely at risk if they had an egfr < 45 ml/min/1.73m 2 . the previous cmsc guideline suggested the use of low or iso-osmolar cm in patients with risk factors for cin and the cmsc considered that this previous guideline should not be changed. the cmsc considered that there was enough evidence to recommend that either volume expansion with isotonic saline or sodium bicarbonate may be used for preventing cin in at-risk patients, while the efficacy of nac and other drugs in reducing the incidence of cin remained unproven. guidelines produced by other societies provide very similar suggestions, thus further validating these recommendations. jia is the most common rheumatic entity in childhood and includes a subset of childhood arthritis, all of which are characterised by chronic synovitis with a potential risk of progressive joint destruction. radiological investigations in jia should ideally be able to determine the presence and degree of active inflammation, precursors of bony destructions and established erosions. however, there are many pitfalls in the interpretation of joint pathology in children. ultrasonography is often the initial tool in the assessment of arthritis and can depict joint fluid and synovitis. erosions and cartilage destruction of small joints may also be seen. the major problems are standardising the imaging technique and the lack of normal standards of anatomy in us in children. radiographs can show bone erosions and may depict cartilage loss indirectly through joint space narrowing, but are insensitive to inflammation and early joint destruction. mri is the only imaging modality that can assess all relevant anatomical structures in joint inflammation and is sensitive to early inflammation and destruction. however, large variations in the amount of joint fluid, bone marrow oedema-like lesions and changes resembling erosions are seen in children and also in healthy individuals. the differentiation between true pathology and normal findings on mri in children remains a challenge, particularly in early disease. in this lecture, the role of radiographs, ultrasound and mri and the typical radiological findings in joint pathology in jia will be presented. current knowledge on validity and reliability of the different imaging techniques in jia will be discussed. brain mri plays an important role in those criteria, as it can demonstrate the classical dissemination in time and space and helps earlier diagnosis, which is of major importance since the present recommendation in children is to start immunomodulating treatments as soon as diagnosis is established. among paediatric ms, 14% begin before the age of 6 years and 30% before the age of 10 years, frequently with an adem presentation in young children as initial manifestation of ms. however, only 20% of the adem indicate ms onset and the most predictive factors should be known, i.e. periventricular, deep white matter, corpus callosum high t2 signal lesions and black holes on t1 sequences. mri evaluation is also instrumental in differential diagnoses such as nonrelapsing adem, vasculitis, immunogenetic diseases and occasionally leukodystrophies. finally, brain mri is useful to evaluate the risk of more severe ms. the obesity epidemic represents one of the most significant european and public health challenges in the 2 1 st century with prevalence of the disease having tripled in many countries during the past 30 years. this is resulting in an ever increasing cost to healthcare systems including hospital and in particular radiology services which face unique challenges when imaging this group of patients. obesity significantly increases the patient's risk of various comorbid diseases including the incidence of cancer, diabetes, and cardiovascular and liver pathology with a multidisciplinary team approach mandatory for optimal patient care. this multidisciplinary symposium will review the implications of the epidemic with cutting edge, in-depth lectures presented by european experts addressing the epidemiology, role of imaging in the bariatric surgical patient as well as the importance of abnormal fat deposition in the liver. session objectives: 1. to learn about the impact of the obesity epidemic on european healthcare. 2. to appreciate the value of imaging techniques in the management of the post-operative bariatric patient. 3. to understand the role of radiology in fatty liver disease and the importance of imaging during subsequent patient surveillance. obesity: causes and consequences to the patient r. batterham; london/uk (r.batterham@ucl.ac.uk) obesity is one of the greatest 2 1 st century public health challenges. its prevalence has tripled in many european union (eu) countries since the 1980s. currently, 52% of eu adult population is overweight and 17% obese, and the numbers of those affected continue to rise. overweight and obesity are risk factors for numerous health problems, including hypertension, diabetes, cardiovascular diseases, respiratory problems, musculoskeletal diseases and some forms of cancer. mortality also increases sharply once the overweight threshold is crossed. because obesity is associated with higher risks of chronic illnesses, it is linked to significant additional health care costs and is already responsible for 2-8% of health costs. changes in our environment are the main driver for this increase in overweight/obese. however, a person's genetic make-up can either increase or decrease their chances of becoming overweight. the gastrointestinal tract is the body's largest endocrine organ producing hormones that regulate bodyweight. dietary modifications, such as caloric restriction, are the first-line obesity treatments. however, dieting produces only moderate weight-loss with poor weight-loss maintenance. compensatory gut hormone changes induced by dieting are thought to contribute to the failure of dieting. in contrast, bariatric surgery is an efficacious treatment modality for obesity, producing durable weight-loss, amelioration of obesity-associated co-morbidities and reduced mortality. consequently, the number of bariatric procedures undertaken within europe has doubled in the last 5 years with 112,000 procedures undertaken in 2011. there is increasing evidence that surgically-induced alterations in circulating gut hormones mediate the weight-loss and metabolic beneficial effects of bariatric surgery. learning objectives: 1. to understand the epidemiology of obesity and its impact on european healthcare provision. 2. to appreciate the aetiology of obesity and the scientific rational for surgical treatment. 3 . to learn about the effects of obesity on health. imaging of modern surgical procedures and their complications m. rengo; latina/ it (marco.rengo@gmail.com) we will illustrate the common bariatric procedures, in particular their normal appearance on different diagnostic technique as well as their early and late complications. we will illustrate the correlation between conventional barium studies and advanced imaging with mdct and mr. we will explain how to optimise mdct and mr acquisition protocol according to the clinical indication. we will explain what to evaluate before redo surgery, in particular quantitative and functional analysis. we will illustrate the role of interventional radiology in the management of early postoperative complications, in particular in the management of patients subjected to gastric banding. non-alcoholic fatty liver disease comprises a variety of pathological disorders ranging from simple steatosis to steatohepatitis. this condition is common in the western population and is typically associated with obesity and the metabolic syndrome. its incidence increases dramatically. diagnosis of fatty liver and distinction between simple steatosis and steatohepatitis are keys because the latter can lead to extensive fibrosis and cirrhosis with an increased risk of hepatocellular carcinoma (hcc). imaging plays a crucial role in diagnosing fatty liver. the two most important imaging modalities are ultrasound and mr imaging. ultrasound can exclude major steatosis but lacks accuracy to precisely quantify fat, while mr is the most accurate for quantification. the technique of reference is mr spectroscopy, but sophisticated sequences based on chemical shift principle have been shown as accurate as mr spectroscopy. unfortunately, imaging has still limitations to assess the presence of fibrosis and inflammation which are associated with steatohepatitis and functional tools could be of interest. today, imaging is combined with clinical and biological biomarkers to evaluate the risk of steatohepatitis. due to the increased risk of hcc and cirrhosis-related complications in patients with steatohepatitis, patients at risk should be enrolled in the surveillance programme. learning objectives: 1. to understand the pathophysiology of fatty liver disease and its link to cirrhosis. 2. to become familiar with the role of imaging in the detection and quantification of fat in the liver. 3 . to learn about the importance of imaging in the surveillance of patients with fatty liver disease. the concept of breast cancer units originates from the need for making available to all women in europe high-quality breast services where breast disease could be looked after by specialists working as teams. such teams have to provide all the services related to breast cancer, including genetics and prevention, treatment of the primary tumour, care of advanced disease, palliation and follow-up of previously treated women. the breast unit is made up of a group of dedicated breast cancer specialists including a radiologist, radiographer, surgeon, reconstructive surgeon, pathologist, medical oncologist, radiation oncologist and breast care nurse. the specialists involved in breast cancer units have access to all the facilities required for high-quality care and spend most of their working time dealing with breast cancer. in our hospital, we routinely work as a team and to make it possible we organise weekly meetings involving specialists from different disciplines to evaluate and plan patient care at any step of the diagnostic and therapeutic process. each year, we take care of about 1.500 newly diagnosed patients with primary breast cancer and of 10.000 patients in follow-up. about 500 are patients who undergo rt. after a short introduction from our fellows from pathology, surgery, oncology and radiation therapy, who will discuss their role in the breast unit, we will try to give a practical demonstration of the everyday work of breast units with particular emphasis on the role of the radiologist. the european society of urogenital radiology (esur) published, in 2012, the new clinical guidelines for evaluation of the multi-parametric mri of the prostate. this structured reporting/scoring system (pi-rads) is based on literary evidence and consensus of experts' opinions. the pi-rads scoring system is similar to that already employed by breast imaging (bi-rads) and reflects the probability of a prostatic lesion to be significant. each lesion can be scored in all sequences used in the multi-parametric prostate mri protocols (t2-and diffusion weighted imaging, dynamic contrast enhanced imaging and mr spectroscopy) based on defined mri criteria, which are specific for each sequence. based on the scoring in the particular sequences a final pi-rads score for each lesion can be assessed. for each lesion a five-grade scoring systems was created where, for example, the score 1 means that clinically significant disease is highly unlikely to be present and score 5 clinically significant disease is highly likely to be present. this lecture elucidates the principles of this scoring system and its impact on the target definition for the invasive diagnostics and therapy. prostate cancer screening with psa and extended systematic biopsy protocols have led to the over-detection and over-treatment of small and well differentiated cancers, considered clinically insignificant. these cancers cover up to 70% of the overall prevalence and may not be of any threat. multiparametric (mp)-mri has shown recently its value in the detection, localisation and characterisation of prostatic tumour foci larger than 0.2 cm, and may be of value to address the issue of over-detection and over-treatment. an mri-targeted biopsy strategy alone, without any additional systematic biopsies, has been suggested to decrease the detection rate of insignificant tumours while increasing that of potentially aggressive tumours. in patients with no evidence of lesion on mp-mri, the biopsy may probably be deferred. in patients with localised prostate cancer, mp-mri may also become a cornerstone in the selection, guidance and surveillance of patients managed with focal therapy. the rational for this new modality of treatment is to decrease over-treatment by destroying exclusively the index lesion detected on mp-mri. the precision of such treatments may be increased with mritransrectal ultrasound image fusion, allowing for real time navigation during the procedure. the accuracy of multiparametric mri has greatly improved the ability of localising tumour foci of prostate cancer. this property can be used to perform a trus-mr image registration, a new technological advance, which allows for an overlay of an mri onto a trus image to target a prostate biopsy towards a suspicious area. three types of registrations have been developed: cognitivebased, sensor-based and organ-based registration. cognitive registration consists of aiming at a suspicious area during biopsy with the knowledge of the lesion location identified on multiparametric mri. sensor-based registration consists of tracking in real time the trus probe with a magnetic device, achieving a global positioning system which overlays in real time prostate image on both modalities. its main limitation is that it does not take into account prostate and patient motion during biopsy two systems (artemis and uronav) have been developed to partially circumvent this drawback. organbased registration (koelis) does not aim at tracking the trus probe, but the prostate itself to compute in a 3d acquisition the trus prostate shape, allowing for a registration with the corresponding 3d mri shape. this system is not limited by prostate/patient motion and allows for a deformation of the organ during registration. the pros and cons of each technique and the rationale for a targeted-biopsy only policy are discussed. radiotherapy of the prostate typically takes the form of either external beam radiotherapy or alternatively, brachytherapy using radioactive seed implants. in both cases, the use of ultrasound has been proven to be highly useful and this presentation will give an current state of the art overview of ultrasound in external beam and radioactive seed radiotherapy. in the case of external beam radiotherapy, accurate localisation of the prostate is essential to ensure adequate target coverage with minimal damage to normal tissue. dedicated ultrasound scanners are able to provide sub millimeter localisation of the prostate superior to the imaging traditionally obtained using ct scanners. this positional information can be obtained daily. in addition, ultrasound allows the imaging of patients with metal hip implants which are normally difficult to image using ct. apart from the benefits of the technique, some pitfalls will also be highlighted. in the case of prostate brachytherapy, the use of ultrasound in the 3-d volume imaging of the prostate both prior and during treatment will be discussed. in both cases, some time will be spend discussing the quality assurance requirements for ultrasound imaging systems. image-guided radiation therapy (igrt) with onboard kilovoltage cone-beam ct (cbct) allows image guidance during radiotherapy treatments for patient setup and dose replanning. all these items will be discussed in connection with other topics: organ dose and image quality. it is compulsory to convert cbctimage's pixels from arbitrary grey scale to hounsfield unit (hu). this conversion was obtained using a catphan 600 phantom. the same phantom is used for image quality evaluation; standard ctdi head and body phantoms and a farmer chamber were used to measure the cbdi to estimate organ and effective doses by monte carlo software of different protocols of acquisition. ctdosimetry software (ver.1.0.4-impact) and pcxmc2.0 rotation software were used. to verify the dose replanning techniques by cbct, horizontal and vertical dose profiles were compared with the same obtained from ct. patient replanning was verified using cbct vs ct in terms of conformity index. image quality parameters of cbct (in comparison with ct images) are fine for spatial resolution, but are less useful for low contrast. cbdi of 5.7 mgy/100 mas was measured; 4 msv effective dose, 26 mgy prostate dose and 32 mgy bladder dose were evaluated and discussed during the presentation. replanning on cylindrical phantom shows a mean percentage difference for each profile 2% and a variation on d mean in all inserts < 3%. the mean percentage difference between parameters characterising ct and cbct-based plan values is less than 5%. the replanning showed a substantial agreement with doses evaluated on the reference ct-image; patient dose must be evaluated for all radiation sources. cranial nerves i-vi have an anteroposterior course and are best examined in the coronal plane. cranial nerves vii-xii run in an anterolateral direction and are therefore best examined in the axial plane. these two planes also allow left-right comparison which makes lesion detection easier. lesions involving the cranial nerve nuclei can be detected on axial proton-density/t2/multi-echo-ge images and diffusion-weighted images can exclude acute infarction. the cisternal segment of the cranial nerves is best detected on heavily t2-weighted images (drive/fiesta/3d-tse/ciss). at 3-tesla, 3d-sequences (e.g. b-ffe) can be used and it is often possible to cover the cisternal segments of all 12 cranial nerves. in the cavernous sinus, the cranial nerves can only be evaluated on coronal gadolinium-enhanced high-resolution t1-weighted images and similar axial images are needed to evaluate the nerves in the jugular foramen and hypoglossal canal. axial and coronal gd-enhanced highresolution t1-weighted with or without fat suppression are used to image the extracranial course of the cranial nerves. today, the tse-dixon sequences provide non-fatsat and fatsat images simultaneously, making cranial nerve imaging faster and easier. time-of-flight images can be used to study neurovascular conflicts, although these can also be detected on submillimetric gd-enhanced t1 images. of course, it is important to know the major anatomy of the cranial nerves and the most frequently occurring lesions. the abovementioned imaging techniques, the most important anatomy and the most frequently occurring lesions will be demonstrated and discussed in this lecture. mri study of the lower neck space includes the study of anatomy and pathologies of the thoracic outlet, or cervicothoracobrachial junction, extending from the cervical spine and the mediastinum to the lower border of the pectoralis minor muscle, the brachial plexus and the supraaortic vessels (carotid, subclavian arteries and veins). for this, use of a dedicated head and neck coil is fundamental to avoid frequent artefacts arising from air and the passage between different surfaces. only in case of thoracic outlet evaluation, a dynamic angio-mri study should be performed and this means the use of a surface coil. mri protocol of the lower neck should include t1-and t2weighted sequences. both fat-saturated proton density and t2 with stir sequences can be used to overcome the inhomogeneity of the magnetic field, especially with large fov. sand bags can be placed on either side of the neck and suprascapular region of the patient to improve image quality. also, flow saturation bands can be utilised to limit blood flow artefacts. also, volumetric sequences are in common use to obtain a quick examination. breath or cardiac gating can be helpful. abnormal findings of brachial plexus consist of nerve signal abnormalities with mild or marked hyperintensity on t2-weighted, being aware of magic angle effects and swelling. in case of thoracic outlet syndrome, mri protocol should define the compression of brachial plexus components arteries and or veins, both in indifferent and dynamic mri acquisition. learning objectives: 1. to learn how to overcome difficulties in performing a lower neck study. 2. to understand how to avoid the most common pitfalls. 3. to become familiar with differential diagnosis. c. ct and mri of temporal bone: user's guide f. veillon; strasbourg/fr ct and mr imaging of the temporal bone must be performed with a precise technique. in ct it is important to locate the box of the study above and not in the orbit to avoid the lenses. irradiation is divided by 10 compared with a study through the orbit. the axial sections must be parallel to the lateral semicircular canal the coronal, sagittal sections are completed by oblique coronal views through the long process of the incus and the head of the malleus to get the ossicular v. double oblique sections through the 2 componants of the v permit a view of the stapes and also the malleus and incus in 3 d (mip : 3 mm). mri must be performed parallel to the roof of the orbit permiting very good axial sections in the plane of the lateral semicircular canal (t1 and t2). the internal auditory meatus and the inner ear must be analysed with 1 mm axial sections (se) after intravenous gadolinium injection completed by a high resolution t2 (gradient echo or se) 0.3-0.4 mm, depending on the machine (3t, 1,5 t). the middle ear in chronic otitis media must be studied with t1, diffusion and high resolution t2. there is no need of contrast medium injection apart from the complication: fistula of the lateral semicircular canal, thrombosis of the sigmoid sinus. the different pathologies are then discussed: external auditory meatus and middle ear pathologies: ct first. mri is useful for postoperative cholesteatomas. inner ear malformations, otosclerosis, trauma: ct. labyrinthitis, inner ear hemorragia, schwannomas, internal auditory canal content: mri. revascularisation time windows for patients with acute ischemic stroke are generally restricted up to 4.5 hours in the anterior and up to 8 hours is the posterior perfusion area. later treatment attempts require more accurate prediction of risk and benefit, as safety and efficacy at these time strata are less well. thus, rapid and effective imaging is important for decision-making concerning intrarterial catheter based recanalisation and/or thrombolytic therapy. advanced imaging techniques identify irreversible infarction as well as tissue at risk. diffusion-weighted mri detects ischemia within minutes of onset, whereas perfusion-weighted mri and ct perfusion studies disclose the ischemic penumbra. combined, they provide information on mismatched tissue, i.e. potentially salvageable brain. in addition, non-catheter angiographic techniques like ct or mr angiography are a useful adjunct to localise arterial occlusion. as an attempt to a reliable emergency examination, the following protocol has been proven to be robust: for the anterior perfusion area, a non contrast ct may exclude cerebral bleeding and is followed by ct angiography (including supraaortic and intracranial vasculature). if technical available, ct perfusion should be performed in addition. in ischaemic strokes of the vertrebrobasilar region, cta is essential to exclude basilary stenoses or thrombotic occlusion. if the stroke onset remains unclear or might extend the above mentioned time window, mr stroke imaging (i.e. diffusion, flair and perfusion sequences) is suggested as mr offers a higher sensitivity. anyway, the best method for each emergency stroke imaging center is depending on clinical availability 24h/365 days, technical equipment and -finally -individual experience of the emergency team. some recent publications have questioned interventional treatment of stroke as an alternative to iv thrombolysis only. these papers -albeit published in highranking sources -usually do not describe the modern concepts of interventional stroke treatment. interventional radiologists, therefore, are convinced by their practical experience that the modern concept of combining iv thrombolysis with mechanical thrombectomy by stent retrievers offers a benefit to a subgroup of patients with severe stroke. this includes anatomical level of occlusion -basilar artery or single vertebral artery, proximal carotid occlusion with distal tandem occlusion, carotid t obstruction and m1 occlusion. m2 occlusions are debatable. besides location, the clinical status of the patient before stroke and time of onset, absence of early ct signs of stroke or bleeding and clinical contraindications to iv thrombolysis such as recent surgery influence the decision-making. more difficult than the description of technical success is prediction of clinical success. there are a couple of scores such as thrive available that may be used for outcome forecasting. the amount of collateral flow is frequently used as a decision tool, but is not always easy to quantify. mismatch scores and penumbra have been questioned recently. in conclusion, anatomical factors are pretty easy to identify to indicate treatment, but the clinical and functional setting still lacks quick and reliable parameters that allow a clear decision-making, particulary in borderline cases. the refresher course addresses the current state-of the-art use of different mechanical revascularisation strategies, devices and potential complications. in addition, multimodal imaging applications with a focus on patient selection for endovascular recanalisation therapies, as well as new techniques to guide endovascular therapy within the angio suite are presented. finally, some organisational aspects important for providing an interdisciplinary interventional stroke service are discussed. the ultimate goal of an acute endovascular stroke intervention is neurological recovery or improvement. recanalisation of an arterial occlusion is key in achieving this goal. clinical data suggest that endovascular stroke treatment results in higher recanalisation rates and may provide superior clinical outcomes when compared with intravenous thrombolytic therapy only. however, these higher recanalisation rates are far away in being paralleled by equally higher rates of favourable outcomes in recanalised patients. thus, patient selection remains crucial. besides the careful neurological assessment, brain imaging is here of major importance. the case presentations illustrate that imaging may help in patient selection for subsequent thrombolytic/endovascular therapies by differentiation of patients who may profit from intravenous or interventional therapy in an even extended time window from those who do not. there are a number of key areas supported by evidence-based medicine necessary for a high-level interventional stroke service. as a precondition, a neurointerventional stroke service has to be organised within a multidisciplinary acute stroke team. inside the hospital, it is all about streamlined pathways. any possible delays should be minimised at every step. sacroiliac joint pain may arise from a number of conditions including inflammatory arthritis, degeneration, fractures and tumours. studies suggest a prevalence of 10% to 60% pain arising from the joint in patients with positive clinical signs. temporary effect is provided by a mixture of local anaesthetics with steroids with a response varying between 50% and 80% in reported series. dual blocks using agents of differing duration are considered more precise, but are less often used in practice. imaging including mr and scintigraphy are of limited predictive value. injections may be into the synovial joint, around the joint or adjacent to the nerve innervation of the joint. there is evidence that para-articular sources of pain are common and injection outside the joint may be more effective. sl-joint injections are performed through a dorsal approach guided by ultrasound, fluoroscopy or low-dose ct. shortacting agents may have lasting benefit, but radiofrequency ablation has been employed in an attempt to obtain long-term response. the evidence for lasting therapeutic response to intra-articular or periarticular injection of steroids and conventional radiofrequency neurotomy is weak. there is fair evidence of longterm response to cooled radiofrequency neurotomy. facet joints account for 25-40% of all low back pain. they are affected by osteoarthritis, joint space narrowing, intra-articular vacuum phenomenon/fluid, osteophytes, synovial cyst and ligament hypertrophy. conservative therapy is initially proposed. percutaneous facet joint steroid infiltrations are minimally invasive procedures involving injection of corticosteroid with or without local anaesthetic inside the joint. they also can provide diagnostic verification of a certain facet joint acting as the pain source. the injectate usually contains a long-acting corticosteroid mixed with a local anaesthetic. sodium hyaluronate solutions or ozone were tested; however more and extensive studies are necessary. other options are either percutaneous ablation or surgical arthrodesis. fluoroscopy, computed tomography or magnetic resonance can be used for guidance. fluoroscopy has the advantage of real-time imaging. cone-beam ct can also be used. computed tomography provides better anatomy information, but has increased radiation dose for the patient. magnetic resonance has higher cost and longer duration. a recent study concluded that it is twice the cost of ct-guided infiltrations. mri can be used in combination with focal ultrasound for ablation, a technique which is still under investigation. success depends upon patient selection (59-94% immediate and 27-54% long-term relief). the level of evidence is moderate for lumbar spine concerning short-and long-term improvement. however, the most recent guidelines released (american society of pain physicians) state that it is the oldest and most commonly used technique. the success rates with its safety profile and least invasiveness seem to make it an attractive therapy. although promising for early assessment of response to treatment, these newer functional biomarkers need extensive validation and standardisation for their wide clinical use. validation includes the assessment of reproducibility and accuracy, whereas standardisation concerns image acquisition and postprocessing. the added value of the more complex functional biomarkers relative to the viability parameters should also be shown. viability and functional imaging biomarkers are evolving and emerging parameters for the early assessment of response to treatment. mri biomarkers must be able to show how tumours respond to specific treatment. they need to allow assessment of the effectiveness of new treatment more rapidly than classical clinical end points. these biomarkers must be easy to obtain to facilitate a large spread of the technique. they have to be reproducible. the longest diameter of the tumour remains the easiest biomarker that can be obtained from any kind of morphologic acquisition with no need of post-processing. additional information about the tissular organisation and cellularity can be now easily obtained using modern scanners through diffusion-weighted sequences. the ease with which those sequences are obtained for a while masked the necessity to perform a more complex postprocessing than the one initially done to get reliable biomarkers. there are numerous mri biomarkers of microcirculation, reflecting o2 consumption, blood volume, blood flow, vessel permeability and extravascular volume. to get them, we need more sophisticated acquisitions and image processing that take into account the t1 of the tissue, arterial input function, respiratory motion, etc. most of these new mri biomarkers are now used in research and in phase i studies, but have not been validated in more advanced clinical trials or in clinical practice. to use them widely and reliably, we need to perfectly understand the consequences of the choices we make during the acquisition and post-processing of these biomarkers. new targeted treatments in cancer can be effective without significantly reducing tumour size. there are already a large number of targeted treatments that are licensed to treat a range of cancers. for some of these cancers, there is currently no reliable method to tell whether the drug is effective and new response, predictive and prognostic biomarkers are required. functional imaging techniques such as diffusion-weighted mri, dynamic contrastenhanced mri and fdg-pet imaging are being developed or applied as response biomarkers. however, for these to be useful in a wider multi-centre setting, the measurements need to be precise, repeatable and reproducible. we discuss these properties in the context of emerging imaging response biomarkers. learning objectives: 1. to understand imaging biomarker precision (repeatability and reproducibility) and accuracy and how it is evaluated. 2. to learn how to interpret biomarker precision and accuracy in the context of the biomarker's intended use. coronary artery disease (cad) and its related cardiac disorders are still the number one cause of death in the usa and the western world. up to date, single photon computed tomography (spect) using traditional radiotracers like thallium-201 or tc-99m sestamibi is the most utilised imaging technique for the assessment of myocardial perfusion. however, over the past decade, there has been a growing interest in cardiac imaging with positron emission tomography (pet) and, indeed, a paradigm shift has been witnessed in the use of myocardial perfusion imaging (mpi) with pet taking advantage of the superior imaging properties of pet over spect. therefore, pet mpi is now being increasingly used for routine clinical evaluation of patients with known or suspected cad. furthermore, it is being used not only at large academic institutions, but also at community hospitals and even in private practice. several factors contribute to this shift in the use of pet mpi, including the growing availability of combined pet and computed tomography (ct) systems, mainly driven by oncological applications, radiotracer, like rubidium-82 or 18 fflurpiridaz, which can be used in clinical routine, changes in reimbursement, and the increasing clinical evidence supporting the value of pet/ct mpi. the lecture "pet for evaluation of perfusion, absolute myocardial blood flow and coronary flow reserve" will cover several aspects of the growing field of pet mpi. besides the visualisation of coronary morphology, computed tomography (ct) has shown feasibility to also assess myocardial perfusion. currently, there are two different approaches to ct-based myocardial perfusion imaging: singleshot and dynamic, sequential acquisitions over a predefined scan time. the presentation will cover basic concepts of both approaches and highlight protocol details and findings in these stress acquisitions. also, emerging scientific results with respect to diagnostic accuracy, the detection of hemodynamically relevant coronary stenosis and prognostic implications will be discussed. over the past few years, cardiovascular magnetic resonance imaging (cmr) has been increasingly established as an important method in the diagnosis of cardiovascular disease. many studies have shown the equality or even superiority of cmr compared to other imaging modalities (e.g. nuclear medicine and echocardiography). cmr offers important advantages like the absence of ionising radiation, high spatial resolution, and the combination of perfusion imaging with tissue characterisation. the main clinical applications in the assessment of coronary artery disease (cad) include ventricular function, myocardial viability and perfusion. in clinical routine, myocardial perfusion is determined by contrast-enhanced first-pass perfusion techniques during pharmacological stress using coronary vasodilators (e.g. adenosine) or ã�adrenergic agents (e.g. dobutamine). non-invasive characterisation of myocardial microcirculation is thought to reflect myocardial tissue supply much better than mere luminographic detection and quantification of epicardial coronary stenosis, and has been shown to be useful for planning of revascularisation procedures and cardiac risk stratification. in several studies on the prognostic value of cmr in cad assessment, normal stress perfusion cmr was highly predictive for a good prognosis, thus able to identify patients in whom invasive angiography can be deferred safely. the purpose of this lecture is to demonstrate how it is possible to sensitise the mr signal to water molecules diffusion in tissue and how to use calculated indices to reflect structural integrity. the concept of diffusion-weighted imaging will be introduced with particular emphasis on the pulsed gradient spin echo (pgse) sequence. methods to calculate the apparent diffusion coefficient (adc) will be described and the concept of the diffusion tensor (dt) will be explained. image processing of diffusion data includes steps like eddy current distortion correction, model fitting and potentially registration of maps to a reference space. indices that are reproducible and rotationally invariant will be described, such as fractional anisotropy (fa), mean diffusivity (md), axial diffusivity (ad) and radial diffusivity (rd). examples of when to use the adc maps or the dt indices will be given in relation to pathologies such as stroke, multiple sclerosis and neurodegenerative diseases. strategies for result presentation such as region of interest approach, histogram analysis and tractbased methods will be shown. limitations and advantages of diffusion imaging methods such as dt do not preclude the use of this technique in research and clinical radiology for investigating structural changes in disease. diffusion imaging methods have a lot of potential to be used in clinical practice. however, although diffusion-weighted imaging has been increasingly applied, clinical use of diffusion tensor imaging is limited to date. this is in part due to the lack of standardisation and the need for more complex analysis tools to evaluate the data. during this lecture, an overview will be provided of some analysis methods for diffusion-weighted and tensor imaging. i will discuss the different parameters that can be obtained as well as some advantages and limitations of the different analysis methods. it is highly recommended to include diffusion-weighted imaging (dwi) in the routine protocols for mri of the brain. dwi as well as automatically calculated apparent diffusion coefficient (adc) map is used for evaluation. the adc values of gray and white matter are identical in the adult brain. restricted diffusion (high signal on dwi and low signal on adc) is seen not only in acute stroke, but can also be present in some brain tumours, the necrotic centre of abscesses, some acute mr plaques, some contusions, encephalitis, creutzfeldt-jakob disease, metabolic diseases, etc. this finding is thus not specific, but is very helpful combined with clinical information and the signal pattern on other sequences. acute stroke has restricted diffusion during the first 7-10 days and the diffusion gradually increases to become very high in a chronic infarct. the diffusion changes in ischemic brain and spinal cord tissue are usually irreversible, but may be reversible. brain tumours with high cellularity, such as lymphoma, glioblastoma multiforme, medulloblastoma and metastases from small cell lung carcinoma, usually have restricted diffusion. the surrounding vasogenic oedema has increased diffusion. in the central necrosis of a pyogenic abscess the diffusion is restricted, while it is increased in the necrotic centre of a malignant brain tumour. reversible diffusion restriction in the cortex, the hippocampi and thalami can be seen in patients with status epilepticus. diffusion tensor imaging has so far had limited clinical use, but may be useful, e.g. for the preoperative evaluation of brain tumours. learning objectives: 1. to understand the differential diagnostic possibilities of high signal intensity lesions on diffusion weighted images (dwi) of the brain and spinal cord. 2. to become familiar with the appearance of acute, subacute and chronic stroke on dwi. 3. to learn about the appearance of cerebral tumours, infection/inflammation, neurodegenerative diseases and traumatic lesions on dwi. 4. to understand the present use of diffusion tensor imaging (dti) and diffusion tensor tractography (dtt) in clinical neuroradiology. the signal intensity in diffusion-weighted imaging (dwi) reflects the cell density in the tissue. dwi, including apparent diffusion coefficient (adc) maps, can therefore be used to differentiate highly cellular from acellular regions of tumours, distinguish cystic from solid lesions, and monitor change in tumour cellularity over time, reflecting response to therapy. in general, tumours have high signal intensities in dwi, but low corresponding adc values compared to normal/benign/reactive tissues. dwi has a wide range of clinical applications, which includes cancer imaging, imaging of infections and inflammations, evaluation of trauma and visualisation of peripheral nerves. of these, the most promising application appears to be in oncological imaging. there is, e.g. now evidence to recommend inclusion of dwi in mri protocols for lesion detection and characterisation in the liver. the advent of whole body (wb) mri including wb-dwi (from root of the neck to groin) has introduced tumour imaging with a systemic approach compared to established multi-modal diagnostic algorithms. it has been found valuable for staging, therapy evaluation and surveillance of tumours, especially in children. however, dwi is generally recommended to be incorporated into oncologic mri protocols of both wb-mri and of selected organs, because it provides additional valuable information to the conventional mr sequences. dwi of the body is frequently prone to imaging artefacts, which can obscure or mimic lesions. to minimise misinterpretations, analysis of the raw b-value images directly in conjunction with adc maps and conventional coregistered sequences is recommended. spinal surgery is most frequently performed to decompress (disc herniation, stenosis, malignant infiltration), fuse and stabilise (particularly following trauma or infiltrative destructive processes) and correct deformity. often, there may be a combination of these procedures at one operation. surgical instrumentation or bone graft is sometimes employed. patients may present themselves with symptoms early or late following the procedure. this interactive session seeks to address the variety of surgical procedures undertaken and subsequently imaged post-operatively because of symptoms. the session aims to help one to understand and become familiar with the expected post-operative imaging appearances related to the surgical procedure, learn about abnormal pathological features as a cause of symptoms in the acute and more chronic situation and explore the diagnosis and differential diagnosis. this may include post-operative fibrosis versus recurrent disc herniation versus post-operative infection. failure of fusion due to failure of instrumentation or inadequate take of bone graft can give rise to pseudoarthrosis. recurrent stenotic symptoms may relate to an inadequate decompression, recurrent disc herniation, postoperative haematoma, extension of a malignant process or ischaemic damage. joint replacement surgery for the treatment of arthritis most often offers the patient excellent results. however, there are potential complications that a radiologist should know about. it is essential to understand the importance of pre-and postoperative imaging for evaluating patients. most commonly, standard radiographs are used to assess the patients after joint replacement. however, ct, nuclear medicine methods as well as mr imaging play an increasing role in such patients. the radiologist should be aware of the most common type of prosthesis and the most common complications after joint replacement. these complications include postoperative prosthesis loosening, prosthesis fractures, periprosthetic fractures, postoperative infection, rotation failure of the prosthesis, and soft tissue abnormalities such as surrounding tendon tears. this interactive session seeks to address the variety of joint replacements which are undertaken and subsequently imaged postoperatively as a result of symptoms. the session aims to help one to understand and become familiar with the expected postoperative imaging appearances related to joint replacement, learn about abnormal pathological features as a cause of symptoms and explore the diagnosis and differential diagnosis. learning objectives: 1. to learn about changes related to surgery. 2. to understand changes related to non-surgical treatments. serbia is a beautiful country where east and west merged and often collided for centuries, and where nowadays eastern cultural heritage meets and mixes with the western heritage in a lovely and unprecedented way, with a lot of charm and with a variety of extraordinarily natural beauty and plenty of both traditional and gastronomical wonders to explore. it extends from the edges of the pannonian flatland in the north, over the danube and sava rivers to the gradually growing wonderful mountains in the south. already in 1897, the first x-ray unit was installed, and only twenty years later x-ray units are present in most state-owned and private hospitals in serbia. nowadays, slightly more than half of the thousand radiologists in serbia perform a broad variety of diagnostic imaging and interventional techniques in different radiological units, including numerous ct, mri, and few pet/ct units distributed in five university centers, a number of public clinical centers and hospitals, and also in the private sector. several centers are fully equipped with pacs and ris systems, and are capable of performing teleradiology services. there are still significant challenges in serbian radiology in the field of education and research, planning and implementation of national radiology networks, improvement of standard clinical practice and financing the new equipment. yet since radiologists' enthusiasm overwhelms most of the difficulties, radiology in serbia provides nowadays a broad variety of modern and competent diagnostic and interventional procedures, improving the management and treatment of our patients. radiology in serbia, since its beginning, has been inextricably linked to european radiology. there are written documents testifying to the fact that the first x-ray appliances in serbia had emerged and had been used for medical purposes only two years after wilhelm conrad rã¶ntgen discovered x-rays in 1895. the real beginnings of diagnostic radiology in serbia can be linked to the establishment of the general state hospital in 1908, where the first x-ray cabinet was installed. later discoveries in the field of radiological techniques, materials and contrast agents were also immediately accepted by the serbian radiology community. the first cerebral angiography was performed in 1935, which may be considered as the beginning of neuroradiology in serbia. the second half of the twentieth century is characterised by the introduction and wide application of ultrasound, ct and mr diagnostics and outbreak of vascular and nonvascular interventional radiology procedures in the areas of neuroradiology, uroradiology, and cardiovascular and gastrointestinal radiology. for years, serbian interventional radiology has successfully kept pace with achievements of the most relevant centres worldwide. nowadays, serbian radiologists monitor and enforce the most complex modern procedures in different areas of radiology. the rapid development of science and information technology has enabled the daily monitoring of all modern developments, methods and approaches and their increasingly faster introduction into practice. non-ischaemic cardiomyopathies (nicm) refer to myocardial diseases caused by mechanical and/or electrical disorder in the absence of significant coronary artery disease, valvular heart disease, hypertension, or congenital heart disease. nicm often present with genetic mutations, but no clinically apparent disease. in some cases, the presence of fibrotic tissue could cause adverse events and, therefore, the use of late enhancement (le) post-gadolinium technique is necessary in evaluating these patients. le suggestive of fibrotic tissue could be found in up to 35% of patients with nicm. in the majority of cases (up to 65%), midwall/subepicardial enhancement could be found; patchy enhancement, often at septal junctions, has been registered in 35% of patients, while the least common pattern of le was subendocardial (5%). in ischaemic cardiomyopathy (icm), subendocardial or transmural is a typical pattern of hyperenhancement and is related to coronary artery distribution. furthermore, le has the potential to provide important information for risk stratification in clinical practice. in nicm, the extent of fibrosis has been shown to be independently associated with increased rates of future adverse events including all-cause mortality, while in icm myocardium with le in more than 50% of wall thickness is unlikely to recover contractile function following coronary revascularisation. as many nicm disorders are associated with the presence of scar tissue, le in nicm is nonspecific and should be correlated with clinical presentation and history, which is critical in the evaluation of these patients. interlude: hop-on, hop-off sightseeing tour of serbia s. stojanovic; novi sad/ rs (tupsons@gmail.com) in the interlude between scientific lectures, you are most welcome to hop on a sightseeing tour around serbia during which we shall stop at a few stations where the natural and cultural heritage of our country will be shown. nota bene: some of the sights will be visible to everyone and some only to radiologists. ten thousand years of human effort and five billion years of european soil refinement will blink in front of your eyes through the window we have made with red churches' walls, azure skies and a silver sparkle of our spirit. all the time, a bit of grayscale shadow will supplement the picture as we in radiology are so used to. fragments of past and present will make a mosaic, the glance of which will hopefully light up your day. when you hop off our tour, we believe, some pictures will become part of your emotional memory and maybe will make you wish to see them in vivo. the role of prenatal mri in foetal central nervous system abnormalities: a case-based pictorial review k. koprivsek; sremska kamenica/rs (katarina.koprivsek@gmail.com) mri provides a unique opportunity for studying in vivo central nervous system development. its higher contrast resolution compared with prenatal sonography allows better visualisation of sonographically occult normal cns structures as well as structural abnormalities. in clinical praxis, prenatal mri has become a mandatory tool in evaluating: a) foetuses that have abnormalities suspected on the basis of foetal sonography; b) foetuses with increased risk for brain abnormalities even in the setting of a normal prenatal sonogram (family history of cns anomalies or a genetic/metabolic disorder); c) foetuses potentially at risk due to maternal illness; d) foetuses with congenital malformation, which are candidates for prenatal or neonatal surgical treatment; e) foetuses that could not be evaluated by sonography due to oligohydroamnion, maternal obesity, difficult position of the foetal head, or us reverberation on foetal calvaria in advanced gestational age. we will present a selection of foetal cns abnormalities detected in our institution during the last 8 years, including ventriculomegaly, abnormalities of the posterior fossa, agenesis of the corpus callosum, cerebral cortex developmental abnormalities, spine developmental abnormalities and a variety of encephaloclastic lesions. in all previously listed cases, prenatal mri could provide either crucial or additional information, which can lead to the accurate diagnosis of different cns developmental abnormalities (cortical, commissural and posterior fossa malformation), specific disorder or syndrome, further enabling adequate pregnancy management and parents' counselling. this lecture will cover the standard mammographic views required, the reporting systems for mammograms together with birads and other european systems, breast density, feature analysis, information the clinician requires in a cancer case and how to approach a b3 lesion. acr practice guidelines (2008) recommend obtaining previous mammograms as you can dismiss an abnormality that is unchanged for 5 years or that has been previously worked up and are able to detect subtle new lesions more easily, although this has not been confirmed in the screening situation. in a structured report the following information is recommended: indication, breast density, description of lesion, size, location, comparison to previous findings, overall assessment, management recommendations and a score to indicate the level of suspicion. examples of different common conditions seen on mammography will be shown including soft tissue masses, microcalcification, architectural distortion and asymmetry. breast ultrasound is one of the main imaging modalities in breast radiology, it allows us to characterise lesions and also guide interventional procedures. the bi-rads categorisation of ultrasonographic findings facilitates the diagnostic approach and also helps the radiologist to use a common language, understood not only by the rest of the radiological community, but also by other breast cancer professionals. ultrasound can be a diagnostic procedure on its own, but is mainly a modality that characterises the findings of other modalities (mammography and mri) and, as such, correlation between all these techniques is the mainstay of everyday clinical practice. this act of correlating and integrating the information of all modalities is what makes a breast radiologist a key actor in the diagnosis, staging and follow-up of breast cancer and other benign or high-risk entities. the final product of this integration will be the radiological report, the means by which we convey all the information we have gathered through all the procedures to our clinical colleagues. this report shall also follow some composition rules to be clear and concise. as with any other modalities, breast magnetic resonance imaging (mri) examinations should be reported in a structured way following the guidelines of the respective national, continental or international societies. adequate nonclinical information (i.e. patient name, date and type of examination, etc). is indispensable. any breast imaging report has to follow a stringent structure including indication, clinical history, clinical findings, brief description of technology used, assessment of parenchymal density, detailed description of significant findings, comparison with previous imaging studies and final assessment according to bi-rads. indications and contraindications of breast mri will be discussed. significant findings at breast mri include foci (small contrast-enhancing spot, nos, < 5 mm), mass lesions, "non-mass-like enhancement" (no mass lesion, partly diffuse regional contrast enhancement of various size) and associated findings. furthermore, as breast mri is a functional study, the different appearance patterns of kinetic contrast enhancement will be presented. the current status and the appropriate use of the bi-rads mri lexicon will be discussed. any breast mri report should not only follow the guidelines, but also follow a red thread, be consistent, express confidence and be comprehensible to clinicians. the overall final bi-rads assessment is based on the most worrisome finding, taking into account both breasts and all imaging methods (mammography, ultrasound, mri) evaluated. furthermore, adequate communication of the result, as well as do's and don'ts of the report wording will be discussed. the prostate is a small glandular organ, whose main function is to secrete seminal fluid. in young men it comprises of mainly the peripheral zone (70%) and a smaller central gland. however, the central gland enlarges with age to form the larger part. the main diseases of the prostate are inflammation, hyperplasia, and cancer (the most important). approximately 70% of cancers arise in the peripheral zone. the main applications of mri are for cancer detection, staging, and recurrence. mri is increasingly used for radiotherapy planning owing to its good soft-tissue contrast when compared with ct scanning. endo-rectal rf receiver coils, usually inflated with air or perfluorocarbon but sometimes of a rigid design, improve signal detection of the prostate. phased-array surface coils may also be used or (preferably) in combination. t1-weighted imaging helps to distinguish haemorrhage caused by biopsy. on t2-weighted images the peripheral zone appears brighter, owing to a larger proportion of prostatic ducts, while tumours generally appear darker. more sophisticated mr methods are increasingly used to help diagnosis. in diffusion-weighted images (dwi) tumours appear relatively bright, but dark in the corresponding calculated map of apparent diffusion coefficient (adc), owing to the more cellularly-dense nature of tumours, and hence, reduced diffusion. in dynamic contrast-enhanced mri (dce-mri) tumours appear bright owing to increased vasculature. magnetic resonance spectroscopic imaging (mrsi) of normal prostate is dominated by high levels of citrate from the prostatic ducts; in cancer this is reduced while choline is increased. prostatectomy samples allow one to verify image contrast against histology. recent studies on prostate cancer have provided a number of relevant targets for imaging and treatment purposes. today, imaging plays an important role in different aspects of the disease, but its role should grow in answering clinical questions at various phases of the disease. relevant targets for imaging include metabolites (including glucose, acetate, choline, and amino acids), antigens (including prostate-specific membrane antigen), receptors (grp receptor, cxcr4, androgen receptor), proliferation, angiogenesis, and hypoxia. in this presentation, a range of radiotracers for potential use in the imaging of prostate cancer will be discussed, as well as options to tailor nuclear imaging tracers to the various phases of the heterogeneous disease. the fusion of morphologic (ct and mri) and functional (pet, spect) imaging modalities (pet, spect) has become widely available and part of the standard diagnostic workup in cancer patients. for many years, neurosurgeons have already relied on multimodal imaging data during brain tumour surgery to identify hyper-or hypometabolic tissue. the availability of pet and spect data during percutaneous ablation procedures may also be helpful to facilitate treatment planning, probe placement, probe re-positioning, and early detection of residual disease following percutaneous image-guided ablation of cancer. however, up to now conventional us-and ct-guided thermal ablation procedures rely on morphologic information only. intraoperative implementation of multimodal data requires the application of frame-based or frameless stereotactic techniques, both relying on the establishment of an accurate relationship between the patient's preoperative image space and the intraoperative physical space. in image-guided neurosurgery, ct/mrt/spect/pet data are registered to the patient using rigid body transformation. due to respiratory motion and different patient positioning during image acquisition and the actual intervention, soft tissue deformations in the liver occur. thus, the images and the surgical presentation do not match between preoperative imaging and intervention, leading to an extensive degradation of spatial guidance. this presentation illustrates solutions for these fundamental problems that occur during 3d-navigated liver interventions, including patient immobilisation and repositioning, respiratory triggering and intraoperative imaging. r. bale: equipment support recipient; isys has supported the section of microinvasive therapy with testing equipment. patent holder; rb is a (co-) inventor of the atlas aiming device and the bodyfix immobilisation device and a (co-)shareholder in its financial returns. the goal of ultrasound-triggered, image-guided drug delivery is to increase the therapeutic index and decrease adverse effects of drugs. the bio-effects of focused ultrasound can lead to local tissue heating, cavitation, and radiation force, which can be used for 1) local drug release from nanocarriers circulating in the blood, 2) increased extravasation and cellular uptake of drugs and/or carriers, and 3) enhanced diffusivity of drugs. thermo-sensitive liposomes have been suggested for local drug release in combination with local hyperthermia more than 25 years ago. microbubbles may be designed to enhance cavitation effects. real-time imaging methods, such as magnetic resonance, as well as optical and ultrasound imaging have led to novel insights and methods for ultrasound-triggered drug delivery. image guidance of ultrasound can be used for: 1) target identification and characterisation; 2) spatio-temporal guidance of actions to release or activate the drugs and/or permeabilise membranes; 3) evaluation of biodistribution, pkpd; 4) physiological read-outs to evaluate the therapeutic efficacy. liposomes may carry both hydrophilic and hydrophobic drugs in their aqueous interior and lipid bilayer membrane, respectively. the circulation half-life may be increased by incorporating polyethylene glycol (peg)-lipids in the bilayer. recent publications have shown that ultrasound-triggered delivery is feasible. realtime imaging methods, such as magnetic resonance, optical and ultrasound imaging may lead to novel insights and methods for ultrasound-triggered drug delivery. up to now, the success of surgical tumour resection has always been limited by the surgeonâ´s vision. the human eye is not an accurate detector of small cancer cell clusters and it cannot accurately differentiate cancerous from healthy tissues due to lack of "visible" contrast. by combining a fluorescent probe targeting the folate receptor and a multi-spectral real-time fluorescence camera to observe the operating field, we found that, using fluorescence molecular imaging, 3-fold more lesions can be identified compared to conventional surgery. these first in-human results point to molecular-based clinical decision-making in surgical and endoscopic procedures as a paradigm shift over decision-making based on human vision. the talk describes current progress with instruments, methods and applications in the field of intraoperative imaging. pre-clinical and clinical results are presented and the advantages and limitations of the method as well as future directions will be discussed. the emerging field of multispectral optoacoustic tomography (msot) is also outlined. mysteries of the human brain unveiled: imaging of white matter microstructure and neuroplasticity p.m. parizel; antwerp/be (paul.parizel@uantwerpen.be) the human brain remains one of nature's great mysteries, and is considered science's final frontier. this greyish lump of tissue with a weight of 1.5 kg contains some 100 billion neurons, each of which are connected to thousands of other nerve cells in an intricate network of white matter fibers. in the previous century, the brain was perceived as a fixed three-dimensional landscape, with brain functions confined to certain locations (e.g. motor and sensory cortex, visual cortex, auditory cortex). this concept of neurolocalisationism was in line with the philosophy that there should be "a place for everything, and everything should be in its place". advanced quantitative mri techniques for acquisition and data analyis (fmri, dwi, dti, vbm), help to unravel white matter connectivity of the human brain, and are able to show that the brain can modify its structure and function in response to changing circumstances (such as learning, memory, hormones). this process, which is known as neuroplasticity, occurs at different levels and different time scales. for example, in response to injury, changes may occur at cellular level as well as on a larger scale with cortical remapping. some processes may take months or years (e.g. physical therapy and training) whereas some forms of neuroplasticity happen within hours or days (e.g. changes in brain volume and connectivity during the female menstrual cycle, which have been linked to behavioral changes). in summary, quantitative mri techniques help to unveil the mysteries of the human brain and have opened exciting new fields of active research such as white matter connectivity and neuroplasticity. there are a host of inflammatory and infective insults that can manifest focally or diffusely within the musculoskeletal system. the appearances of the underlying pathological processes in both the soft tissues and skeleton cover a very wide imaging spectrum. the appearances vary, depending on the timing and degree of inflammatory insult and the host response in the involved tissues. the approach of this lecture will cover the imaging manifestations using all modalities covering radiography, ultrasound, ct, scintigraphy and magnetic resonance imaging. the basic knowledge that is required will be displayed in 4 major musculoskeletal categories covering disorders involving the soft tissues, joints, bones and entheses. the imaging manifestations will also be linked with the evolution of the pathological processes covering acute, sub-acute and chronic stages of the inflammatory/infective disorders. by the end of the session the audience should have a clear understanding in making best use of the imaging modalities in the correct diagnosis of a wide variety of inflammatory and infective conditions that can affect the musculoskeletal system. arterial pta and stenting is firmly established as primary treatment in the management of athero-occlusive disease, particularly of peripheral limb arterial disease (pad). patients are selected on the basis of symptoms such as short distance claudication or critical limb ischaemia for lower limb disease or appropriate ischaemic symptoms in other territories in the renal and mesenteric territories and head and neck vessels. commonly used grading systems such as the fontaine or rutherford scores can be useful in patient selection. where treatment is required, noninvasive imaging is utilised to look for the site, severity and extent of arterial disease. most centers use duplex imaging as the primary imaging modality; mra or cta are often used with a higher sensitivity and specificity; and invasive angiography is reserved for problem solving or immediately prior to intervention. the tascii classification has been devised to select patients for either endovascular or surgical intervention. however, most centres will adopt an endovascular approach first. all patients should be on good medical therapy, i.e. aspirin and statins, with good blood pressure and diabetic control where appropriate. when carrying out interventions, an access sheath is used, peri-procedural heparin administered and lesions crossed using selective catheters and commonly hydrophilic guidewires. subintimal crossing of occlusions can be much simpler than trying to cross lesions luminally. balloon angioplasty and or stenting may be applied differently depending on the site and extent of the lesions. the evidence for drug-eluting technologies has also been growing with improved patency rates compared to standard balloon angioplasty. during the efrs meets russia session, radiographers have the opportunity to get information about the role and education of radiographers in the different european countries. the radiographer is a health-care team member who interacts with other professionals in the primary and secondary health-care environment to provide an optimum diagnostic or therapeutic outcome. radiographer education therefore requires that the curriculum covers a wide range of scientific, medical, pathological, sociological, ethical and technical subjects together with the development of appropriate clinical skills. the curriculum should also include the development of research and audit skills to ensure the constant improvement of service quality for the benefit of service users. the session will include a panel discussion about the role of the radiographer in image acquisition and processing. the tasks of the assistant to the radiologist are: filling of the protocol of research, survey of the patient, instructing the patient according to safety measures, positioning the patient, placement of coils of strengthening, beginning of magnetic and resonant research -the research is approved by the doctor, introduction of contrast substance (in the presence of the certificate of the procedural sister) and supervision over the patient during mr research. furthermore, the other tasks are briefing on patient safety, excluding introduction of the patient to metal objects on mr tomography, explaining the procedure of the study, informing about the duration of the study, wearing noise-cancelling headphones, warning about possible vibration and loud sounds, and providing a globular button to call the nurse. today coronary ct-angiography has become a well-established and proven diagnostic modality. quality of coronary and cardiac cta datasets has tremendous significance for correct diagnosis. a radiographer has a pivotal role in performance of coronary cta. coronary cta is one of the most challenging examinations for radiographers because even a small mistake at any stage of examination may ruin the whole study. before the scanning procedure, the radiographer performs a check for possible contraindications to contrast media injection (history of adverse reactions to contrast media and impairment of renal function are the most important ones). the radiographer checks the patient's heart rhythm and takes part in administration of betablockers for control of the heart rate. a detailed knowledge of different scanning modalities of ct-machine is a must. radiation exposure to the patient from coronary cta examinations has been one of the major public concerns. this is why the radiographer should be aware of different approaches to the performance of low-dose cta (prospective gating, tube current modulation, high-pitch scanning) according to patient body composition. the radiographer should have knowledge of when and how to use radiation dose control in an appropriate way. another big issue is injection protocols. selection of optimal bolus timing and iodine load results in highquality cta images. the radiographer has to know the basics of ct image reconstruction and interpretation in order to perform different types of reconstructions from the raw data according to the radiologist's requests and be able to recognise image artifacts. clinical examples of the radiographer's role for performance of coronary cta will be given. every country is famous for its architecture, history, literature, music, museums, etc. however, there are some distinctive features for russia. "russia is a riddle wrapped in a mystery inside an enigma." these words by the famous british statesman winston churchill aptly throws light on the pulsating art and culture of russia. the different aspects of russian art and culture find its best expression in the rich heritage. just feeling the nature and boundless expanses of the country can understand the mysterious russian soul, works of art and real masterpieces. cardiac mdct in children with congenital heart diseases v. bereznitskiy, k. serkova; moscow/ ru (vsber@mail.ru) in ct studies of children with congenital heart diseases, it is mandatory to keep the x-ray dose, amount of contrast agent and study time as low and as short as possible and simultaneously get the best diagnostic image quality. how can we reduce the x-ray dose? by minimising the volume coverage, reducing the voltage, minimising the effect of "overranging", use of x-ray protective equipment, use of tube current modulation technique, use of iterative reconstruction technique. how can we reduce the amount of contrast agent by volume? by covering of only necessary anatomic volume, minimising scanning time, use of adequate speed injection in ml/sec, which depends on catheter position and size, blood flow and anatomic structures. how can we reduce the amount of iodine concentration in the contrast agent? by lowering the voltage we may reduce the iodine concentration and get higher absorption ct values (hu). how can we reduce the time of cardiac ct studies? by preparing the study protocol ahead, preparing all necessary equipment in the ct room, warming up of the contrast agent before the study. what is the radiographer's role in cardiac ct studies? to take care along with the responsible radiologist the above-mentioned needs, to take care of adequate room and instrument temperature, to take care that only absolutely necessary people with adequate x-ray protection are in the study room, for performing the necessary image post-processing, archiving and distribution of studies. the purpose is to evaluate the quality of imaging in forced position of patients with anesthetic support. the role of laboratory technician in ct post processing. we analysed images of unconscious patients on artificial lung ventilation on 24-and 64-slice computer homographs ge and siemens and monitored them through the infusion. during investigation the patients were in forced positions, as a result they got artifacts from upper extremities on the abdominal cavity. we analysed 157 patients -hands under the butt, 135 patients -hands on the chest (abdomen), 57 patients -arms along the body. according to the images the smallest number of artifacts was identified when the patient was on the table with hands under the butt. different variations of the patient's hands position and the problem of choice of this position will be offered for researching. the reconstruction the laboratory assistant can execute and also the results of tests will be presented. by order of the doctor the laboratory technician builds 3d and 4d reconstructions of fractured ribs, pelvis, facial skeleton, sagittal and coronary reconstructions of spine in case of its fracture. gastrointestinal stromal tumours (gist) are a rare disease that metastasises in up to 85% of patients with subsequent median progression-free survival (pfs) of around 30 months. tumours are characterised by activating mutations in the kit or the pdgfra gene and treatment is mainly based on tyrosine kinase inhibitors designed to block mutated receptors. however, drug resistance is often based on mutations changing the conformity of the receptor, leaving little effective therapeutic options. to date, second line chemotherapy offers a median pfs of 6-9 months and external beam radiotherapy is limited by organs at risk close to the tumour. alternative approaches like endoradiotherapy or minimally-invasive ablation techniques are effective for local control but are inconsistently used and are not tailored to the individual patient's type of disease. to address these issues, the mitigate project proposes a closed-loop personalised treatment concept combining endoscopic-assisted tissue sampling, inline biotechnology and targeted molecular pet imaging probe development combined with minimally-invasive treatment monitored by new mr imaging techniques. a consistent value chain across european research institutes and smes will be established for mass spectrometry of tumours, linkage of radiochemical molecular imaging probes, design of new animal models and targeted therapeutic radiopharmaceuticals. this closed-loop platform will minimise fragmentation of treatment approaches by a coherent molecular-based multimodality concept, thus providing new treatment options. the mitigate platform can be expanded to further patient cohorts with oligometastatic diseases such as other sarcomas or renal cell carcinoma. gastrointestinal stromal tumours (gist) are characterised by highly specific genetic mutations. several specific targets are overexpressed in a majority of the tumours. on the other hand, secondary resistancies limit the usability of highly specific chemotherapeutics such as imatinib. instead of applying cascades of alternative tki inhibitors in order to find an efficient one, quantitative molecular imaging and targeted endoradiotherapy could be considered. for the detection of gist by imaging, 18 ffluorodeoxyglucose (fdg)-pet is widely accepted to visualise the tumour burden. however, as fdg gives no molecular information of potential targets for treatment, new radiopharmaceuticals have to be developed to visualise and quantify other target-structures expressed by gist that would be able to be addressed. this molecular information can be used both for designing a conventional treatment or an advanced strategy: i.e. targeted endoradiopharmaceuticals. compared to conventional chemotherapy this method has the great advantage that not only tumour cells expressing the targeting vector are affected but also tumour cells within the range of the radiation of the decaying radiopharmaceutical. this method is used with great success in the case of neuroendocrine tumours using labeled octreotate derivatives (a small cyclic peptide binding to the somatostatin-receptor) and non-hodgkin's lymphoma applying y-90 labeled zevalin (a monoclonal antibody binding to the cd20 antigen). the success of these methods relies on the crossfire-effect, meaning that a certain margin of tissue surrounding the cell targeted by the specifically accumulating endoradiopharmaceuticals is destroyed as well, depending on the penetration range of the emitted radiation. thus, the development of new radiopharmaceuticals for the specific diagnosis and treatment of gist would strongly improve the outcome of the tumour patient. stereotactic radiofrequency ablation of liver tumours: does improved targeting increase tumour response? r. bale, g. widmann, p. schullian, m. haidu, w.r. jaschke; innsbruck/at (werner.jaschke@i-med.ac.at) the purpose is to describe stereotactic radiofrequency ablation (srfa) and to review its inital results in the treatment of patients with primary and secondary liver tumours. one retrospective review includes 90 consecutive patients with 106 srfa sessions for the treatment of 72 hepatocellular carcinomas (hcc) and 105 metastases (1). in two other studies the outcome after srfa of intrahepatic cholangiocellular carcinomas (icc) (2) and colorectal liver metastases (crlm) (3) was evaluated. the overall technique effectiveness was 95.5% with a local recurrence at 1 year of 2.9%. technique effectiveness was not significantly different for lesions< 3 cm (95.9%) and 3-5 cm (100%). after treatment of 17 inoperable consecutive patients with 52 iccs a median overall survival of 60 months was achieved. a median os of 58 months and os rates of 92%, 66% and 48% at 1, 3 and 5 years in patients with resectable crlm were achieved. tumour size did not affect os and dfs. rfa probes can be precisely planned, positioned and distributed by means of stereotaxy. especially in large liver tumours the local recurrence rate can be greatly reduced by precise stereotactic placement of multiple radiofrequency probes. these improved local control rates result in better long-term survival rates. author disclosure: r. bale: shareholder; coshareholder atlas aiming device. other; coinventor atlas aiming device. functional and molecular imaging in tumour therapy response assessment s. aime; turin/ it (silvio.aime@unito.it) in the mitigate project further development of currently used mri and ct techniques will be tackled in order to obtain functional and metabolic information which are mandatory to detect early response to the targeted radiopharmaceutical approach. new gd-based agents are under scrutiny in order to improve dce-mri procedures and attain more precise information on the tumour microvascularity level as well on the vessel permeability and the assessment of extracellular ph and mmp activity. the x-nuclei mri ( 23 na sodium) is a non-invasive imaging technique, which enables the measurement of the tissue sodium concentration (tsc) in humans. the direct link of the tsc with the tissue integrity and viability provides a promising approach for monitoring tumour tissue, and could also help to assess cytoxicity and cell death by means of breakdown of the sodium-potassium-pump. however, 23 na mri is challenging because of the low in vivo abundance, the fast transversal relaxation rate and the low gyromagnetic ratio of the 23 na ions in human tissue. new mr measuring sequences for x-nuclei mri will be developed to establish a standardised tsc measurement method within the eu for better comparability. furthermore, the x-nuclei mr data will be reconstructed, scaled and fused with further imaging modalities. lung cancer is the leading cause of death related to cancer. most patients are inoperable as they present with advanced stage disease or even a localised tumour associated with poor general condition, limited cardiopulmonary function or a too high surgical risk. according to the stage of the disease, chemotherapy, radiotherapy and percutaneous ablation therapies are the current therapeutic options for inoperable patients. it is important that radiologists are familiar with the various response and complication imaging patterns related to each of those treatments. the timeline modifications after radiation therapy and percutaneous ablation and the diagnostic management of drug-induced lung disease will be reviewed. this presentation will summarise the current evidence and how to detect early recurrences after those treatments. learning objectives: 1. to learn about changes after radiotherapy. 2. to learn about sequela after percutaneous ablation of lung tumours. 3. to understand changes after chemotherapy of lung cancer. cardiovascular medicine owes much of its spectacular development to the parallel evolution of imaging techniques in the last thirty years. the complex contemporary techniques in interventional cardiology, electrophysiology, and cardiac surgery require advanced imaging modalities. in current times, a wide spectrum of imaging techniques -such as fluoroscopy, mri, non-contact mapping, echo techniques -is performed in organised cardiovascular labs while computed tomography and nuclear techniques are provided by the collaborative departments of radiology and nuclear medicine. it is indeed the collaborative spirit among specialists that bring about the results patients desire. cardiac magnetic resonance (cmr) is a very versatile imaging technique for the assessment of patients with left ventricular dysfunction and has become a central method for characterising the etiology of the dysfunction. indeed, wall thinning less than 6 mm and aneurysmal motion are morphological signs of transmural necrosis. furthermore, a low dosage of dobutamine (10-20 microg/min) is used to detect functional reserve in the case of viable tissue. a further option offered by cmr is late contrast enhancement (le) imaging, which allows identifying the presence of fibrotic tissue as well as necrotic infarcted myocardium. the sensitivity and specificity of late hyperintensity is, respectively, 0.86 and 0.94. similar results can be obtained with 99mtctetrofosmina g_spect. there is a relation between transmural extension of hyperenhancement and the recovery of contractile function after coronary revascularisation. the chance of recovery decreases progressively with the transmural extension of late hyperintensity, since the average value of the latter is 10â±7% in the segments that recover and 47â±14% in the segments that do not recover contractile function. cmr was also shown to be able to predict response to cardiac resynchronisation therapy differentiating between nonischemic and ischaemic cardiomyopathy le-cmr may allow to precisely delineate the presence and the location of fibrosis, avoiding the placement left ventricular leads in necrotic areas and in particular when the scar is located in the posterolateral area. at the beginning of the presentation, a short overview will be given on the relevance and prevalence of valvular heart diseases with special focus on europe and the data collected in the euroheart survey. also, the aetiologies of the various valve diseases will be briefly mentioned. in the second part, special attention will be given to aortic stenosis (as) and mitral regurgitation (mr), as these two entities are responsible for up to 60% of all valvular heart diseases. echocardiography is well accepted as the backbone examination of any valvular heart disease evaluation. echocardiographic criteria for severe as and mr are reviewed as well as their importance for the indication of valve repair or valve replacement. in the third part, we will focus on newer "cross-sectional" imaging technologies such as cardiac mr and ct. in particular, the strengths of cardiac mr in the assessment of regurgitant lesions will be demonstrated. in addition, the value of cardiac mr for the pre-interventional evaluation of congenital heart diseases will be discussed. similarly, the crucial role of cardiac ct in the workup for transaortic valve implantation (tavi) will be illustrated. finally, the yield of these novel techniques in the context of combined valvular and ischaemic heart disease will shortly be reviewed. learning objectives: 1. to better understand the role of cardiac mri in valvular heart disease. 2. to appreciate the added value of mri vs other imaging modailities. cardiac resynchronisation therapy (crt) and transcatheter valve heart (thv) interventions have been important therapeutic breakthroughs for heart failure patients and patients with valvular heart disease and contraindications for surgery. patient selection is crucial to optimise procedural outcomes and therapeutic efficacy. multimodality imaging plays a central role in patient selection and procedural strategy planning. assessment of left ventricular dyssynchrony, cardiac venous anatomy and extent and location of myocardial scar are key to identify heart failure patients who will respond to crt. stepwise use of non-invasive imaging modalities, including echocardiography, nuclear imaging, magnetic resonance imaging and multidetector row computed tomography (mdct), has been common practice to select patients for crt. recent technological advances have allowed integration or fusion of imaging modalities to create 3-dimensional models that provide relevant information. multimodality imaging is also crucial to optimise the results of thv interventions. detailed anatomical and geometrical evaluation of the mitral valve with current 3-dimensional imaging techniques has permitted better selection of patient candidates for transcatheter edge-to-edge mitral valve repair and accurate procedural guidance. for transcatheter aortic valve implantation, accurate measurement of the aortic annulus with 3-dimensional echocardiography or mdct allows us accurate selection of the prosthesis size to minimise the risk of complications, and evaluation of the procedural access (transarterial or transapical) with mdct permits accurate procedural strategy planning. the learning objectives of this session include: providing an overview of current imaging modalities to select patients for crt and thv interventions and how to use them in clinical practice. the inner layer of the anal canal consists of squamous and columnar epithelium with the transitional zone at the dentate line. the muscular component of the anal sphincter consists of an inner layer of circular smooth muscle (internal sphincter), extending downwards from the rectum, and an outer striated muscular layer extending downwards from the levator ani muscle, comprising the puborectalis muscle and the external sphincter. between these layers is the fat-containing intersphincteric space, including the continuation of smooth-muscle fibers of the longitudinal muscle of the rectum. outside the anal sphincter is the fat-containing ischioanal space. magnetic resonance imaging (mri) and endoscopic ultrasonography have become the mainstay for preoperative imaging of perianal fistulas. for complex tracts, mri seems preferable. mri can be performed using an endoluminal coil or a phased-array surface coil. a state-of-the-art imaging protocol should include t2 tse sequences in three orthogonal planes, with the axial and coronal sequences angulated at the anal canal. addition of a fat-saturated t2 tse sequence is recommended for optimal conspicuity of inflammatory changes and post-contrast t1-weighted imaging can also be helpful. intersphincteric infection is the principal feature of perianal fistulas; this is generally not found in other conditions. veins can be mistaken for fistulas, but in contrast to fistulas, veins usually are thin-walled, tortuous, symmetric structures. a pilonidal sinus may resemble a fistula, but absence of extension to the intersphincteric space helps one to discriminate between them. haemorrhoids and anal tags may resemble small submucosal fluid collections, but are easily diagnosed at clinical examination. this lecture will describe the pathogenesis of fistula-in-ano, with a focus on cryptoglandular disease, so that the radiologist can understand how the various classifications of fistulas arise. the park's classification for fistula-inano will be described with reference to cryptoglandular disease and other aetiologies. the surgical questions that need to be answered by imaging will be presented, followed by a description of what the radiologists need to include in their report for it to be clinically useful. the role of anal ultrasound and mri for preoperative fistula imaging will be described, with explanation as to why the latter is fundamental to modern management of the disease. perianal fistulising disease develops in approximately half of the adult and paediatric patients with crohn's disease (cd), with a relevant impact on their quality of life. in patients with cd, particularly those with severe fistulising ileal or colo-rectal disease, complex ramified anal fistulas associated with abscesses (parks' classification type 3-4 or s.james hospital classification type 4-5) are more frequently observed than in other patients. perianal disease thus represents a severe complication of cd, which may change disease management, by requiring specific pharmacological and/or surgical treatments. a non-responsive disease eventually may lead to total proctectomy with ileostomy. mri represents the gold standard diagnostic modality, because it provides a comprehensive staging of both enteric and perianal disease, with high accuracy and without invasiveness. moreover, mri is the ideal tool for monitoring disease response to therapy, being able to detect the inflammatory activity of perianal fistulas with high accuracy. so far, several clinical indexes have been proposed to measure fistula's activity, including the perianal disease activity index (pdai). similarly, several mri classifications of fistula's activity, based either on t2-weighted or t1-weighted contrast-enhanced imaging, have been proposed, although a widely accepted imaging severity score is not available yet. several cases of complex perianal fistulising cd of increasing severity will be shown, with anatomical and clinical correlations, staging and activity description, particularly in patient follow-up and treatment monitoring. finally, differential diagnoses with other benign conditions which may affect the anal canal, including inflammatory infective diseases, hydradenitis and pilonidal disease will be discussed. ground glass opacity (ggo) is characterised on hrct by the presence of a hazy increase in lung opacity that does not cause obscuration of underlying bronchial and vascular margins. although a very common finding, it also constitutes a very nonspecific term since it can be seen in a variety of different intraalveolar and interstitial processes with different histology including inflammatory, infectious and neoplastic diseases that have a common physiologic mechanism: partial displacement of air. ground glass opacity may even be seen in normal processes such as poor ventilation in dependant lung areas and in expiration. moreover, ggo can represent either an ongoing, active and potentially treatable disease or an irreversible process. to interpret correctly this highly nonspecific but very significant finding, it is crucial to attempt to further classify the different large main entities in which this radiological finding appears. are there specific radiological and hrct findings that can help us differentiate ggo in autoimmune inflammatory conditions from infectious and neoplastic processes? are there associated findings other than ggo, such as nodules, reticulation or focal disease, and distribution of findings that can narrow the differential diagnosis? systematic evaluation of ggo and associated findings as well as integration with clinical information (acute, subacute or chronic symptoms) is essential in defining ggo subtypes to improve the radiological diagnosis. radiologists who regularly review high resolution ct (hrct) should be aware of the range of patterns and, more importantly, their potential pathological meaning. a pattern of ground-glass opacification is one of the more common hrct findings but, to the unwary, its interpretation can be problematic. an important underlying principle is that a ground-glass pattern may be caused by any process -physiological or pathological -which partially displaces air. physiological (i.e. non-disease-related) ground-glass opacification is perhaps most commonly seen in subjects who, for whatever reason (e.g. breathlessness, obesity), are unable to maintain or achieve a satisfactory inspiratory effort during scanning. a generally increased lung density (in contrast to adults) is also a feature in infants and young children simply because there are fewer alveoli in the developing lung. finally, it is worth noting that intravenous contrast administration (presumably because of a relative but temporary increase in capillary blood volume causing partial displacement of air) can unpredictably increase lung density. disease processes which lead to partial filling of the air spaces, thickening of the interstitium, partial collapsing of alveoli, and/or increased capillary blood volume will also manifest as a pattern of ground-glass opacification. in clinical practice, the recognised causes of ground-glass opacities on hrct include pulmonary oedema (cardiogenic or otherwise), infections (e.g. pneumocystis jiroveci pneumonia) and some of the idiopathic interstitial pneumonias (e.g. non-specific interstitial pneumonia and respiratory bronchiolitis associated interstitial lung disease). the presentation will review and revise the causes of physiological and disease-related ground-glass opacification on hrct. ground-glass opacity (ggo) is defined as increased attenuation of the lung parenchyma without obscuration of the pulmonary vascular markings on ct images. ggo may be the result of a variety of interstitial and alveolar infectious and noninfectious inflammatory diseases. as an imaging finding alone, ggo does not usually allow a specific diagnosis. ggo in inflammatory disorders is often present in the company of other interstitial or alveolar findings. however, the number of diseases that cause diffuse isolated ggo or ggo as the predominant finding is relatively small and can be prioritised with clinical information. the most common cause of diffuse isolated ggo in immunocompromised hosts are a variety of diffuse, opportunistic pneumonias, e.g. pneumocystis jiroveci pneumonia (pcp), cytomegalovirus pneumonia (cmv) or herpes simplex pneumonia (hsv), which constitute the first differential. chronic onset disorders in immunocompetent patients include cellular nonspecific interstitial pneumonia (nsip), subacute hypersensitivity pneumonitis (hp), organising pneumonia, air-space sarcoid, and drug-induced lung disease. in these disorders, ancillary findings such as an associated reticular pattern with traction bronchiectasis/bronchiolectasis (nsip), mediastinal lymphadenopathy (sarcoidosis), superimposed nodularity or cysts or may help to refine the diagnosis. in patients with collagen vascular disorders, e.g. scleroderma, ggo secondary to pulmonary involvement needs to be differentiated from drug-induced lung disease. this refresher course will put ggo in the context of outpatients versus inpatients, the acuity of clinical symptoms, e.g. fever, cough and dyspnoea, signs of massive systemic inflammation, and the clinical situation such as inhalational history, pneumotoxic drug administration, immunocompromise, or bone marrow suppression. in this course, we will review the dysplastic and neoplastic conditions that are associated with persistent ggo in the lung parenchyma. we will separate these conditions into those that are responsible for localised diseases such as single nodular ggo and those responsible for more extended diseases. nodular ggo can be separated into pure or mixed or part-solid nodules. pathology-radiology correlations show that nodular ggo are related to atypical adenomatous hyperplasia (aah), adenocarcinoma (adc) in situ (ais), minimally invasive adc (mia), and invasive adc according to the new iaslc/ats/ers lung adenocarcinoma classification. differential diagnosis includes exceptional metastases of angiosarcoma and melanoma as well as infection, inflammation and localised fibrosis. diffuse ggo related to neoplastic conditions is rare and may be due to lepidic adc (former advanced adc with bac component), diffuse large b-cell non-hodgkin's lymphoma, intravascular lymphomatosis (ivl) or mucosa-associated lymphoid tissue (malt) lymphoma. these neoplastic diseases should be differentiated from infectious and inflammatory causes of diffuse ggo. we will review the value of different morphological ct criteria to differentiate benign from malignant localised ggo, such as the size, the morphology (round, oval, flat), presence of mixed vs. pure ggo, and the multiplicity of nodular shadows. discussion will also include the changes that may occur within the nodule as well as the mean doubling time. the role of pet ct and transthoracic biopsy will be discussed. finally, we will present the current recommendations regarding the management of nodular ggo. it is the purpose of this lecture to briefly discuss ankle distortion-related lesions with emphasis on failed radiographic diagnosis, discuss their significance and management implications and define the diagnostic pathways in the acute and subacute stage. significant lesions are those with no return to sports activities after 12 months; these have our major interest. in the acute setting of ankle distortion, the ottawa clinical decision rules are accepted to decide whether or not radiographic evaluation is needed; about 35% of radiographic examinations can be avoided. additional evaluation is restricted to patients with residual pain during reevaluation one week after trauma. assessment of fractures with the lauge hansen classification has a major advantage, as it defines the stability at the talocrural and distal tibiofibular joint. only in restricted cases, additional examinations may be needed to rule out instability. although radiographs easily detect displaced fractures, occult fractures may occur; also, grade ii-iii ligament lesions and peroneal tendon dislocation may go undetected. additional imaging evaluation should focus on the detection of significant lesions. significant lesions are talar fractures and complete calcaneofibular ligament tears. the latter is explained by the instability at the level of the subtalar joint with associated sinus tarsus syndrome. in case of residual local tenderness posterior and inferior to the lateral malleolus, the fibulocalcanear ligament and retinaculum peroneorum lesions are best evaluated with (dynamic) ultrasound. mri or ct is used to detect occult fractures in case of residual talocrural joint effusion with anterior talar tenderness during endorotation and plantar flexion. the ankle and foot can be affected by inflammation from a number of diseases. the main focus of this lecture will be inflammation secondary to infection and systemic inflammatory disorders. due to its function in locomotion and weightbearing, the foot is specifically susceptible to infections secondary to penetrative trauma including foreign bodies or to abnormal repetitive pressure. in addition, both seropositive and seronegative arthropathies can affect the foot. other unusual causes of inflammation include chronic recurrent multifocal osteomyelitis, osteoarthritis, mechanical disorders and sensory loss. this lecture will deal with the various patterns of inflammation in the context of pathogenesis and discuss the imaging features that aid in diagnosis. the importance of the clinical context in diagnosis will also be discussed. characterising tumours before deciding on the most appropriate treatment is a general rule in oncology. cystic tumours are now adequately graded based on bosniak's classification. however, this pre-therapeutic characterisation is not currently systematic in case of solid renal tumours, as it remains difficult in clinical practice due to the high prevalence of renal cell carcinomas (rcc) and the lack of reliable imaging criteria for recognition of benign versus malignant tumours. as a result, approximately 10% to 20% of surgically excised renal masses are actually benign. to avoid these unnecessary ablations, pretherapeutic image-guided biopsy has been proposed, but its use is still debated as it is invasive and time consuming. new validated imaging criteria, able to accurately differentiate the most common tumour types but also indolent vs more aggressive malignant lesions, would be useful to reduce the number of unnecessary biopsies or to consider the most appropriate treatment for a tumour or active surveillance. among these, mr imaging plays a major role based on chemical shift gradient echo (gre) sequences, signal intensity on t2-weighted images, dynamic contrast-enhanced sequences, diffusionweighted sequences and late contrast-enhanced images. multiparametric mr imaging is now performed in clinical practice in most primary care centres. therefore, using different combinations of two or several parameters, it is now possible to distinguish certain renal tumours. a larger validation of all these combinations is still necessary to define those having a clinical significance for routine practice. targeted therapies such as vegf mab bevacizumab, vegf tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib and sorafenib) and mtor inhibitors (temsirolimus and everolimus) have been approved and included in european guidelines. pre-therapeutic imaging prerequisites are mainly based on the natural history of mrcc. this justifies imaging through a thoracoabdominal ct scan. outside clinical symptoms, there is no need for bone imaging or brain ct scan; the latter nevertheless could be done because of influencing the therapeutic strategy. pet scan should not be done due to low sensitivity. the evolution of metastatic sites by comparison from previous imaging is useful to evaluate the natural history. outside clinical trials or research imput the strategy is to use the drug in an optimal way to increase pfs. so far, monitoring has to inform about change in recist criteria for cr, pr, sd or pd, and if pd is a real pd such as recist pd or a slowing pd. in conclusion, standard ct scan and recist are adapted to real life. nevertheless, more information on the mode of action of targeted drugs should be interesting for knowledge and research purpose, without any impact on the management of patients. additional imaging could be done with additional criteria than recist on ct scan, by vascular functional imaging and pet scan. breast mri is recognised as a useful tool for a number of clinical indications, but remains relatively challenging. recognising the importance of an evidencebased approach to the development of protocols will influence the further integration of this technique into everyday clinical practice in the management of breast cancer patients. there remain concerns regarding the potential of over-diagnosis from breast mri. the aim of this integrated rc is to inform the clinical practice with regard to the establishment of breast mri in specific clinical and imaging scenarios, namely, using mri for surveillance in high-risk patients, monitoring response to neo-adjuvant chemotherapy and developing protocols for the indeterminate imaging scenario of non-mass-like enhancement. the establishment of protocols to maximise the specificity and sensitivity of the technique of breast mri in such indeterminate clinical and imaging scenarios will be discussed. non-mass like enhancement is a frequent finding in breast mri. it relates to the fact that enhancement occurs in the normal-appearing fibroglandular tissue that surpasses that of the other parts of the parenchyma. there is no associated space-occupying lesion. in pre-contrast non-fat-suppressed or fatsuppressed t1-and t2-weighted images, there is usually no correlate observable. the differential diagnosis of non-mass-like enhancement is between benign nonspecific fibrocystic disease/adenosis, hormonal stimulation, and subclinical mastitis on one hand, vs dcis or (less likely) diffusely infiltrating (usually lobular) cancer on the other. key components of differential diagnosis is configuration of the enhancement (does it follow the orientation of the milk duct or not?) and symmetry (symmetric or asymmetric). less important criteria are internal enhancement (internal architecture) and enhancement kinetics. it is important to realise that enhancement kinetics can only be used to corroborate the suspicion of dcis -but they cannot be used to alleviate the indication to biopsy a finding which, based on configuration and asymmetry, is suspicious. management depends on the different constellation of clinical, mammographic, and mri findings. it usually includes short-term follow-up (6 months) and, if stable/persistent, mr guided vacuum biopsy. assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics. tumour shrinkage and time to the development of disease progression are important end points in cancer clinical trials. however, these end points are useful only if based on widely accepted and readily applied standard criteria. criteria, known as recist, were published and are updated on a regular base. the revised recist includes a new imaging appendix and underlines the importance of moving from anatomic unidimensional assessment to either volumetric anatomical assessment or functional assessment with pet or mri. the goal of the lecture is to discuss the value of the different mr imaging techniques (e.g. mr spectroscopy, diffusion-weighted imaging, angiogenesis mapping, pet-mri), which evaluate response to treatment in breast cancer. participants will learn about particular imaging challenges of assessing response to neo-adjuvant chemotherapy. in addition, they will learn to understand clinical aspects of neo-adjuvant chemotherapy based on recist. currently, the esr has been using social media in many successful ways to improve the contacts among members and to boost our fast development as one of the most advanced scientific communities in the world. our session "the role of social media in radiology" presents the view of 4 experts, acknowledged leaders of international it projects. it seems to be important to discuss the major implications of social media for radiology, the leading clinical discipline in information technology. davide caramella will clarify the relationship of social media to professional societies and especially to the esr, including their basic features. the "social media generation" has developed from schoolkids to students and, recently, to teachers as well. alexander sachs represents the young professional expert of elearning in radiology and will reflect the current user behaviour. osman ratib will share his view on how social networks enhance the communication between radiologists, nonradiologists and patients. critical aspects of the pros and cons of large communication scenarios are followed by some ideas of future developments. jã¼rgen brandstã¤tter will indicate the patientâ´s view. most patients see social network communications with their radiologist as useful for, e.g. appointment management or other non-sensitive communication. besides communicating personal health data, a wide area of potential useful other possibilities are at hand, like anonymised health data for reviewing purposes, second opinion or education of patients. the fast development of social media may induce hopes and fears; the four speakers of this session will present them in a panel discussion. the widespread use of social networks in all professional activities has attracted a great interest in the recent years. in medical applications, the main concerns include the possible consequences in terms of patients' confidentiality protection, perceived role of the physician, patient-physician relationship, and caregivers' distraction during professional activities. there are no doubts, however, that social networks are beneficial in enhancing the information flow between scientific societies and their professional members, without any interference at the point of care. social networks have proved to be extremely effective in updating members about relevant news concerning their areas of interests and in allowing them to be informed about the educational activities promoted by their scientific societies. this presentation focuses on the social network activities promoted by the esr via facebook, youtube, twitter and other blogs. impact of social media on the training of radiologists a. sachs; vienna/ at (alexander.sachs@meduniwien.ac.at) in modern times, social media have gained more and more important value in exchanging first experiences in radiology from resident to resident. social networks such as facebook, twitter, google plus and others are used to start discussion groups about cases and share the growing knowledge with different educational concepts in each hospital. growing e-learning modalities as moocs, applications for smartphones or tabs and web-based case series or learning platforms support the training of radiologist in social media. modern elearning platforms use social media as their first choice of sharing knowledge around the whole world about certain illnesses, cases or different decisions of therapy. though sharing information seems to be easier and shows several advantages than in former times, social media can also highlight new problems. this lecture focuses on user behaviour to improve learning, the pedagogic evidence for large group learning with networks and the importance of using networks to manage time. social media networks in communication between radiologists, nonradiologists and patients o. ratib; geneva/ch while social networks have gained unprecedented popularity in our daily environment, they have only limited utilisation in medical applications. the paradigm of communication within a given community for exchange and sharing of imaging data would certainly have its place in a medical environment where there is an increasing need for multidisciplinary collaborative work. the required security and confidentiality in management of sensitive patient data have often precluded the usage of existing public social networks. professional proprietary systems have emerged in a more restricted way with much less flexibility leading to limited use. the exchange of medical images adds a level of complexity due both to the size of the data and the need for appropriate browsing and visualisation tools. traditional pacs and teleradiology system offer such features, but in a very limited way, far from the desired convenience of social networking between groups of users. a prototype of such a system aimed essentially at the community of users that need to exchange anonymised medical images and data for academic and research purposes will be presented and discussed. the project nicknamed dicom sandbox is being tested and evaluated by some users in europe under the coordination of the esr subcommittee of ehealth and informatics. developed with open source software components, it allows using existing cloud-based storage services with additional layers of secure dicom file management and visualisation. it allows the community of users to share dicom data with all social networking and notification features beyond simple peer-to-peer exchange. interactions between patients and radiologists through social media j. brandstã¤tter; wiener neudorf/ at (j.brandstaetter@codewerk.at) social networks have become integral parts of most citizen's use of the internet. especially, the younger generation uses social networks extensively; however the way those tools are used should be chosen carefully. it is one thing to use a social network for private interests, but a different one to use it as transport media for sensible data like personal health-care data. the sensitiveness of citizens regarding privacy has been increased recently by different events of misuse or fraud, especially accelerated by the recent privacy affairs caused by governmental agencies. though most patients see social network communications with their radiologist useful for, e.g. appointment management or other non-sensitive communication, personal medical reports or images shall not be shared across this media. besides communicating personal health data, a wide area of potential useful other possibilities are at hand (e.g. anonymised health data for reviewing purposes, second opinion, education of patients, â�¦). future developments shall make use of social media where useful, but always with deep respect to the patient's privacy rights. apart from the historical, but ever present clinical expectation from the neuroradiologist is the answer to the most important question if the patient has a brain tumour or not. nowadays, due to the outstanding technological advances in imaging techniques during the last decades, the stakes are growing much higher and it is the neuroradiologist on whom lies the initial responsibility of answering a large number of questions that are of utmost importance for further brain tumour patient care and treatment. having the opportunity to provide the usual and generally basic information regarding tumour morphology and exact location and to narrow the differential diagnostic possibilities, neuroradiologic expertise now opens a wide spectrum of techniques, especially those derived from mri, such as mr spectroscopy, mr perfusion, dwi, dti, swi, etc. these provide us the unique possibility of not only obtaining and comparing images, but also of exploring multiparametric brain maps, allowing us to gain insight into the internal architecture of the tumour and the functional and molecular features of the tumorous tissue. this consequently defines the actual stand of neuroradiology, indicating the uprising clinical urge not only to provide the answers regarding the tumour type, grade and possibilities of the most appropriate and patient-individualised therapy modality, whether surgical or nonsurgical, but also to accurately assess the post-treatment tumour behaviour and status, by differentiating the true tumour progression from pseudoprogression, represented by inflammatory responses to the radio-and/or chemotherapeutical treatment, and to monitor other neurooncological response assessment criteria. a. differential diagnosis and pseudo-tumoural lesions h.r. jã¤ger; london/uk (r.jager@ucl.ac.uk) conventional contrast-enhanced mr imaging gives an indication about the likely tumour type and histological grade, but advanced mr imaging methods, including perfusion-weighted (pwi) and diffusion-weighted (dwi) imaging, mr spectroscopy (mrs) and pet imaging provide additional information which helps to refine the diagnosis of intrinsic brain tumours. contrast enhancement can be a feature of low-grade (pilocytic astrocytoma and ganglioneuromas) as well as high-grade gliomas (who grade iii anaplastic gliomas and who grade iv glioblastomas). infiltrative low-grade (who grade ii) astrocytomas do not usually enhance, whereas who grade ii oligodendrogliomas can enhance. higher-grade glial tumours (who grade iii and iv) tend to have an elevated relative cerebral blood volume (rcbv) on pwi, a decreased adc on dwi and increased choline turnover on mrs and pet imaging. a raised rcbv can, however, also be seen in low-grade oligodendrogliomas, particularly in those with a 1p/19q chromosomal translocation, which is associated with a better response to chemotherapy. pwi and dwi are useful in the differentiation of glial neoplasms from cerebral lymphoma, which has an increasing incidence in the immuno-competent population. dwi and pwi are also very useful in the differentiation of enhancing pseudo-tumoural lesion such as cerebral abscesses, tumefactive demyelination, pseudoprogression and radiation necrosis. perfusion imaging plays an important role in the characterisation and management of brain tumours. low-grade brain tumours may transform into high-grade gliomas at some point, which is a transformation that is highly variable and difficult to predict in an individual patient. conventional contrastenhanced computed tomography (ct) and magnetic resonance (mr) imaging are found to be insufficient to depict this transformation and angiogenesis and therefore to detect malignancy. however, perfusion imaging provides additional information over conventional imaging in terms of tumour physiology and haemodynamics, providing important biomarkers for malignancy and prognosis. perfusion ct and mr perfusion techniques such as arteriel spin labelling and dynamic susceptibility-weighted perfusion imaging are more practical and widely used compared to nuclear medicine methods. these perfusion techniques should be considered and used in routine clinical workup of brain tumours to asses grading and prognosis. maximal safe resection, radiation therapy and temozolomide chemotherapy are the current standard of care for newly diagnosed high-grade gliomas. still, hgg have a poor survival rate. a contributing factor to the poor survival is the inability of currently available imaging techniques to accurately delineate the tumour, with the result that targeted focal treatment my not be effective. conventional imaging is not able to give an early assessment of the effectiveness of radiation and/or chemotherapy. in addition, conventional imaging has difficulties in differentiating pseudo-progression, which is a common phenomenon in conventional chemo-radiation therapy, from true progression. early identification of patients who suffer from tumour recurrence can be of great advantage: it provides the opportunity to adjust individuals more rapidly, sparing patients unnecessary morbidity and delay in the initiation of other, maybe more effective, treatment. in recent years, different functional imaging approaches such as perfusion mri, diffusion-weighted imaging and spectroscopy, have been complementarily used for imaging evaluation of treatment response. in this lecture, different advanced mr and ct imaging methods used to support differentiation between pseudo-progression and true tumour progression to assess treatment response will be discussed. in addition, a novel recently published promising technique, the parametric response mapping (prm), a novel voxel-wise analytical method of monitoring physiological and environmental changes in a tumour volume during treatment will be presented and compared to the traditional methods used. finally, the aim of the lecture is to consolidate the present knowledge and novel ideas in brain tumour imaging for assessment of pseudo-progression versus true tumour progression. learning objectives: 1. to understand the challenges and limitations of routine mri in monitoring brain tumour treatment. 2. to become familiar with the role of advanced imaging biomarkers for early assessment of treatment response. 3. to learn how to integrate routine and advance mri into clinical practice after tumour therapy. the purpose of this lecture is to describe the role of functional radiological imaging modality-ct and mr perfusion in the evaluation of head and neck tumors. conventional contrast-enhanced ct and/or mr imaging are the current standard techniques for the diagnosis and treatment evaluation of the head and neck tumors. however, this method is limited in its ability to depict the angiogenesis which is a hall-mark of tumor growth. perfusion imaging provides a rapid evaluation of tissue perfusion and can be easily implemented in every head and neck ct or mr protocol. the determination of tissue perfusion is based on examining the relationships between the arterial, tissue and potentially the venous enhancement after the introduction of a bolus of contrast material. the quantification of the perfusion values helps to outline the malignant tissue as well as to differentiate recurrent disease from nonspecific post-therapeutic changes and can be used as a therapeutic monitoring tool during and after tumor therapy. in recent years diffusion-weighted mri (dwi) gained increasing importance and also acceptance in head and neck radiology. although this functional technique is challenging due to air tissue interfaces, its ability to improve the diagnostic accuracy is widely accepted. dwi can be applied to detect lesions not only in adults, but also in children. it is helpful in lesion characterisation and has a great potential to differentiate recurrence from posttherapeutic changes. initial promising results to improve lymph node staging however are difficult to reproduce. image interpretation is performed qualitatively based on visual assessment of the high b-value images (b= 800-1000sec/mm 2 ) and the corresponding apparent diffusion coefficient (adc) map. quantitative image analysis is based on the measurement of the underlying adc value. solid tumors including recurrences are bright on the high b-value images and dark on the corresponding adc map, whereas posttherapeutic changes are bight on both the high b-value images as well as the adc map. cystic and necrotic lesions are typically dark on the high b-value image and bright on the adc map. furthermore, malignant lesions tend to have a lower adc compared to benign and cystic lesions provided that no necrosis is present. therefore, image interpretation always has to be performed together with morphological images to avoid misinterpretation of functional images. pet/ct has established itself as a robust, rapid and reliable technique in head and neck oncology. it is mainly used to stage nodal disease, to detect distant metastases and synchronous tumours, to identify unknown primary tumours in patients with metastatic neck nodes, to assess treatment response and prognosis after chemoradiotherapy and for radiotherapy planning. mri with diffusion-weighted imaging (dwi) is routinely used for the assessment of submucosal tumour spread, to stage nodal disease, to monitor treatment response and to detect recurrent disease. the information provided by pet/ct and mri is often complementary and the recent implementation of hybrid mr/pet systems in clinical settings holds promise because it can combine morphologic, functional and molecular information. this lecture focuses on clinical applications of pet/ct and mr/pet in the head and neck. current evidence about the combined use of pet/ct and mri with dwi is discussed. the principles of mr/pet data fusion are summarised as well as current knowledge regarding the diagnostic performance of mr/pet in the head and neck. typical radiologic findings of tumour manifestations are reviewed with particular emphasis on the early detection of lesions, their appearance on different imaging modalities and the added value of hybrid imaging techniques. the variable appearance of functional phenomena mimicking disease as well as the potential pitfalls of image interpretation and how to avoid them are equally addressed. major emphasis will be put on how to report the findings in a comprehensive way. multi-energy and functional imaging ct has reached a robustness allowing the use of this new technology in clinical routine for a variety of different clinical questions. this presentation will discuss the basic principles and the strengths and limitations of the techniques. implementations of multi-energy methods for material characterisation and of ct methods for functional imaging will be discussed. contrary to normal single-energy ct systems, multi-energy ct scanners allow simultaneous scanning at two peak x-ray energies. when the attenuation is measured at two energies, their values are not exactly proportional to each other, which open new diagnostic possibilities. measurements at two spectra can be achieved using multiple kvp and/or filtration or with detectors with energy discrimination. these methods have different pros and cons such as sensitivity to subject motion and dose efficiency. to be able to acquire functional data such as perfusion, images are acquired dynamically following the injection of a contrast agent and physiological models are used to convert the measured contrast agent concentration to perfusion estimates. methods that acquire multiple images have the potential to increase the radiation dose to the patient, so ct protocols need to be optimised. in computed tomography, 3d images are reconstructed from a number of x-ray radiographs that were acquired at different angles. tomographic reconstruction relates to the generation of a 3d image based on these acquired radiographs. most tomographic reconstruction methods are based on a technique called filtered back projection (fbp) in which a sharpened version of the radiographs are back projected to generate the 3d image. while it has been the standard reconstruction method, mostly due to its speed and good quality if many radiographs are available, iterative reconstruction methods are emerging. the reason for that is that fbp suffers from important disadvantages. in this talk, the basic concepts of iterative reconstruction are explained and its virtues are detailed. the flexibility of iterative reconstruction methods is demonstrated for the field of x-ray computed tomography. finally an outlook is given with respect to future research on tomographic reconstruction. interventional radiology (ir) has been increasingly applied in the management of obstetric and gynaecological haemorrhage. national reviews of maternal deaths from post-partum haemorrhage have recognised that maternal deaths may be prevented by ir and that all obstetric units should have protocols and arrangements in place to ensure appropriate and timely referral to ir. the important role that irs play in the management of fibroids has also highlighted how these techniques can be applied to other gynaecological conditions which may result in haemorrhage. this session will start by describing which gynaecological disorders may result in haemorrhage and the technical aspects of treatment followed by the published evidence for embolisation. the session will then focus on obstetric haemorrhage, with an emphasis on prophylaxis and how women deemed at high risk for haemorrhage might be managed safely. the techniques used for prophylaxis of haemorrhage will be described in detail and the published data presented. the final presentation will concentrate on the technical aspects of embolisation when haemorrhage has occurred to ensure the best results by knowing the relevant anatomy and appropriate technique of embolisation. the published evidence of the results of embolisation in pph will be presented. these presentations will be followed by a panel discussion on how irs can reduce the radiation dose whilst simultaneously ensuring successful outcomes for their therapies, an important issue in a young and fertile group of women. gynaecologic massive bleeding related to benign and malignant causes is under the scope of all radiologists because of being diagnostic and also because of its implication in interventional radiology procedures. the causes are uterine fibroids (uf) and post-partum hemorrhage (pph). however, oncologic disease, arterio-venous abnormalities, or iatrogenic injuries are less commonly known to be eligible for embolisation procedures. usually, surgical homeostasis attempts or radical hysterectomy is preferred to embolisation procedures. despite the good clinical outcome for hysterectomy and the hazardous success rate of conservative treatment, both are unsatisfactory to patients. pelvic artery embolisation (pae) could dramatically change the patients' clinical issue. the purposes of this lecture are to: revise the pelvic arterial anatomy (possible arterial anastomosis or variation); outline the aetiology of non-obstetric massive menometrorrhagia; expose the typical clinical presenting features; describe the imaging appearances of the etiologies; and discuss patient section, procedure technique, pitfalls and complications. obstetric haemorrhage occurring mainly in the postpartum period is a significant cause of maternal morbidity and death. blood loss of over 500 and 1000 ml after vaginal delivery or caesarean section, respectively, complicates 4% of deliveries. major blood loss of more than 1000 ml occurs following less than 1% of all deliveries. the causes include uterine atony, retained placenta products, placental abnormalities, uterine rupture, lower genital tract laceration, cervical ectopic pregnancy and coagulopathies. generally, treatment is based on administration of uterotonic drugs, vaginal packing, surgical ligation of uterine arteries and even hysterectomy is sometimes needed. transcatheter embolisation of uterine, pudendal, vaginal arteries and ovaries is considered to be superior and should be the first-line treatment for intractable obstetric haemorrhage where interventional radiology is available. angiography reveals extravasation of contrast agent in more than 50% of these patients. the most frequent extravasation is from vaginal artery, and then from pudendal and uterine arteries. depending on the extravasation location and haemodynamic stability of a patient, 5 f catheters or coaxial microcatheter technique is utilised for catheterisation. gelatin foam, microparticles acrylic glue and microcoils are the most frequent embolic agents. the embolisation procedure usually does not require general anaesthesia and can be repeated if bleeding continues. primary success rate in bleeding control is reported from 80 to 90 %. the most commonly reported long-term side effects after embolisation were transient buttock numbness and urinary frequency. the transcatheter pelvic artery embolisation for obstetric intractable bleeding is a fertility-preserving alternative to hysterectomy. medical imaging has nowadays integrated the diagnostic armamentarium of anosmic patients regarding not only qualitative assessment of the olfactory tract, but also quantitative evaluation of olfactory bulb volumes which are known to closely correlate to the olfactory function. many clinical studies on various pathological conditions have evidenced the value of such measurements in the workup of olfactory dysfunction for both aetiologic and prognostic purposes. imaging workup also plays a role in the medico-legal evaluation of post-traumatic anosmia together with electrophysiological and clinical olfactory tests. technical improvements in fibre tracking (ft) using diffusion-tensor imaging (dti) and appropriate designs of olfactory stimulation at bold-based functional mri (fmri) are expected to allow insights into the neurophysiological processes and circuitry of olfaction in the very near future. imaging workup of the anosmic patients will be the cornerstone of this lecture. the relevance of the different imaging techniques will be detailed. beyond the workup of anosmia, a comprehensive overview of the most common lesions of the olfactory tract seen in clinical practice will be given. additional review of lesions observed at the anterior cranial fossa in the near vicinity of the olfactory tract will be done, which comprehensively includes all commonly observed developmental, traumatic, inflammatory and neoplastic conditions not arising from the olfactory tract. their potential impact on the olfactory function or on other sensory/neurological functions will be underlined. clues to clinical/radiological differential diagnoses of the most common conditions and radiological features of the anterior cranial fossa will be highlighted. the central skull base, the floor of the middle cranial fossa, has a complex anatomy and is pierced by a variety of foramina and canals providing crossroads for spread of disease between the extra-cranial head and neck and the intracranial compartment. disease spread into the intracranial compartment indicates a dismal prognosis, as often it becomes inoperable due to involvement of vital structures including cranial nerves, carotid artery and/or brain parenchyma. imaging plays a pivotal role in the assessment of these structures which are not amenable to clinical inspection and can dramatically change the patient's management. in this complex anatomical area, ct and mr have a complementary role in providing a comprehensive roadmap for treatment planning. of major importance is the pterygopalatine fossa, the cavernous sinuses and orbital apex. the former, lying between the pterygoid plates and the maxillary sinus, is a major crossroad between the intra-and extracranial compartments and should be carefully inspected. pathologies affecting the central skull base are varied and may originate from the skull base proper, from the middle cranial fossa or from the extracranial head and neck. by looking at the centre of the lesion, its tissue characteristics and pattern of growth, it is often possible to provide a useful differential diagnosis and, most importantly, to map the lesion's extent. here, we present a radiologist-friendly approach to central skull base pathology highlighting the most important features in the differential diagnosis and treatment planning. 1. the jugular foramen: the jugular foramen is an opening in the skull base. the radiologic evaluation requires high-quality imaging with ct and mr. angiography is reserved for preoperative embolisation. it is important to recognise the "pseudo lesions". the most common tumour of the jugular foramen is the paraganglioma. the second is the schwannoma of the lower cranial nerve, and the jugular foramen meningioma is the third most common. the differential diagnosis shall be discussed. 2. the cerebellopontine angle (cpa) and the internal auditory canal (iac): the iac is a bony conduit for several nerves and a vessel, the neurovascular bundle. the cpa is a cistern of the peripheral cerebral spinal fluid, and several anatomical structures pass through this. it is also the place of some frequent disease processes. most of the lesions in the cpa are benign tumours with order of frequency: vestibular schwannoma and meningioma. the third most common lesion is a benign cystic lesion: the epidermoid cyst. in the iac, you can encounter the same benign tumoural lesion as in the cpa, but also inflammatory lesions, viral lesions and malignant lesions. why is it important in your imaging protocol of the iac and cpa region to use gadolinium? the differential diagnosis of different lesions shall be discussed. learning objectives: 1. to learn about the imaging techniques and anatomy in the posterior cranial fossa. 2. to become familiar with the imaging findings of common posterior cranial fossa pathologies. 3. to learn how to differentiate between the lesions in the posterior cranial fossa. health care is characterised by several specific features making it different from traditional markets. two of the key features are: the impossibility of patients to make choices, due to asymmetry of knowledge between them and their health-care providers; the fact that patients create an agency relationship with health-care providers, delegating to them the decision about the care delivered. due to these characteristics and to the fact that patients are fragile when they need care, there is a natural tendency for patients to rely on healthcare professionals. it is in this complex socio-technical environment that radiographers must be aware of their roles and responsibilities and ensure professional autonomy and accountability; demonstrate an ethical and knowledgeable understanding of the profession; apply professional practice in securing, maintaining or improving health and well-being; develop knowledge, skills and competences that underpin their education and training, contributing to the wellbeing of the patient; understand that professional advancement arises out of evidence-based practice and is acquired through focused research. this demands for a focus on patient care and safety, based on high professional standards. ebp is the best way to achieve this desideratum, as it combines the best research evidence with clinical knowledge and expertise, addressing the patient in a holistic way. since the radiographer is the ultimate interface between patient and technology, it is crucial to create a real teamwork concept, using guidelines for the roles and responsibilities of each team member as the pathway to minimise practice error, maximising patient and staff safety. the use of ionising radiation in medical exposures is well documented across countries. recent studies indicate that a substantial fraction (20 to 50%) of these procedures is unnecessary when taking into consideration patient clinical indication. defensive medicine, economic interest, poor patient clinical information, patient pressure and the lack of knowledge about other alternative procedures, taking into account the benefits and risks, are the principal causes of unnecessary radiological examinations. patients must be referred to a medical imaging department for an examination that should be justified according to clinically appropriate image criteria and informed of the potential benefits and risks. following justification, the optimisation of practice is essential to ensure the minimal exposure of radiation dose to the patient whilst diagnostic efficacy is maintained. the principal aim of optimisation is getting a narrower dose distribution, with lower mean and 75 th percentile values of the diagnostic reference level. optimisation processes need to consider several factors including the type of examinations, body region, clinical information, available equipment technology and image processing tools. to implement this process, a multidisciplinary teamwork is essential where radiographers, being the pivot between patient and technology, have an essential role. to understand and apply optimisation procedures, radiographers should be aware of the international guidelines, standards and directives. all medical imaging procedures must be audited to analyse if the workflow processes (referral, justification, optimisation and radiation protection principles) are according to the recommendations to create a radiation protection safety culture. although we are approaching the year 2014, a lot of clinical radiography is not based on best evidence. lot of clinical decision-making is based on, for example, traditional practices that we cannot argue as being the best possible ones. in this presentation, barriers to using research and other sources of evidence and facilitators of evidence-based (eb) radiography are described. the role radiographers have in developing eb guidelines and procedures may vary according to educational level and work description. developing eb guidelines is not the work of every radiographer, but obeying them is. the speaker gives some suggestions on what to do in a situation if there are no eb guidelines and procedures in ones' country or institution and no group that develops them. with the framework of "the new work order" and increasing implementation of new work processes, professionals are faced with new modes of collaboration requiring communicative skills as well as multiprofessional competencies between all the stakeholders across the hospital. some evidence about the consequences of ineffective communication in the field of radiography is presented. in addition to benefits associated with the procedure of clinical audit, uniform good quality protocols for examinations and uniform national/international criteria help to perform comparisons between radiology units. clinical audit also works as an educational tool and as a feedback tool for the staff on their performance. it also points out the need for corrective actions. initiatives from professional organisations are probably the most powerful engines for the construction of europe, and in many cases open the road for legal and political advances. many medical specialties felt that there was a need for the harmonisation and standardisation of medical training over europe. the esr has shared this opinion and has elaborated a unanimously appreciated training curriculum, which is constantly updated. establishing the ebr (european board of radiology), with the mission to organise a european diploma was the logical next step. today, 10 examinations have already been organised and more that 350 candidates from european countries and abroad have applied. the trainee who passes the examination proves his professional skills and has reached the objectives assigned in the curriculum. in this session, we will explain how esr organises the diploma. we will review, capitalising on our current experience, the main lessons learnt from the past editions, the keys for success and reasons for failure, as seen by the examiners. we will also learn about the "diploma adventure", from the point of view of a successful candidate. national radiology training programmes in europe differ to a large extent, regarding length of training, content, and the presence or absence of a national board examination for certification. thus, for cross-border radiologic activities, the level of training and expertise applying to radiologists is difficult to assess under these circumstances. there is an increasing number of medical subspecialties, which organise european diplomas. more than 20 subspecialties (e.g. anaesthesiology, ophthalmology, urology, etc). organise european examinations, which are well received among the respective communities. growing numbers of residents in training successfully stand this test of knowledge and practical skills. recognition of european diplomas by national authorities is an issue, which will increase the level of acceptance. the present status of the recognition process in european countries will be summarised. case material for the diploma will test knowledge in general radiology at a standard to be expected at the end of training as outlined in the esr curriculum. all ten esr-recognised subspecialty areas of the curriculum will be tested. the written exam comprises two computer-based sections, a multiple response section, and a short case section. there will be 75 multiple response questions. these questions comprise both multiple options format, a single stem with 5 answer options, and short imaging studies where candidates are asked to either annotate the image from a drop-down menu, or select the radiological features displayed or differential diagnosis from the options given. a special scoring system has been developed to prevent guessing. the short case section comprises 4 or 5 case-based questions. you may practice using the self-assessment tests on the esr website which follow the same format as the written examination. for the oral cases, you must have a systematic method and perform under pressure, which takes practice. you may rehearse with experienced radiologists who feedback on your performance. you can break a radiology report into 3 areas, observations, interpretation and conclusion. conclusions should take into account the clinical information. candidates often forget this under pressure, so ask for it to be repeated. your differential diagnosis should be logical and comprehensive. the 3 commonest causes of an abnormality is a good topic to revise. suggest if further imaging tests are indicated and give an indication of urgency. each case is marked separately. as a well-known statement in the academic world of education, "assessment drives learning". with the help of carefully prepared and performed examinations, it is possible to emphasise and instill the training curriculum. due to different reasons, training of radiology in european countries is highly varied. like in our experience in turkey, a central examination system, accompanied by a neatly prepared training charter and curriculum, is a good starting point to solve the problem. we believe that a common european assessment system like edir will contribute a great deal to the harmonisation of radiological training and establishment of quality standard in every country. the need for harmonising the training is not unique to radiology. this is why in more than 30 medical disciplines, european diploma examinations are now being organised. furthermore, in some disciplines like urology, annual and online "in-service assessment" of residents and practising urologists allows the participants to evaluate their current knowledge base against the current european standards, and also provides the trainers and directors knowledge about the teaching and learning process in education centres. although there are huge diversities among different european centres, the urgent need of harmonising radiology training and setting a standard of quality are felt by all radiologists in europe. establishing and institutionalising a common assessment system in european radiology appears to be the shortest way to reach this goal. this is why we should support "european diploma in radiology" by any means and work hard to promote its recognition throughout the continent. the majority of emergency ct studies reported by junior radiologists or general radiologists out-of-hours comprise brain scans. brain ct studies are often performed to detect acute life-threatening abnormalities, such as stroke, intraparenchymal or subarachnoid haemorrhage, cerebral edema, etc. misrecognition of these often subtle, but life-threatening abnormalities can lead to inappropriate patient management and worsen patient outcome. errors in interpretation can generally be categorised as either perceptual or cognitive in nature. perceptual errors are those in which the radiologist does not see the abnormality, resulting in a false-negative interpretation (e.g. basilar artery thrombosis, deep cerebral venous thrombosis, pres,â�¦). cognitive errors, on the other hand, are those in which an abnormality is identified but the meaning or significance of the abnormality is not recognised. cognitive errors can result in false-positive interpretation if, for example, a normal anatomic variant is mistaken for a pathologic condition. while the more common normal variants and artefacts often do not present a problem to experienced clinicians and neuroradiologists, less experienced individuals should beware of these diagnostic hazards. to reduce false-negative and false-positive reporting, a checklist of the review areas (blind spots) to be verified on any brain ct scan will be offered and the most frequent normal variants will be discussed. pitfalls in brain imaging comprise perceptual or cognitive errors of interpretation of imaging findings. errors of perception refer to a missing of a pathology that is present on an image, while cognitive errors consist of a wrong interpretation of a seen structure or pathology. interpretation may be false negative or false positive. in addition, a wrong conclusion may be drawn resulting from missing, incomplete or false clinical information, or as a consequence of a lack of knowledge of differential diagnoses. perception errors are frequently the consequence of incomplete examination protocols where lesions are missed (for instance, acute ischaemic changes without the use of diffusion-weighted imaging) or signals, for instance, flow-related phenomena are misinterpreted. asymmetric positioning of the patient`s head may also lead to misinterpretation of side differences, especially in the temporal lobe. another source of perception errors might be reduced attention (especially at night shifts) and have been proved to occur in regions that are "potential blind spots", as the sulci, cavernous sinus, meckel cave, dural sinuses, brainstem, and skull base foramina. perceptual errors may be avoided by following a checklist when reading images. all sequences should be used for comparison of signal intensities to distinguish artefacts from pathology. another very important fact to avoid misinterpretation lies in a profound knowledge of morphologic and metabolic age-related changes of the brain and of anatomical normal variants (such as, for instance, accentuated virchow robin spaces in certain locations). cystic liver lesions can be classified based on their nature as benign and malignant. in the benign category are, among others, developmental and infectious/inflammatory cysts, while neoplastic cyst can be subdivided into primary and secondary. developmental cysts originate from abnormal ductal plate malformation and consist of hepatic (bile duct) cyst, bile duct hamartomas, caroli's disease and polycystic liver disease. infectious/inflammatory cysts include, among others, abscesses (pyogenic and amoebic) and hydatid cysts. primitive neoplastic cystic lesions are cystoadenoma and cystoadenocarcinoma. secondary lesions can originate mostly from mucinous tumours such as colon and ovary. the role of crosssectional imaging in the detection and characterisation of these entities will be discussed, with an emphasis on the differential diagnosis with ct and mr imaging. benign hepatocellular neoplasms are being recognised with increased frequency using cross-sectional imaging. one of the main goals is to be able to make a clear-cut differential diagnosis between focal nodular hyperplasia (fnh) and hepatocellular adenoma (hca) since patient management is substantially different. despite the sound knowledge acquired in the last few years about the morphological features of fnh using various cross-sectional imaging techniques, new players in the field have arisen such as diffusionweighted mr imaging (dwi) and use of hepatobiliary contrast agents. these new biomarkers offer a different view over fnh and allow a more accurate characterisation even in more atypical cases. concerning hca, current knowledge implies that the sub-types of this neoplasm should be known since, again, patient management differs and these patients are no longer seen as compulsory surgical candidates. these sub-types will be further discussed and the role of imaging for risk stratification (haemorrhage and malignant transformation) will be addressed. further, illustrative cases of combined fnh/hca cases will be demonstrated along with the main imaging clues for a successful differential diagnosis. imaging in the early postoperative period is complex. it is essential for radiologists to know the new anatomic arrangement after surgery and to understand the range of normal postoperative appearances. this latter aspect can be particularly difficult, because the radiological findings are affected by the type of operation performed (open vs. laparoscopic) and the complexity of the surgery (such as the presence of adhesions or haemorrhage) as well as the underlying comorbidity of the patient. patients may be considered in 4 broad categories: haemodynamically unstable patients who may be bleeding; patients with distension or unopened bowels who may have obstruction or ileus; patients with sepsis in whom to search for an intraabdominal collection or leak; and patients who do not follow an expected recovery for which the cause is unclear. ct is the primary imaging technique, with ultrasound reserved predominantly for liver and renal transplants or assessment of perihepatic collections, and fluoroscopy for routine postoperative assessment of upper and lower gi anastomoses. ct protocols should be optimised to detect particular complications with positive luminal contrast for assessment of anastomotic leaks (8%), triple phase imaging for bleeding (without positive oral contrast) and delayed phase imaging to detect ureteric injury. since each operation has a specific range of expected complications, these should be considered when deciding on the protocol and in light of the patient's clinical status. excellent communication with the surgical team is required to make an accurate diagnosis and in particular where haemostatic compound or mesh for hernia repair was used. learning objectives: 1. to understand the best imaging options for investigating suspected postoperative complications. 2. to appreciate the normal appearances of the abdomen and pelvis after surgery, in particular with regard to free fluid, haematoma and free gas, and when to suspect complications. radiologists should be aware of the newer surgical techniques and expected post-operative alterations, to yield a correct interpretation of a post-surgery imaging examination, thus being able to differentiate a normal post-operative finding from a potential complication. in this setting, it is crucial to perform a technically adequate imaging examination, so that post-operative anatomical and functional findings may be evaluated. therefore, the aim of this lecture is to give an overview of the contribution of various imaging modalities in the diagnosis of late post-operative complications following gi tract surgery. it will include a mention of the technical issues that need to be considered to achieve better diagnostic accuracy, as well as a description and illustration of the main imaging findings of late post-operative complications. those include diseaserelated (recurrence for malignancy or inflammatory disease) and procedurerelated (anastomotic strictures, internal herniation, adhesions and intussusception, among others) complications. focus will be placed on crosssectional imaging techniques, which at present constitute the workhorse for detecting and characterising late post-operative complications after gi tract surgery. in this way, imaging has an obvious and pivotal role in planning therapy, since some late complications are usually treated in a conservative way while others require a surgical approach. lung biopsy of a suspected lung cancer remains a well-established technique for histopathologic examination in patients with suspected lung cancer. complications can nevertheless occur and therefore indication should be given after carefully balancing the benefits and drawbacks for a particular patient. the method should be clearly considered complementary to alternate methods of tissue sampling, fiberoptic endoscopic, mediastinoscopy or us-guided endoscopy, surgical biopsies and resection during a multidisciplinary discussion. several steps are needed in the preparation of the biopsy procedure, including informed consent, management of anticoagulation and anti-platelet medications, imaging assessment of the lesion and its environmental lung, and planing of the needle trajectory procedure. the choice of the guiding method and the most appropriate biopsy needle is still largely dependent on local skills and habits. ct-guided percutaneous biopsies using coaxial automated core biopsy needles offer many advantages. needle manipulation can help to reach difficult targets. participation of the patient is needed in terms of respiratory manoeuvres and breathhold. complications may occur such as pneumothoraces haemorrhage and air embolism. knowledge of the respective risk factors and the potential method of prevention or treatment by operators are essential. the therapeutic response of lung cancer can be objectively evaluated on the basis of changes in the tumoural size or depiction of metastases, such proposed in the recist criteria (response evaluation criteria in solid tumours). recent advances in cancer biology have triggered development of novel targeted therapies designed to disrupt specific biologic pathways. among them, antiangiogenic drugs represent a promising strategy for non-small cell lung carcinomas (nsclc). these agents are more cytostatic rather than cytotoxic, explaining the limitations of tumour response assessment based on morphological criteria. dynamic contrast-enhanced imaging techniques have the potential to quantify tumoural angiogenesis. in particular, dynamic contrastenhanced multidetector-row ct (dce-ct) represents a promising tool to provide non-invasive and repeatable assessment of the angiogenic process within non-small cell lung cancers (nsclc), offering the possibility to generate morphological and functional information from the same examination. dce-ct allows the calculation of regional tumour blood flow, blood volume, flowextraction product, and permeability-surface area product, over the entire tumoural volume, using mathematical models and dedicated softwares. dce-ct can depict early changes in lung cancer vascularity, before tumour shrinkage, that could help predict response to antiangiogenic drugs. becoming familiar with this technique enables the radiologist to integrate it into clinical practice and to assist the thoracic oncologist in the pre-therapeutic and follow-up evaluation of nsclc patients treated by antiangiogenic drugs. this new approach should improve patient's selection for targeted therapies. a-343 09:30 it is now accepted that pet-ct is of value in the staging of lung cancer and reduces the number of unnecessary thoracotomies. its role has been further clarified by recent publications on its value in assessing mediastinal nodal involvement, tumour aggressiveness using either standardised uptake value or total glycolytic volume, and response to neoadjuvant chemotherapy. more recently, mri has been investigated as a tool to detect distant disease using diffusion-weighted imaging, and there are a number of trials that have compared both pet-ct and dwi mri retrospectively and prospectively. this presentation will summarise the current available data and the likely benefits of either imaging modality neurological deficits in children are an urgent condition that depends significantly on imaging for a prompt and accurate diagnosis because of the significant overlap present in clinical history, presentation and neurological examination. different imaging modalities, such as ultrasound, computed tomography (ct) or magnetic resonance imaging (mri), are utilised dependent on the age of the patient and neurological symptoms. the purpose of the present lecture is to discuss the causes and imaging appearance of acute neurological conditions in childhood, broadly classified into stroke, infection, inflammatory demyelination, metabolic disorder, cerebral neoplasm or neurotoxicity. imaging also plays an outstanding role in the management of paediatric oncology patients presenting with acute neurological symptoms related to disorders of blood cell counts, immunosuppression, neurotoxicity of therapy, or progression of the primary malignancy. a review of the main indications to perform a neuroimaging procedure in these children will be undertaken as well as a differential diagnosis based on representative cases selected from the daily routine in a paediatric tertiary hospital. practical algorithms with the preferential use of either ct or mri will be developed for each section. ct continues to be the first imaging modality in these patients in many centres, despite the accompanying radiation, because of the easy availability and no requirement of sedation. however, mr imaging is nowadays better for imaging these children owing to no radiation, the more completely provided information and the useful advanced techniques that can be used, such as diffusion imaging (di), spectroscopy, arterial spin labelling (asl), and susceptibility weighted imaging (swi). learning objectives: 1. to learn about the currently limited role of ct in the non-traumatic acute setting. 2. to become familiar with radioprotection strategies and protocols adapted to children. 3. to consolidate knowledge on the role of mri as the modality of choice for acute non-traumatic neurologically ill children, with an emphasis on newer techniques. 4. to become familiar with imaging findings and the main differential diagnosis of acute neurological conditions in children. b. imaging of acute chest pain and distress in children c.e. de lange; oslo/no (clange@ous-hf.no) acute chest pain in children is a common complaint in the emergency department, but patients rarely present with significant distress or lifethreatening symptoms requiring immediate care or resuscitation. the most frequently reported cause is benign musculoskeletal pain followed by respiratory and gastrointestinal causes, while cardiac causes are less frequent. a thorough clinical history and careful physical examination will determine, in most cases, the patients in need of further investigation to establish a diagnosis. in this regard, radiology plays an important role, especially in the emergency setting in patients with more serious associated symptoms like acute breathing difficulties, swallowing problems, fever or sepsis. when choosing the appropriate technique for investigation, the consequences of radiation exposure in children must be considered. plain radiography and fluoroscopy still remain the most important and frequently used tools to gain information on various acute chest/pulmonary problems. ultrasonography is the first choice for diagnosis/treatment of pleural effusions. multidetector computed tomography and magnetic resonance imaging are mainly used for investigating pulmonary/mediastinal masses and congenital abnormalities of the great vessels and the lungs. this lecture will discuss the choice of imaging technique and the urgency of radiological management depending on the symptoms and age of the patient. the imaging characteristics of the different causes of acute chest pain and/or distress in children will be reviewed, represented by the more common conditions involving the chest wall, respiratory tract, oesophagus and the heart, as well as less frequent causes such as tumours, manifestations of congenital malformations and nonaccidental trauma. outcome data from trauma series have demonstrated improved patient survival by the prompt diagnosis of a range of injuries and the recognition of life-threatening sequels, principally that of active arterial haemorrhage. widely used trauma scoring systems are applicable in the paediatric population, although the mechanisms and combination of injuries may differ from those encountered in adults. a ct diagnosis of active haemorrhage demands early operative or non-operative intervention with embolisation or use of alternative endovascular techniques including deployment of vascular stents. this principle is applicable to blunt or penetrating liver, splenic, renal or pelvic trauma. it is also applicable in some cases to severe mediastinal and limb vascular injury. important caveats are firstly the use of ct in an overall trauma service and avoidance of any inappropriate irradiation. secondly, in paediatric interventional practice, due regard needs to be given to the delivery of implantable devices that may have adverse sequels in later life. nevertheless, the demand for immediacy in intervention may outweigh any such consideration. this presentation will summarise the importance of imaging and intervention in both the early and delayed complications of trauma with an emphasis on abdominal and thoracic trauma. brachial plexus originates from the ventral branches of the cervical nerve roots from c5 to t1. it is composed of roots, trunks, divisions, cords, and branches, topographically divided into supraclavicular (roots and trunks), retroclavicular (divisions), and infraclavicular sections (cords and branches). mri has the advantages of multiplanar imaging, high tissue contrast, and relative paucity of artefacts. the t1-weighted sequences display topographic anatomy including muscles, blood vessels, and nerves stressed by tissue fat planes. the nerves appear as elongated fibres that are isointense to the scalene muscle, posteriorly and superiorly to the curvilinear flow void of the subclavian artery. the fat-suppressed pd and t2-weighted and stir sequences detect signal alterations of the bp. general abnormal findings include: loss of fat planes around part or all bp components, nerve signal abnormalities with mild or marked hyperintensity on t2-weighted images that can be associated with swelling, focal or extensive enhancement of the nerves after gad injection on t1 fat sat images. differences in signal intensity should be judged by visual inspection, which is susceptible to a subjective point of view; the comparison of both sides of bp has a relevant role in judging the presence of signal alterations, especially when they are smooth and/or focal. the pathology of brachial plexus can be divided into nontraumatic and traumatic brachial plexopathies. among nontraumatic brachial plexopathies, we find radiation fibrosis, metastatic breast cancer and primary or metastatic lung cancer. other pathologies are tumours and inflammatory disease or thoracic outlet disease. the peripheral nerves of the upper limb are affected by a number of entrapment and compression neuropathies. these syndromes involve the brachial plexus as well the musculocutaneous, axillary, subscapular, ulnar, radial and median nerves. clinical examination and electrophysiological studies are traditionally the mainstay of diagnostic workup. however, ultrasonography and magnetic resonance imaging (mri) may provide key information about the exact anatomic location of the lesion or may help to narrow the differential diagnosis. in certain patients with the diagnosis of a peripheral neuropathy, imaging using either ultrasonography or mri may help establish the cause of the condition and provide information crucial for conservative management or surgical planning. in addition, imaging is particularly valuable in complex cases with discrepant nerve function test results. a variety of peripheral neuropathies can be encountered in the lower limb. most are entrapment syndromes affecting many nerves, such as the sciatic, gluteal, femoral, lateral femoral cutaneous, obturator and pudendal around the hip, the peroneal and its branches and the saphenous at the knee, the superficial peroneal at the lateral leg, the tibial with its plantar and calcaneal branches at the ankle, the deep peroneal and the interdigital nerves in the foot. although clinical examination and nerve conduction studies are the mainstay of the diagnostic workup of peripheral neuropathies, ultrasound (us) and magnetic resonance (mr) imaging may provide key information about the exact anatomic location of a lesion and the nature of the constricting finding or may help narrow the differential diagnosis. in patients with peripheral neuropathies of the lower extremity, us and mr imaging may provide critical information for planning an adequate treatment strategy. although us and mr imaging have followed parallel paths for nerve imaging with little comparison of the two modalities, us seems to have some advantages over mr imaging, including higher spatial resolution, time effectiveness, the ability to explore long nerve segments in a single study and to examine tissues in both static and dynamic states. advances in diagnosis of acute stroke have been achieved by brain imaging. ct or mri distinguish ischaemia from haemorrhage and may identify acute clot (dense artery sign) or vessel wall pathology by "black blood mri". dwi provides evidence of early infarction. ct and mra enable identification of large vessel pathology as potential source of embolic or haemodynamic ischaemia. supplementary techniques are ct or mr perfusion. on mri perfusion, a mismatch between the area of restricted diffusion and perfusion (pwi) is a signature of the penumbra. the tissue of pwi restriction outside of the dwi abnormality represents "tissue at risk". similarly on ct perfusion, the region of reduced cerebral blood volume presumably represents irreversible infarction and the area of reduced cbf and extended mtt visible beyond the cerebral blood volume abnormality represents potentially reversible ischaemia. morphologic imaging and advanced standardised perfusion/penumbral stroke protocols aim at identifying lesions that are amenable to acute stroke therapy and exclude pathologies that mimic stroke but do not represent vascular disease. since iv tpa has become an approved therapy from 1996, the number of acute stroke patients entitled for treatment has remained limited (~ 5) despite extension of the time frame from 3 to 4.5 h. dwi-flair mismatch and an individualised assessment of the ischaemic penumbra may serve in the identification of patients within the appropriate time frame. by selection of patients with advanced brain imaging and initiation of appropriate therapy, a further increase in good outcomes and reduction of the incidence of symptomatic haemorrhage may be achieved. in recent years, the role of imaging in the patient admitted with an acute neurologic deficit has changed significantly, due to the arrival of new treatments for acute stroke, aimed at re-establishing blood flow, reducing infarct size and protecting the brain at risk. the first goal is to differentiate haemorrhagic from ischaemic stroke and to rule out other stroke mimics. this can be achieved by performing nonenhanced ct scan of the brain. the next strategic imaging objectives include: demonstration of major blood vessel occlusion (e.g. by ct angiography) and identification of potentially salvageable brain tissue, the so-called "penumbra" (e.g. by ct perfusion). ct angiography is performed during rapid intravenous bolus injection of a high-concentration iodinated contrast agent. the fov should cover not only the intracranial arterial circulation, but also the arteries of the neck, to exclude dissection. ct perfusion is also achieved by bolus injection of contrast, followed by a series of fast images or volume acquisition. ct densities change over time and reflect the iodine concentration. perfusion images are processed to generate parametric maps, which reflect: regional cerebral blood flow (rcbf), blood volume (rcbv), mean transit time (mtt), and time to peak (ttp).the combination of ct angiography and ct perfusion provides a unique insight into the pathophysiology of the cerebral circulation. these techniques are now essential tools in the management of acute stroke and in selecting those patients who are potential candidates for advanced therapies such as thrombolysis or thrombectomy. learning objectives: 1. to become familiar with a comprehensive imaging protocol in patients with suspected stroke. 2. to understand the advantages and limitations of cta and perfusion in the initial work-up of stroke patients. 3. to recognise the different imaging patterns in stroke and their prognostic value. a-352 08:58 b. stroke mimickers and pitfalls p. vilela; lisbon/pt (ferrovilela@sapo.pt) "stroke mimic" is classically used to describe nonvascular diseases that present with acute focal neurologic deficit corresponding to a consistent vascular distribution, which may resemble or may even be indistinguishable from stoke. it is estimated that up to 15% of stroke-like presentations are due to mimickers. there are several neurological and psychiatric disorders that can have such a clinical presentation, such as seizures and/or postictal status, the most frequent one. the other classical clinical stroke mimickers include: multiple sclerosis, migraine (specially hemiplegic migraine), metabolic disturbances (more commonly hypoglycaemia/hyperglycaemia), intracranial tumours or infections and the conversion reactions. brain imaging plays a key role in the diagnosis and management of acute stroke by differentiating ischaemic from haemorrhagic lesions, identifying the vessel occluded and estimating the viable brain tissue that is at risk for stroke. imaging is also important to exclude some of the aforementioned stroke mimics. the more comprehensive stroke imaging protocols, with ct perfusion/angiography and/or with mri, have reduced significantly the misdiagnosis of stroke. mri-dwi is the most sensitive and specific imaging modality for depicting ischaemic stroke. however, it is also essential to be aware that there are some pathological processes that can mimic stroke in imaging studies. these include some disorders that may present themselves with lesions associated with restricted diffusion, like transitory postictal brain abnormalities, migraine and encephalitis. the author reviews the most common clinical and imaging stroke mimics and highlights the importance of brain imaging in depicting these mimickers and avoiding the potential adverse effects of stroke therapy in these patients. learning objectives: 1. to learn the differential diagnosis of stroke. 2. to understand the role of ct and mri in the work-up of stroke and related disorders. 3. to recognise imaging patterns that may mimic stroke clinically and radiologically. imaging plays a central role in the management of stroke, which is an important health issue according to the number of patients involved and the severity of the disease. it helps to select patients who will benefit from a revascularisation therapy (iv thrombolysis or endovascular treatment) at the acute phase of stroke. if the value of perfusion/diffusion mri mismatch in the evaluation of penumbra is still a matter of debate, other imaging factors are associated with the clinical outcome including length of clot, flair positivity, and collateral circulation. if iv thrombolysis using rtpa is still the reference treatment, endovascular treatment is emerging since several years as a feasible and efficacious alternative singularly since the appearance of stent retrievers. recent neutral randomised trials comparing iv thrombolysis and endovascular treatment have shown the critical role of appropriate imaging in the selection of patients who can benefit from acute revascularisation as well as the importance of using the most efficacious endovascular devices. prevention of stroke is partially based on the treatment of cervical and intracranial stenosis. several randomised trials comparing carotid angioplasty and carotid endarterectomy were initially negative, but a recent meta-analysis showed that below the age of 70 years both techniques were equivalent. the place and value of endovascular treatment of intracranial arterial stenosis is still controversial after the publication of the sammpris results. the management of thyroid nodules has been continuously evolving. i hope that during this session you will understand the important differences in the upto-date national and international guidelines on thyroid nodule management and understand the role of the radiologist in the multidisciplinary thyroid meetings. the features that are suggestive of benign, indeterminate and malignant nodules will be demonstrated. advances in both radiological and cytological techniques such as us elastography and braf mutation analysis that may help triage patients with thyroid nodules will be covered. the differing biopsy techniques (fine needle aspiration, non-aspiration (fna and fnnac) and trucut biopsy) and their roles will be highlighted. there will be time for an open question and answer discussion with all the speakers before the end of the session. the management of thyroid nodules and the guidelines of the various interested parties, surgeons, endocrinologists, nuclear medicine physicians, radiologists and ultrasound specialists, vary across the world, indeed between different countries within the eu, and are constantly evolving. i will discuss how the thyroid multidisciplinary meeting (mdt) works at our institution and the role of the radiologist in it. the current differing international guidelines on the management of thyroid nodules will be mentioned, highlighting their salient points and differences. the role of the differing imaging modalities used in the management of thyroid nodules will be discussed based on differing clinical scenarios. finally, the management of the common clinical scenario of the incidental thyroid nodule will also be discussed. learning objectives: 1. to understand the role of the radiologist as part of a multidisciplinary team. 2. to learn about current guidelines on the management of the thyroid nodule. 3. to understand the role of various imaging modalities in the patient with thyroid nodule. thyroid disease is ubiquitous and usually benign; therefore accurate imaging of the thyroid is a major challenge for radiology. significant advances in conventional ultrasonography allow superb visualisation and anatomic characterisation of thyroid pathology and the impact of broader bandwidths, higher frequencies, spatial compound imaging and novel signal processing techniques will be discussed in this session. the key b mode features of thyroid nodules are discussed with reference to relevant clinicoradiological guidelines, specific pitfalls and limitations. a significant number of nodules remain indeterminate after conventional assessment, and imaging advances that enable more accurate, non-invasive thyroid characterisation are highly attractive, potentially reducing unnecessary biopsy and surgery for a large number of patients. ultrasound elastography offers a potentially useful adjunct to conventional sonography in thyroid disease with a growing evidence base indicating that thyroid malignancies are typically stiffer than benign lesions and that a 'soft' cutoff value with a high negative predictive value is feasible. however, elastography studies have included a variety of different techniques, patient/nodule selection and assessment methods; therefore the current role of elastography will be discussed. fine needle biopsy of the thyroid nodule f. campoy-balbontã­n, m.c. jurado-gomez; sevilla/es (fcampoy2000@gmail.com) thyroid nodules are very common. the clinical importance of thyroid nodules rests with the need to exclude thyroid cancer, which occurs in 5-15%. ultrasound (us) has been widely attempted to differentiate benign from malignant nodules and to guide fine needle biopsy (fnb). however, considerable overlap between benign and malignant characteristics has been found. nowadays, there are a number of different guidelines for the management of thyroid nodules. at our hospital, we have adopted the guideline proposed by the society of radiologist in ultrasound (2005). the different elements necessary to perform the fnb procedure are demonstrated; the transducer probe, the needles, the slides, the syringe. the way of managing these elements is shown by figures and videos, with different skills and performances to optimise the procedure and get the best sample. uscontrol fnb can be in parallel or perpendicular, both methods are demonstrated. thyroid fnb is usually non-aspirated, but sometimes it has to be undertaken with aspiration; when and how to change from one method to another is explained. with good technique, the insufficient cytological rate can be significantly reduced, with which the need for core biopsy diminishes. although the complication rate for core biopsy is low, fnb is safer and if performed correctly has a high diagnostic yield. core biopsy should be limited to those nodules with a second insufficient fnb cytological result, with us findings suspicious for malignancy. multimodality breast imaging is emerging as radiologists have access to new technologies coinciding with the refinement of operative techniques. one of the challenges for radiologist remains the correct preoperative staging, especially the metastatic involvement of axillary lymph nodes. multimodality imaging has new accurate solutions. the imaging follow-up of patients with sophisticated oncoplastic techniques is another challenge where multimodality breast imaging is the solution. coincident with this increasing contribution to the diagnostic process is the emerging role of the breast imager as a therapeutic clinician, making use of innovative image-guided procedures. in this integrated rc, experts will present a clinical update on these newer techniques and there will be an opportunity to discuss how the evolution of such techniques is changing the nature of the modern multidisciplinary team meeting. a. conventional, functional and interventional lymph node assessment r.m. pijnappel; utrecht/nl (r.m.pijnappel@umcutrecht.nl) metastatic involvement of axillary lymph nodes has been known to be one of the most important prognostic factors for women with breast cancer. the traditional approach to staging the axilla is either lymph node sampling procedures or sentinel node biopsy. the main diagnostic features of potentially malignant involvement of the axilla are abnormal lymph node morphology (shape and cortical thickness). there has been a concerted effort in recent years to find imaging techniques that might facilitate accurate axillary staging. so far, no imaging technique alone (ct, mri, scintigraphy and ultrasound) has been capable of differentiating between positive and negative lymph nodes of the axilla in breast cancer. recent techniques like gadofosveset-enhanced magnetic resonance imaging and high spatial resolution 7-t mri imaging appear promising; however ultrasound-guided sampling of suspicious lymph nodes by core or fna remains the standard of care in assessing the axilla prior to treatment planning. ultrasound-guided axillary lymph node sampling is an effective method of assessing the axilla. a recent meta-analysis shows that ultrasound can be expected to achieve sensitivity approaching 50% for detecting abnormal nodes in those that eventually prove to be nodal metastatic disease. the false-negative rate where biopsy is performed is around 25%. it is impossible to detect the sentinel node by ultrasound alone. therefore a new promising technique was introduced, injecting an ultrasound-contrast agent around the nipple. using this method, it is possible to detect the sentinel node in 90% and therefore lower the false-negative rate of us-guided biopsy with another 15%. oncoplastic breast procedures were introduced to fill the gap between comprehensive oncologic surgical treatment of breast cancer and the achievement of cosmetic results that fulfill patient expectations in both, body imaging and psychological well-being. due to its complexity and relevance for the patient, the decision of performing these procedures must be made as part of the multidisciplinary approach of breast cancer treatment. as a consequence, the role of breast radiologists has expanded beyond the anatomic region of the breast and the usual imaging techniques. basic knowledge of the different oncoplastic techniques is mandatory to understand the spectrum of findings from a multi-modality approach. implants and/or autologous reconstruction techniques (pedicle, free or perforator flaps, as well as lipofilling techniques) are widely applied. the role of the radiologist in the multidisciplinary team is twofold: assessment during the planning stage, and imaging evaluation at follow-up. the assessment during the planning stage includes the determination of the local extent of the disease that makes the choice of the appropriate surgical technique possible, and the imaging study of the donor site in those cases where autologous reconstruction is elected. imaging evaluation at follow-up comprises the recognition of changes and potential pitfalls after reconstruction, the identification of short/mid/long-term reconstruction complications, and the detection of recurrent/second carcinomas. controversial aspects will be reviewed, such as the probability of recurrence after oncoplastic surgery, the need to establish multimodality follow-up protocols and the interrelations between the autologous tissues and the mastectomy bed or remaining breast. the use of image guidance for surgical planning has only recently been accepted. the use of intraoperative ultrasound in women undergoing lumpectomy is associated with a higher rate of negative margins. the combination of image guidance and radiological intervention techniques also harbours the possibility of tumour treatment without surgery. most techniques make use of the placement of needles within the tumour. treatment is performed by heating, freezing or extracting the tumour tissue. currently, radiofrequency ablation under ultrasound guidance is being furthest evaluated. however, in rfa even after optical complete tumour ablation, residual vital tumour tissue is still found in many cases. this is mainly dependent on tumour size with poorer results (50-60% success rates) in tumour over 2 cm, and better results (~90% success rate) in smaller tumours. adequate tumour size estimation is thus of vital importance. currently, since remaining vital cells cannot be excluded, the technique is limited to use in patients who cannot undergo surgery due to poor health state. larger series in which rfa is combined with radiotherapy have not been reported. it is therefore not clear whether it is important to actually excise residual vital tumour. similar restrictions currently hold for cryotherapy, laser ablation and hifu. large vacuum-assisted needles and the breast lesion excision system can be used to remove the tumour through a minimal incision in the skin. however, margin evaluation is difficult. nevertheless, these techniques are already optional for the removal of high-risk lesions and can potentially be combined with (focused) radiotherapy. the mã¼llerian ducts are paired embryologic structures that undergo fusion and resorption between the 6 th -11 th weeks of gestation to give rise to the uterus, fallopian tubes, cervix, and upper two-thirds of the vagina. non-development, defective vertical or lateral fusion, or resorption failure of the mã¼llerian ducts can result in formation of mã¼llerian duct anomalies (mdas), whose reported prevalence ranges between 0.4% and 8%-10%. the classification revised by the american society for reproductive medicine in 1988 is the most widely accepted. obstructive mda can occur in infants as palpable pelvic mass, at menarche with cyclic pelvic pain, or pelvic mass, and primary amenorrhea. complications include hematocolpos, hematometra, hematosalpinx, endometriosis, pelvic adhesions, and obstruction of urinary tract. mdas are commonly associated with renal and other anomalies; thus, identification of both kidneys is important. accurate diagnosis of an mda is essential because of the high associated risk of infertility, endometriosis and miscarriage, and since the management approach varies depending on the type of malformation. hysterosalpingography (hsg) is routinely used in evaluation of infertility. because a key component of mdas characterisation is the external uterine fundal contour, hsg is limited for this purpose. ultrasonography (us) is initially performed to evaluate uterine anatomy and to assess for associated renal abnormalities. mri is reserved for complex or indeterminate cases to characterise the uterine anomaly and evaluate the possibility of a vaginal abnormality, or after a seemingly normal us when clinical opinion ensures its use, or to make decisions on management strategies and preoperative planning. this refresher course will focus on the radiologist's approach to using pet-ct within the context of the gynaecologic oncology multidisciplinary meeting. the current indications for using fdg-pet/ct will be discussed for cervix, endometrial and ovarian cancer as well as the potential use of fdg-pet/ct in rare gynaecologic cancers. the value of adding fdg-pet/ct to the patient management pathway will be presented alongside the potential pitfalls in interpretation as well as controversies. future developments, including potential new tracers, will be mentioned. cystic lesions account for the vast majority of ovarian masses and are detected incidentally in 5-18%. their spectrum ranges from non-neoplastic cysts to benign tumours, e.g. cystadenomas and dermoids to the rare ovarian cancer. diagnostic criteria in us, ct and mri are based on the clinical background (age, menopausal status, medical history, and tumour markers) and the morphology of the ovarian mass. typical of a benign cystic lesion is its pure cystic structure or thin septations, fatty or haemorrhagic contents, and mild enhancement of solid components in a complex solid and cystic ovarian mass. thus, patients can be categorised into 3 different risk groups. sonography has been established as the first-line imaging modality to assess the ovaries. recently, management guidelines have been adopted for cystic ovarian lesions. in these guidelines, also cystic adnexal incidentalomas are included. mri is most useful as a complementary technique in sonographically indeterminate masses. an algorithmic approach will render a specific diagnosis in the vast majority of cases. in complex cystic lesions, integration of dwi and dynamic contrast-mri allows differentiation of rare benign complex tumours, e.g. cystadenofibroma from ovarian cancer. pitfalls of cystic ovarian tumours include cystic fibroids, peritoneal cysts, and extraperitoneal cystic tumours. compared to us, both ct and mri are superior in assessing large cystic pelvic masses. criteria to differentiate between intra-and extraperioneal origin include displacement patterns and identification of the vascular pedicle. careful analysis of imaging and clinical findings usually allows differentiation of inflammatory tumours from ovarian cancer. learning objectives: 1. to learn about specific imaging algorithms of ovarian cystic tumours. 2. to understand certain imaging features that can differentiate ovarian from non-ovarian cystic tumours in the pelvis. 3. to become familiar with the pitfalls in imaging of ovarian cystic tumours and the lessons to be learned from them. the diagnostic methods available in patients with conductive hearing loss are: personal and family history, otoscopy, audiology, imaging, surgical inspection and counseling. the most important reasons for imaging are: atypical history, suspicion of congenital hearing loss, suspected otoscopic image, asymmetric bone conduction thresholds, profound mixed hearing loss and suspected tympanometry. ct can be used to detect otosclerosis, tympanosclerosis, posttraumatic ossicular lesions, superior semicircular canal dehiscence and cholesteatoma. mri can be used to exclude schwannoma, congenital cholesteatoma and residual and recurrent cholesteatoma after prior surgery. this lecture will illustrate the value of ct and mri in the evaluation of cholesteatoma patients as well as prior to first stage surgery and prior to second look surgery. different subtypes of surgery will be highlighted and illustrated. the growing importance of mr imaging and diffusion weighted (dw) imaging in particular will be illustrated in the evaluation of cholesteatoma patients. the role of echo-planar and non-echo-planar dw imaging will be discussed as well as the eventual use of delayed gadolinium-enhanced t1weighted imaging. mr is the modality of choice in patients with congenital or acquired sensorineural hearing loss (snhl) and the complete auditory pathway from the cochlea to the auditory cortex must be studied in these patients. the labyrinth, internal auditory canal (iac) and cerebellopontine angle (cpa) are best studied using submillimetric heavily t2w images, showing the intralabyrinthine fluid and nerves. but submillimetric gd-enhanced t1w images or 3d-flair images remain more sensitive. the auditory pathway in the brainstem is best studied with a multi-echo sequence (m-ffe/medic/merge) or t2w tse sequence and the auditory cortex is best studied on t2w tse images. the clinical information provided by the otologist will direct the radiologist to a certain part of the auditory pathway or will let him use certain imaging techniques. for instance, congenital malformations in the labyrinth and iac must be excluded in case of congenital snhl, and in case of mixed hearing one will start with ct to exclude otosclerosis. the most frequent pathology in the labyrinth (labyrinthitis, intralabyrinthine schwannoma, congenital malformation, post-traumatic lesions), the iac and cpa (cochleovestibular schwannomas, meningiomas, epidermoid tumours and facial nerve neuritis) and central auditory pathway (ms, infarction, tumor and trauma) will be illustrated using clinical examples and the important "otologist-radiologist" team work will be stressed. for tumours that nearly always arise from the investing mucosa, like in the larynx and hypopharynx, it is endoscopy that directly maps the superficial extent and grades the functional impairment (arytenoid and vocal cord movement, pyriform sinus distensibility). in addition to white light, the recent use of narrow band imaging endoscopic technology, enhancing fine capillaries in the mucosal surface, enables the detection of neoangiogenesis caused by early squamous cell carcinoma. conversely, submucosal spread is the domain of cross-sectional imaging techniques. therefore, it is the integration of the two classes of data, along with the information about patient conditions, which permits the choice of the most proper treatment strategy. in early and advanced glottic cancer, treatment planning is modulated by information about deep neoplastic invasion into the paraglottic space, the cartilage or the suprasubglottis subsites. this information can be derived by discriminating the tumour tissue from intra-laryngeal muscles, fat spaces and the cortical rim of ossified cartilages. though mr shows a greater contrast resolution than ct, it is hampered by a significantly longer acquisition time. this means more artefacts caused by breathing and movement. nevertheless, mr has the potential to unravel the signals from submucosal tissues, separating tumour from oedema, muscles, fat and ossified cartilages. advanced laryngeal and hypopharyngeal cancers need to preliminary assess local (nodes) and distant (metastases) spread. ct-pet is the more accurate tool. the multidisciplinary approach to the processing of the whole frame of data is essential to offer the patient the best care. traditionally, x-ray ct scanners were equipped with a single or a few detector rows only, image reconstruction was assuming parallel slices, which was a good approximation for these fan-beam systems. about a decade ago the number of slices increased to 16 or more and the parallel slice approximation was no longer valid. the cone-beam nature of these multi-slice ct (msct) scanners had to be taken into account by specific cone-beam reconstruction algorithms. while these msct systems -today they are simultaneously acquiring up to 320 slices -are cone-beam ct systems in a general sense, the notion of cone-beam ct (cbct) is also associated with a specific kind of conebeam ct, namely those equipped with flat detectors, i.e. the non-diagnostic or non-clinical ct systems. msct, in contrast, is a cone-beam ct system for diagnostic use, i.e. a clinical ct system. this distinction between msct and cbct is useful, as there are decisive differences in application, performance, and in image reconstruction. these differences will be reviewed in the presentation, with a particular focus on why image quality in msct is so much better than in cbct. cone-beam (cb) imaging with flat detectors is performed on a variety of different imaging systems. the most important area is cb imaging using interventional c-arm systems. the minimally invasive procedures carried out on these systems benefit from the availability of high-resolution 3d images for intervention planning, guidance and outcome control. interventional cb imaging was first applied in neuroradiology using rotational angiography acquisitions. today, it is used for a variety of procedures in interventional radiology, cardiology and oncology based on angiographic and soft tissue protocols. one of the inherent advantages of this approach is the direct registration of the volume images into the interventional procedure. other application areas of cb imaging using different scanning systems are onboard imaging in radiation therapy or the integration of flat detector tomography and spect. this part of the course teaches the generation of 3d volume information from flat detector systems and its utilisation in different clinical applications. image acquisition protocols, scan modes, and system design parameters are explained. application-specific calibration and processing steps are introduced to show how cb imaging is tailored for specific clinical applications. examples are presented for angiographic and soft tissue volumetric imaging. medical applications utilising the tomographic images for diagnosis, intervention planning, guidance, or outcome control are discussed. in the last decade, three-dimensional dentomaxillofacial imaging through conebeam ct (cbct) technology has become widely available. dental cbct (digital volumetric tomography; dvt) equipment is compact and often affordable to dentists. the driver for dental cbct was implant dentistry, but its use has spread to other areas, including paediatric applications. radiation doses are variable. some systems offer a fixed, large, field of view and others fixed exposure factors, obstructing attempts at optimisation. typically, doses are at least an order of magnitude greater than for "conventional" imaging. image quality is also variable, which means that certain equipment may be unsuitable for some clinical applications. there is often scope for lower exposure factors to be used than those recommended by manufacturers. a key aspect of using cbct relates to justification. imaging in three dimensions may be perceived by dentists as inevitably superior, a view which is often implicitly encouraged by those selling equipment. the research on diagnostic efficacy is, however, limited. in 2012, the european commission published "radiation protection 172: evidence-based guidelines on cone beam ct for dental and maxillofacial radiology". this provides a comprehensive set of recommendations, including referral criteria, a quality assurance programme and optimisation strategies. priorities for future research relate to exposures to the necessary image quality requirements for specific clinical applications, along with research on the impact on clinical outcomes of cbct-based treatments. it is clear that much work remains before the place of cbct in dentistry can be established. the role of nonvascular interventional radiology of thorax for both diagnosis and treatment has significantly increased in the last 20 years. although these procedures are technically easy with highly successful results, thoracic nonvascular interventional procedures are not unfortunately routinely performed in all of the interventional units. the most commonly performed procedures generally under ct guidance are transthoracic biopsies of the lung, mediastinal lesions and pleura. the others include percutaneous drainage of thoracic collections such as pleural effusions, empyema and mediastinal collections. image-guided tumour ablation performed by either radiofrequency ablation (rfa) or microwave (mw) as a nonvascular thoracic intervention has become a serious treatment alternative in patients with lung tumours (either non-small cell lung cancer or lung metastasis) since the year 2000. interventional radiologists are expected to understand the clinical indications of these procedures at the first step. in addition, the techniques of the procedures and possible risk of complications in their management methods should be learnt by interventional radiologists as well. this refresher course will help us to discuss the main indications, techniques and complication management of these procedures. a. lung biopsy t. sabharwal; london/uk (tarun. sabharwal@gstt.sthames.nhs.uk) lung biopsy is most commonly now performed under ct guidance. it has a high technical success rate. common complications include pneumothorax, bleeding, sepsis, pain and failure. air embolism is a rare complication. pet scan is a useful tool to guide for appropriate target. ultrasound is useful for biopsying pleural-based lesions. drainage of thoracic fluid collections is a relative emergency. we will review the different thoracic fluid collections that can be drained by radiologists: pleural (parapneumonic, empyema, and malignant effusions), mediastinal, chest wall, pulmonary (lung abscesses and infected tumours) and pericardial effusions. we will answer the following questions about the main thoracic fluid collections: how to diagnose, when and how to drain, which guidance (ultrasound or ct-fluoroscopy), and procedures to perform before and after the drainage. the choice of imaging to detect thoracic fluid collections and guide drainage depends on the availability of the modalities, the imaging characteristics, location of the collection, and the comfort and expertise of the operator with the specific modalities. we will also review the main complications of percutaneous drainage of thoracic fluid collections (pneumothorax, pain, drain dislodgement and drain blockage) and compare these complications with those related to large-bore chest catheters inserted by thoracic surgeons. the incidence of lung cancers continues to increase and primary lung cancer remains the leading cause of cancer-related deaths in both women and men. therapy of lung tumours includes resection, radiation therapy, chemotherapy, thermal ablation or a combination of these treatment modalities. image-guided percutaneous thermal ablation therapies are minimally invasive techniques established in the local treatment of hepatic, renal, or osseous tumours. among these techniques, radiofrequency ablation (rfa) has now attained consideration for therapy of small pulmonal tumours. other ablation techniques that have been used for treatment of lung tumours include cryoablation, laser (litt) and more recently microwave ablation (mwa) and irreversible electroporation (ire). ablative techniques may produce a complete and irreversible tumour tissue destruction through application of either hot or cold thermal energy, or through permeabilisation of the cell membrane while using ire. ct is currently the imaging modality that is most widely used for planning, monitoring the ablation's course and for assessment of treatment response. only patients with stage i and stage ii lung cancer and those with small metastases are potential candidates for ablation. the medical history and physical examination of the patient as well as recent imaging with ct should be evaluated to determine the indication for thermal ablation. percutaneous lung rfa is considered as a safe procedure with an overall morbidity rate from 15.2% to 55.6% and mortality rate from 0% to 5.6%; it requires less costs and offers faster recovery, and reduced morbidity and mortality. sorafenib, a tyrosine kinase inhibitor, has shown clinical efficacy in patients with hepatocellular carcinoma (hcc) and is the standard of care for patients with advanced-stage hcc. nowadays, many targeted therapies are evaluated in hcc either as sole treatment or in combination with other treatments such as tumour ablation, chemo-embolisation, and surgical resection. therefore, there is a need to assess the efficacy of targeted therapy in hcc. recist is the reference method to evaluate treatment efficacy in solid tumours, but does not seem appropriate in evaluating targeted therapy as objective responses are seen in very few cases in patients treated with sorafenib or sunitinib. new criteria have been proposed to evaluate the treatment efficacy of nonsurgical treatments in patients with hcc. the most common ones are the choi criteria, the easl criteria, and the modified recist criteria. all these criteria mainly focus on internal tumour changes such as appearance of necrosis or disappearance ot tumour hypervascularity. many examples will be shown during the lecture. another approach is based on functional imaging and especially perfusion-related imaging. contrast-enhanced ultrasound, ct perfusion and dynamic contrast-enhanced mr imaging have the capability to assess perfusion changes in patients under treatment. the advantages and disadvantages of these modalities will be discussed. lastly, other functional tools that are not routinely used will be presented. the evaluation of treatment efficacy is a key issue with prognostic and patient survival implications. it is crucial to have objective and reproducible criteria for specific groups of patients. the goal of ablative therapies of hcc is to induce tumoural tissue destruction. complete response (cr) after initial chemical and thermal percutaneous ablation, defined as the absence of contrast enhancement of the treated tumour at ceus, dynamic ct or dynamic mr, has been reported to correlate to long-term survival. nevertheless, the clinical effectiveness of imaging techniques to assess initial treatment success differs according to tumour size. the success rate of rf has been demonstrated to be superior to pei in hccs > 2 cm, and depends on the ability to ablate all viable tumour tissue including an adequate tumour-free margin all around the lesion of 0.5 to 1 cm. thus, the effectiveness of rf directly depends on the tumour location and size. rf is considered an effective treatment in lesions 3 cm and its effectiveness is progressively reduced along with tumour size and it is not effective in lesions > 5 cm. ceus beyond 1 month may confirm or detect residual tumour, deserving a final ablation procedure. ct and mr are more effective in the follow-up to confirm cr and detect local recurrence, or additional hcc lesions in the liver parenchyma. the presence of transient hyperaemic inflammatory changes in the periphery of the treated area is a common finding that should be considered to avoid overestimation of the recurrence rate. one of the major characteristics of medical imaging in the twenty-first century is the dramatic influx of novel technology. this impact of new technology and techniques is experienced in all imaging modalities. the continuous development and implementation of highly sophisticated medical products and devices is key to the evolution of medical imaging leading to the improvement of patient care in terms of quality and positive outcomes. this session will analyse state-of-the-art displays (monitors, smartphones, tablets) and their applications in modern imaging. the session will provide a brief overview of displays in the current imaging chain. it will then evaluate the various specifications and parameters associated with displays. the session will evaluate current qa standards of modern displays as well as the challenges surrounding such novel technologies. image quality can be described in terms of resolution and contrast. an image displayed on a monitor consists of differences in brightness. the display monitor is at the end of the image chain in radiology, which starts at the x-ray tube. there are several factors in this chain that have influence on the contrast displayed on the monitor. diagnostic image quality can be described as observed contrast, which is not only dependent on the displayed image, but is also influenced by ambient conditions. for the primary class displays, typical characteristics of display monitors; such as resolution, homogeneity, luminance, contrast, monochrome or color, must be appropriate for the radiologist to execute a reliable diagnosis. calibration of display monitors is also important. which parameters are significant and what is the effect of variation of these parameters. there are standards like dicom gsdf and technical standard from acr-aapm-siim. both within and outside the clinical environment, the use of smartphones and tablet computers is increasing. reported applications range from teaching and education to navigation in surgical procedures. interest in the use of smartphones and tablets for viewing radiological images has been growing. however, these portable displays can differ significantly from conventional radiological displays. in order to determine where and how smartphones and tablets can be used appropriately, it is important to understand these displays and the challenges associated with them. this presentation will outline the current and potential uses of smartphones and tablet computers in radiology and compare their performance with other radiological displays and standards. the possible limitations/benefits of smartphones and tablets as display devices for radiological images will be discussed. recent research in the field will be reviewed, with emphasis on studies of diagnostic efficacy. in modern clinical environment, diagnostic monitors have replaced glowboxes and films and have become an important part of the imaging chain. the required specifications and the quality of monitors largely depend on their purpose, beginning from quite simple monitors used for the preview of radiographic images placed on modality or in control room to monitors used by high-end diagnostic workstations. decision about the kind of monitor for certain workplace is also very important from the economic standpoint as there are large differences in their prices. besides monitor specifications, also ambient conditions and ergonometry in the reading rooms are also very important issues which need to be considered to ensure optimal environment for clinical image reading. some of good and bad examples will be given in the presentation. as with other radiological equipment, also diagnostic monitors need to be controlled to ensure their optimum performance. quality control begins with monitor acceptance testing and setting up measurement parameters which are to be followed. practically all monitor vendors include some qc software within their workstations which can, together with some independent measurements, form an efficient quality control programme. in the last steps, how to deliver all information regarding image quality and possible presets on the diagnostic monitor and how not to confuse the user are important. sitting an examination is always a source of anxiety. the edir exam is no exception. this workshop is dedicated to those who want to take the edir exam, or become examiners, and would like to learn more about its format and discover some tips and tricks. the edir organisers and examiners have decided to build an interactive, friendly and enjoyable session in order to teach the essentials. some will play the role of the examiners, some the role of the candidate. in order to simulate the candidate's experience, this session will have no safety net. some senior members will expose themselves to real difficult questions in general radiology. fortunately, we hope that the attendees will be able to help the "candidates" to succeed. hopefully, you will enjoy this session and get some very useful information for your edir exam. abdominal malignancies are an important health problem in mexico. like in many other middle-income countries, there has been an epidemiological transition with an overall increase in oncologic diseases. colorectal, gastric and liver carcinomas are some of the frequent abdominal malignancies. colorectal cancer is a disease that is curable if detected early and even preventable if precursor polypoid lesions are removed. imaging plays a critical role in staging at diagnosis. additionally, virtual colonoscopy is an accepted modality in cancer screening. high-resolution magnetic resonance imaging (mri) has become a pivotal modality in the pretreatment assessment of rectal carcinoma. computed tomography (ct) is an excellent modality in the preoperative staging of gastric cancer and follow-up after treatment. positron emission tomography (pet) combined with ct (pet/ct) is particularly helpful for gastric and colonic carcinoma staging. hepatocellular carcinoma (hcc) is also common. cirrhosis related to alcohol and hepatitis c infection are by far the commonest aetiologies. ultrasound (us) in conjunction with alpha-protein is the most widely used modality for screening purposes. ct and mr are confirmatory modalities. the advent of hepatospecific gadolinium contrast agents has been very helpful in the characterisation of focal lesions in cirrhotic patients. the use of multidetector ct (mdct) in pancreatic carcinoma for the detection of vascular and adjacent organ invasion is crucial in treatment planning. over the last few decades, there has been an important improvement in imaging techniques resulting in better quality images. imaging is critical not only for the diagnosis, but also for treatment planning and follow-up. learning objectives: 1. to learn about the imaging of common oncologic gastrointestinal diseases. 2. to understand the importance of imaging in liver and colon cancer. 3. to learn how imaging supports oncologic institutions. activity, ultrasound is readily available and gives detailed local information but is limited by the restricted field of view, communication of results to clinicians and comparison of examinations on time. computed tomography (ct) is fast, readily available and gives a detailed, reproducible overview, but radiation exposure and contrast resolution are limitations. magnetic resonance imaging combines a good, reproducible overview with high contrast resolution, dynamic information and no radiation exposure and is therefore preferable in many situations, but the longer examination times than for ct, availability and costs are limiting factors. for the diagnosis of stenoses, fistulas and abscesses, either technique can be used, although the unrestricted view of ct and mri favour these techniques in many situations. in acute situations, us and ct are more accessible than mri. in that setting us can be considered, but when the examination is inconclusive or the patient has clear inflammatory signs, ct is preferable. endoscopy is currently considered the reference standard for the evaluation of colonic pathologies, including colitis. it allows direct visualisation of the mucosa and in obtaining tissue sample. however, it has major limitations including the invasiveness of the technique, incomplete endoscopy and risk of perforation. endoscopy cannot, therefore, help to estimate the depth of involvement of transmural inflammation and extraluminal complications. by contrast, an evolving role for cross-sectional imaging in the evaluation of patients with colitis has been increasingly recognised, especially in the setting of crohn's disease (cd), since cross-sectional imaging has been demonstrated to have a high diagnostic accuracy not only for assessing the presence and extension of luminal disease, but also for evaluating cd-related acute or chronic complications. establishing the ultimate cause of colitis may sometimes be challenging and histology cannot be conclusive. however, cross-sectional imaging may provide additional information that is useful in the workup of colitis. the use of cross-sectional imaging has been increasing in the evaluation of inflammatory bowel disease. following their presentations on imaging protocols and features of small bowel disease and colitis, each speaker will present a case to illustrate the learning points covered in their lectures. the session will be moderated by the chairman and the audience will have full opportunity to ask questions of all the panel. multimodality imaging is essential in a wide variety of oncology situations. anatomic imaging, whether using us, ct or mri, is mandatory for tumour localisation. moreover, the evaluation of treatment response mostly relies on size assessment, whether uni-or bi-dimensional. with the advent of new targeted bio-therapies, functional imaging has progressively been integrated in the imaging strategies whether for better tumour characterisation or for optimal evaluation of treatment response. hence, assessment of molecular targets by pet is supplemented by the recent developments of diffusion mri, reflecting tissue architecture and cellularity, tissue perfusion, reflecting angiogenesis, and magnetisation properties of tissues. hcc is a primary liver tumour where the use of multimodal anatomic, functional and metabolic imaging appears of particular interest. according to easl and aasld recommendations, noninvasive diagnosis of hcc can be performed using dynamic contrast enhanced cross sectional imaging. liver mri provides optimal sensitivity and specificity for the detection of as small as 1 cm large hcc. recent reports have suggested that the prognosis of hcc lesions could be anticipated based on the combined analysis of metabolic 18 f -fdg pet ct, as well as with diffusion weighted imaging. the objective of this lecture will be to highlight the potential of combining both metabolic and multimodal cross sectional imaging in order to improve the management of patients with hcc. the (extra)ordinary night shift at the er k. petrovic; novi sad/rs (smakap@sbb.rs) besides the accuracy, working at the er requires maximal shortening of the diagnostics time, which has a significant influence on the patient's outcome. thus, it is the radiologist's duty to be familiar with the pathophysiological mechanism of the disorders, specific protocols, possibilities and limits of certain examinations, and also to be aware of all possible pearls and pitfalls, to make the correct diagnosis. pathology encountered at the er has an extremely wide range and requires expertise in all imaging modalities from head to toe. the more the radiologist is aware of all possible situations, the more is the diagnosis accurate, and information given to the clinician is more valuable. the aim of this presentation is to point out the possibility of encountering different pathological conditions in different body regions. moreover, it is important to be reminded that in radiology there are different modalities, each of which has its own indications and limits. this lecture reviews the selected series of cases from the er department of clinical center of vojvodina, pointing out the most common possible differential diagnosis and possible diagnostic mistakes, which often occur due to the lack of experience. learning objectives: 1. to point out the in-depth knowledge and experience in all imaging modalities and all body regions required for a radiologist to perform a routine work at the er. 2. to present a series of cases that are most and less often encountered at the er, discuss the possible differential diagnosis and mistakes which could potentially be made. diagnosis and management of pancreatic cystic lesions r.j. mã©ndez; madrid/ es (ramiro.mendez@salud.madrid.org) pancreatic cystic lesions are frequently diagnosed in patients with clinically suspected pancreatic disease, but they are also increasingly detected on imaging studies performed due to other abdominal processes. the prevalence of pancreatic cysts increases with patient's age. most symptomatic cysts will be surgically resected, whereas asymptomatic lesions should be managed depending on the likelihood of causing harm to the patient. cystic lesions can be inflammatory or neoplastic. the incidence of pseudocysts is low without a history of pancreatitis. some pancreatic cystic neoplasms are malignant, but even benign lesions can become symptomatic depending on its size and location in the pancreas. the radiologist detects most of the pancreatic cystic lesions and should also play an important role in the clinical decision-making process. cyst size, morphology, calcifications, contrast enhancement, location in the pancreas, relation with pancreatic ducts, patient's age and gender are important data to classify the lesion. a specific radiological diagnosis is not possible in every patient, but in many cases this information is enough to decide on a conservative approach with imaging follow-up. if a more aggressive lesion is a concern, then endoscopic ultrasound and fluid analysis can help to better characterise some pancreatic cystic lesions. cyst puncture is only recommended if fluid analysis results will modify the patient's management. patient's age, status and preferences should also be taken into account. when follow-up is recommended, the preferred imaging technique and interval should be indicated. the chair will set the scene for the need for effective radiation protection in clinical radiology and highlight the role of clinical audit as a tool in achieving this. clinical audit is defined as a professionally led method of improving patient care through the systematic examination of systems, processes and outcomes against chosen and agreed standards. it can readily be carried out by individuals, groups or whole departments. if properly conducted, clinical audit can be an effective way of examining what we do to provide reassurance on performance, and to improve patient care. the clinical radiology audit committee (crac) of the royal college of radiologists (rcr) co-ordinates national radiology audit activity. it promotes and facilitates audit through nominated audit leads in each hospital, who act as a link between the rcr and their department. at least one national audit is carried out annually, with data collected via electronic submission and the anonymised results presented at an annual audit forum. individual departmental results are analysed using statistical process control (spc) methodology. this enables identification of departments underperforming against the national mean, and recommending corrective action, by redesigning the process being audited, or by identifying and eliminating specific root causes locally. the committee has developed a web-based tool for facilitating local audit, "auditlive", a fully searchable collection of templates which can be downloaded and adapted. fellows are also able to submit their own templates for publication hence sharing best practice. trainees are encouraged to participate in audit through audit poster competitions at national radiology scientific meetings. our experience leads us to believe that audit succeeds when relevant, locally owned and properly structured, and multi-professional, and the rcr model encourages this. models of external audit in the netherlands s. geers-van gemeren; utrecht/nl in the netherlands clinical audit is legally obligatory for healthcare professions in order to be able to practise since 2010. clinical audit is a tool designed to improve the quality of patient care, experience and outcome through formal review of systems, pathways and outcome of care against defined standards, and the implementation of change based on the results. the quality of the provision of care by professionals is assessed by peers. in the fields of radiology, nuclear medicine and radiotherapy, different models of clinical audit are used. for radiotherapy a multidisciplinary audit has been used since 2003. for nuclear medicine a multidisciplinary audit has been implemented since 2013. for radiology the clinical audit for radiologists and for radiographers are separate. implementation of the multidisciplinary audits needs requirements and adjustments of the audit system. this process is complex and needs approval of the members of all involved societies. to support the clinical audit a web based tool adas (general digital audit system) is used. the development of professional standards is a prerequisite to start clinical audit. the use of adas in multidisciplinary audits is a requirement to be able to audit different professions and focus on the content and the quality of their contribution to patient care. clinical audit is a good tool to improve the quality of patient care. important are the professional standards, the culture of learning and willing to improve by the professionals. "every defect is a treasure." learning objectives: 1. to learn about the different dutch models of external clinical audit. 2. to comprehend the importance of professional standards, the culture of learning and willingness to improve. 3. to become familiar with the use of a digital audit system to support multidisciplinary clinical audit. external regulatory audit in finland r. seuri; helsinki/fi (raija.seuri@hus.fi) directive 97/43/euratom states that the clinical audit of medical imaging should be carried out in accordance with national procedures. the finnish solution has been regulatory external audits every five years by radiological professionals with special training for audits. all radiological units have so far been audited at least twice, and the third time is performed on site in the unit. although the purpose is to audit the process of radiological practises compared to "good practise", special focuses are recommended by the finnish advisory committee for clinical audit, set by the national institute for health and welfare. at the beginning focus was on the organisation and documentation of the structure and processes of imaging practise like justification, optimisation and quality control, but also encouragement and guidance to self-assessment. later special focus has been on paediatric imaging and ct, and the third cycle will target deeper to ct practises. the auditing group includes at least a radiologist and a radiographer to audit a small unit, and a medical physicist if the unit has high-dose modalities like ct. during the audit the auditors work for an independent organisation. multi-professionality gives both insight and the possibility to contact all professionals in imaging practise. the focus of clinical audit is on quality improvement; it is a way to both give and get feed-back and education. it is not control or inspection, but encouragement and guidance to self evaluation and implementation of good practises. we often think of the scientific researcher as detached, objective, and dispassionate, nobly labouring without any expectation of reward. nothing could be further from the truth. scientists are as subject to ambition, competitiveness, envy and even guile as any person. lifting the veil on scientific discovery reveals to us the human dramas that underlie not only the coveting of recognition, but also great conflicts over priority and credit. nowhere are the stakes higher than for that pinnacle of scientific honour: the nobel prize. mri has had a notably tempestuous genesis -a cogent episode that has much to teach us. it involved an explosive clash of personalities; deceit and rampant self-interest; challenges to the basic concept of scientific behavior; legal suits and validation by the united states supreme court; and declamations of denunciation in the international press. it persisted as a 30year battle -a prize fight, a blood feud -between two protagonists: one whose seminal contribution established the biologic basis of mri, and the other whose flash of insight served as a cornerstone of diagnostic imaging. 1. metabolic disorders of the skeleton involve the mineralised components of the skeleton. they affect all bone components histologically, but involvement patterns may vary depending on the age of the patient (growing versus adult skeleton) as well as the type of bone (cortical versus trabecular bone). they can be depicted on radiographs and ct images, but remain occult on mr images because the bone marrow is spared in the vast majority of these disorders. mr imaging can help in the assessment of local complication such as fractures. 2. metabolic disorders of the bone marrow can affect either red (anemiaâ�¦) or yellow marrow as well as the balance between these 2 marrow types in the body. medical imaging plays a limited role in the assessment of these disorders, but marrow changes associated with these metabolic conditions must be recognised to avoid confusion with neoplastic conditions. in primary and secondary malignant tumours of solid organs, in most of the cases surgical resection is considered the curative treatment. however, this is possible only in about 20% of the cases with tumour-dependent recurrence rates of 60% and even more. the main components for adjuvant, neo-adjuvant and finally palliative therapy are the permanently growing number of chemoand antibody therapies. nevertheless, in many cases these therapies provide no definitive or long-lasting success, necessitating multimodality treatment concepts. in the meantime, local ablative techniques represent the main components of these concepts. three main minimally invasive tumour-ablative techniques can be differentiated: chemo-ablation (percutaneous alcohol injection, transarterial chemo-embolisation, chemotherapy, chemo-perfusion), thermo-ablation (radiofrequency-, microwave-, laser-ablation, high-intensified focused ultrasound, cryo-ablation) and radio-ablation (radio-embolisation, interstitial brachytherapy, percutaneous stereotactic radiation). these ablation techniques differ significantly among each other with respect to their mode of action and indications; nevertheless, their benefit is high tolerance and at the same time high therapeutic efficacy, which can easily be combined with other treatment modalities. the different minimally invasive techniques will be discussed together with specific short-and long-term results and complications. missed lung lesions are one of the most frequent causes of malpractice issues. chest radiography plays an important role in the detection and management of patients with lung cancer, chronic airways disease, pneumonia and interstitial lung disease. among all diagnostic tests, chest radiography is essential for confirming or excluding the diagnosis of most chest diseases. however, numerous lesions of a wide variety of disease processes affecting the thorax may be missed on a chest radiograph. the chest radiograph will also help narrow a differential diagnosis, help to direct additional diagnostic measures, and serve during follow-up. the diagnostic usefulness of the radiograph will be maximised by the integration of the radiological findings with the clinical features of the individual patient. ct has a tremendous spatial resolution that helps detect lesions in the chest and has proven to be more sensitive and specific than chest radiographs. however, missing lesions or misinterpreting lesions in ct of the chest is not uncommon. in this session, we will provide interactive cases of chest examinations (radiographs and ct) in which lesions have been missed and or misinterpreted, with a special focus on how correlation with mdct of missed lung lesions can help improve interpretation of plain chest radiographs. this session will explore the value of imaging for facilitating precision medicine, in which molecular data (including genomics, proteomics and metabolomics) is used to classify patients into subpopulations and tailor treatments to the specific molecular characteristics of their diseases. imaging already plays a limited role in precision medicine, primarily through the use of molecular imaging techniques (e.g. pet/ct, mri/pet and hyperpolarised mri) and theranostics (the combination of an imaging agent with a therapeutic entity). in the near future, the role of imaging in precision medicine will increase at a gradually accelerating pace through the development of new molecular imaging probes and theranostic agents and through progress in radiogenomics (the correlation of radiologic findings with genomic features). this session will discuss recent findings and methodologies in radiogenomics as well as the use of nanotechnology for designing novel molecular imaging probes and theranostics. in addition, as theranostics is often considered the essence of precision medicine, the session will provide an in-depth look at current and emerging theranostic strategies and their special benefits for treatment selection, assessment of dose distribution of targeted therapies, and treatment follow-up. radiogenomics and personalised (precision) medicine g.p. krestin; rotterdam/nl (g.p.krestin@erasmusmc.nl) "precision medicine" as well as related notions, such as personalised medicine, or stratification medicine, all revolve around the idea that the consideration of individual characteristics -molecular and otherwise -can improve medical research and practice. precision medicine is a multi-faceted approach to medicine that integrates molecular and clinical research with patient data and outcomes. individual assessment of the location and extent of an alteration is and always has been the basis of medical imaging, whether the 'alteration' is a disease, a malformation, or an injury. as such, medical imaging intrinsically enables "precision medicine". the addition of genomic data in the last twenty years allows new correlations to be made between cellular genomics and tissue-scale imaging. structural and functional imaging and the automated analysis of large amounts of image data have only recently reached a stage where they can be used on a large scale and in a population setting. identifying common genetic variants that contribute to explain variance in imaging phenotypes by a systematic analysis of the genome is based on genome-wide association studies (gwas). the power of gwa analyses has been recently demonstrated with the identification of susceptibility genes involved in a range of imaging phenotypes like coronary artery calcifications, intracranial volume, or size of the hippocampus. these developments highlight new etiological pathways and are expected to improve the understanding of the molecular basis of some diseases. correlation between genotype and imaging phenotypes may be relevant for further characterising the development of disease states. use of nanotechnology, imaging and therapy t. lammers; aachen/ de (tlammers@ukaachen.de) advances in nanotechnology and chemical engineering have led to the development of a significant number of novel materials for diagnosis and therapy. many different diagnostic and therapeutic nano-and micro-materials have been designed and evaluated over the years, including, e.g. gadoliniumcontaining dendrimers, uspio nanoparticles and microbubbles for functional and molecular imaging, and drug-loaded liposomes, polymers and micelles for temporally and spatially controlled drug delivery to tumors and to sites of inflammation. in the literature, such advanced nano-and micromaterials are generally claimed to be highly useful and broadly applicable. a critical reflection on their specific capabilities, however, as well as on their pharmacokinetic properties, biodegradability and toxicity is often lacking. in the present lecture, i will briefly introduce the rationale for using diagnostic and therapeutic nanomaterials. i will highlight several clinically relevant examples in which nano-and micromaterials hold potential for improving disease diagnosis and detail how combining diagnostic and therapeutic properties within a single 'nanomedicine' formulation can be used to individualise and improve (chemo-) therapeutic treatments. learning objectives: 1. to learn about the design and construction of nanoparticles for use in imaging and therapy. 2. to appreciate both the advantages and limitations of using nanoparticles as agents for both imaging and therapy. 3. to learn how nanotechnology enables multimodality imaging and therapeutic agents. theranostics w. weber; new york, ny/us precision medicine requires diagnostic tests that predict the effectiveness of specific therapeutic interventions for individual patients. this close interaction between therapeutics and diagnostics is expressed in the term "theranostics". a frequently used example for a theranostic is the staining of tumours for her2 expression prior to therapy with her2 antibodies, such as trastuzumab or pertuzumab. theranostic has also been practised since many years in nuclear medicine by using radioiodine scans to select patients for treatment with iodine-131. a more recent example is the selection of patient for peptide receptor-targeted radiotherapy (prrt) by somatostatin receptor imaging. imaging is highly attractive for theranostics, because it allows investigators to study the spatial and temporal heterogeneity of target expression, whereas in vitro assays generally analyse a small part of the tumour at one point in time. several molecular imaging probes, such 89 zr-trastuzumab or folate receptor targeting ligands, are in clinical development as in vivo companion diagnostics. imaging companion diagnostics can also be used to assess tissue pharmacokinetics and thereby help to determine the optimal dose and dose schedule of therapeutic agents. they can also identify unexpected interactions between two therapeutic agents. for example, studies with 11 c-docetaxel have shown that bevacizumab can markedly decrease the intratumoral delivery of docetaxel. finally, imaging-based companion diagnostics can assess target inhibition, as demonstrated by the inhibition of uptake of the androgen receptor ligand 18 f-fdht in metastatic prostate cancer treated with anti-androgens. imaging-based companion diagnostics are therefore expected to play an important role in establishing precision medicine. erus technique as well as the state-of-the-art mr imaging protocols tailored according to the presenting rectal tumor site, allowing trained radiologists to obtain all necessary information for appropriate treatment decision-making, will be described. normal cross-sectional appearances as well as morphological and signal changes encountered in pelvic structures/tissues that may be involved in primary rectal cancer will be illustrated. the influence of imaging findings on initial therapeutic approach and potential limitations of different imaging techniques will be discussed. the staging and categorisation of malignant lymph nodes in patients with rectal cancer is a topical issue and has resulted in some degree of confusion. much enthusiasm has been expended in determining whether mesorectal nodes are, or are not, involved in the primary disease process, as there is a perception that nodal disease is an important determinant of local recurrence. this incorrectly perceived association of nodal status and a high risk of pelvic recurrence have propagated the concept that this should be the primary indication for neoadjuvant therapy regardless of whether tme surgery is to be performed. furthermore, misinterpretation of involved local nodes results in over-treatment of patients, if firstly involved nodes alone are considered as a poor prognostic factor, and secondly the optimal treatment of involved nodes is pelvic radiotherapy plus a non-systemically acting but radiosensitising dose of chemotherapy within chemoradiotherapy (crt) schedules. in this lecture, the evidence for risk factors associated with nodal disease and validated risk factors for local recurrence will be reviewed. the evidence for both the optimal techniques and objective criteria for assessing lymph nodes with magnetic resonance imaging (mri) will be presented. the standard treatment for advanced rectal cancer is preoperative chemoradiotherapy (crt) followed by standard resection of the rectum and mesorectum. neoadjuvant crt allows downsizing and downstaging of the tumour, leading to improved resectability and local control. while the role of mri in rectal cancer treatment is recognised and mri is recommended as part of the standard staging workup, its role for restaging after preoperative treatment is more controversial. this lecture will provide an understanding of whether and how mri can assess treatment response in rectal cancer and how it may impact treatment decision. the attendees will learn about the difficulties in image interpretation and learn about potential new imaging techniques to improve its performance. primary tb typically presents with consolidation in the middle and lower lobes, and necrotic lymphadenopathy. fibrosis, tuberculomas and calcified nodes may result as sequelae. cavitation and tree-in-bud appearance involving the apical and posterior segments of the upper lobes and the superior segments of the lower lobes are the hallmarks of reactivation tb is typically seen in immunocompetent patients. in immunocompromised patients, primary tb findings are more commonly observed, as miliary or disseminated disease or atypical manifestations in case of severe immunosuppression. pleural effusion and tracheobronchial involvement may be observed. the "classical" appearance of non-tb mycobacteria (n tm ), less common and more indolent than tb, typically affects males more than 50 years old with pre-existing pulmonary disease or underlying immunologic disorder. despite a great overlap in the radiologic appearances of both infections, the presence of cavities on sites other than the upper lobes should suggest an n tm infection. the "nonclassical" form related to mac infection that predominantly affects elderly women with no pre-existing pulmonary disease mainly consists in mild bronchiectasis and centrilobular nodules predominantly located in the lingula and middle lobe. a high rate of lymphadenopathy and disseminated disease are seen in immunocompromised patients. the radiologist has to ensure the diagnosis of active tb and mention scarring before starting specific treatments; to suggest n tm infections, immune reconstitution inflammatory syndrome with paradoxical worsening in haart treated hiv-infected patients as multi-drug resistant tb; to appreciate the extent of disease and follow-up; to diagnose the complications; to propose mri or pet scans in some situations. learning objectives: 1. to appreciate the imaging features of primary and post-primary infections in tb. 2. to learn about the similarities and differences between tb and non-tb mycobacterial infections. 3. to understand the radiologist's role in diagnosis. the appropriate investigational technique, frequently targeted differential diagnosis, and the special needs of immunocompromised patients need to be understood by the referring physician as well as by the radiologist. thus, an intensive interdisciplinary co-operation on a patient basis, as well as on a department basis is essential. early detection of a focus is the major goal in febrile neutropaenic patients. as pneumonia is the most common focus, chest imaging is a special radiological task. the sensitivity of chest x-ray, especially in the supine position, is known to be low. therefore, the very sensitive thinsection multislice-ct became the gold standard in neutropenic hosts and might be cost-effective in comparison to antibiotic treatment. the infiltrate needs to be localised, so that this information can be used as guidance for invasive procedures for further microbiological workup. furthermore, the radiological characterisation of infiltrates gives a first and rapid hint to differentiate between different sorts of infectious (e.g. typical bacterial, atypical bacterial, fungal) and non-infectious aetiologies. follow-up investigations need careful interpretation according to disease, recovery, and concomitant treatment. due to a high incidence of fungal infiltrates, interpretation of the follow-up of an infiltrate must use further parameters besides the lesion size. besides the lungs, also other organs systems such as brain, liver and paranasal sinuses need attention and are to be imaged with the appropriate technique. despite advances in diagnosis and treatment, new pulmonary infections have been diagnosed. streptococcus pneumoniae remains the main aetiological agent in outpatients with community-acquired pneumonia (cap). elderly patients or those with toxic habits and various comorbidities favour the development of severe cap. in addition, the development of nucleic acid amplification techniques has emphasised the role of concomitant bacterial and viral pneumonia in the outcome of cap in elderly patients. healthcareassociated pneumonia has been recently defined as a different infectious condition by the american thoracic society/infectious diseases society of america (ats/idsa). the main concern of this new disease is the risk of having an infection due to multidrug-resistant pathogens. with the advent of haart and increased long-term survival of hiv-positive patients, the range of pulmonary manifestations has also evolved. in patients with haematological malignancies or after hsc transplant, aspergillus is a common infection. actually, aspergillus spp. isolation from lrt samples in copd may indicate an increased diagnosis possibility of ipa. new emerging viruses such as human metapneumovirus (hmpv), sars-associated coronavirus, and avian influenza caused by the h5n1 virus have been diagnosed. in 2009, an outbreak of a novel swine-origin influenza a (h1n1) virus was reported. the clinical diagnosis of new pulmonary infections as well as the presence of concomitant bacterial and viral infections has been significantly enhanced by improved laboratory methods. a systematic approach to the radiological evaluation of lung infections is essential and includes not only chest imaging pattern recognition, but also integration of available demographic, clinical and laboratory information. the paediatric central nervous system is a complex structure undergoing rapid development. as such, there is a rapid, continuous modification of what is "normal" in relation to age and the stage of development. knowledge of the normal patterns of brain development in the clinically relevant ages from 0 to 18 years is necessary to interpret neuroimaging findings correctly. knowledge of embryology and normal variants is also greatly helpful. mr imaging equipment and parameters need to be adjusted and optimised for paediatric studies. pitfalls often occur from the misunderstanding of normal conditions that are perceived as abnormal based on a comparison with the appearance of the normal brain in adults. this includes, for instance, the evaluation of the brain in the first 2-3 years of life during the course of the process of myelination. a summary of the most frequent conditions that may lead to misinterpretation of findings will be provided. a wide spectrum of anomalies of thoracic and abdominal organs may be encountered on radiologic evaluation. these anatomic variants and developmental anomalies can all pose a diagnostic challenge to the radiologist. familiarity with these anomalies, the imaging techniques available for their study, and their variable imaging manifestations is necessary for differentiating them from pathology. a basic understanding of the embryologic development and normal anatomy of thoracic and abdominal organs and vessels is also essential for identifying these anomalies. this review explores the wide variability in appearance of the normal thoracic and abdominal organs during imaging, stressing a thorough understanding of normal anatomy to recognise normal variants. the skeleton of a child is a developing system with a variety of changing normal appearances. imaging studies, especially plain films, are requested for many clinical reasons, and the radiologist is in the position to determine if an image is a normal finding or we are dealing with a lesion. the way the physis and epiphysis grow, ossify, and fuse constitutes a great source of physiologically bizarre appearances, which the radiologist must be familiar with. this talk will concentrate on the plain film diagnosis of some of the most common musculoskeletal variants. other imaging modalities will also be shown when appropriate for the case. irregularities, asymmetries, partial fusions, hypo-or hyper-dense bone areas, accessory bones, prominent normal structures, external artifacts, and potential fracture lines are the most often encountered pseudolesions. a defective radiological technique may also be potentially misleading. patient age, location of the supposed "abnormality" and lack of significant local symptoms are key factors. usually plain films, correlated with regional clinical findings, are the only imaging method that is required. however, in certain doubtful situations, ultrasound, ct, mri, bone scan, or even biopsy may be needed to reach the right diagnosis. unnecessary overuse of these imaging modalities, and the subsequent family anxiety that ensues from this overuse, should be avoided with careful analysis of the x-ray and clinical findings. the purpose of this lecture is to cover the clinical presentation, underlying pathological processes and essential mri features of relatively common conditions affecting the hip. as the hip is afflicted by different conditions according to age, this is how the various pathological entities will be presented. a simple imaging algorithm is presented showing the role of mri. the role of mr arthrography in the assessment of the dysplastic hip and femoroacetabular impingement is covered. a structured approach to mri reporting is outlined. (claudia.schueller-weidekamm@meduniwien.ac.at) mri of the hand requires high spatial resolution, perfect immobility, and homogeneous fat suppression. the hand can either be placed in the superman position, which often is uncomfortable for the patients, or both hands can be placed above the abdomen next to each other while the patient is in the supine position. standard sequences are axial pd, followed by coronal t1 tse, and t2 tse fs in the coronal and sagittal planes. additional 3d gradient echo sequences with fat saturation are recommended to assess ligaments and cartilage, as well as the triangular fibrocartilage complex (tfcc). in certain cases, mr arthrography with thin-slice t1 fs is helpful for further evaluation of the wrist ligaments. in inflammatory diseases, such as rheumatoid arthritis, static or dynamic t1 fs sequences are useful to assess tenosynovitis and synovitis. the most common injuries and inflammation of the hand and wrist are discussed with special emphasis on key findings for an accurate diagnosis. the awareness of advantages and drawbacks of other imaging modalities, such as conventional radiographs and ct, should be strengthened. the clinical impact of the radiological report is discussed to strengthen the importance of proper terminology for the description of pathological findings. the structure of the report should be clear and concise, and should allow an interaction and broad communication with clinicians. gastro-enteropancreatic neuroendocrine tumours (gep-net) are a heterogeneous group of cancers that differ in their biology and clinical presentation. diagnosis of these tumours has been improved by advances in pathology and classification and by the combined use of structural imaging and functional imaging modalities. multimodal imaging is increasingly recognised both in detecting and staging disease and also in characterising biological patterns of lesions that may be relevant to the selection and delivery of therapy. in this course, the complex nature of gep-net and the intrinsic uses and limitations of each diagnostic imaging modality will be underlined. insights to hybrid structural and molecular imaging techniques will be provided and discussed. a. tumour biology, pathogenesis and classification b. wiedenmann; berlin/ de (bertram.wiedenmann@charite.de) neuroendocrine tumour cells are characterised by the coexpression of neuronal and epithelial proteins and cellular organelles such as synaptic vesicles containing synaptophysin of neurons and intermediate filaments/cytokeratins of the epithelial cells. based on the presence of secretory vesicles and the continous, uncontrolled vesicular release of biogenic amines, neuropeptides and hormones, patients suffer in half of the cases of so called functional symptoms and syndromes. examples are the carcinoid syndrome (excessive release of serotonine) or the zollinger-ellison syndrome (excessive release of gastrin). activation or inhibition of certain g-protein coupled receptors (e.g. somatostatin receptors) or channel proteins (r-type calcium channels) can lead to the control of the hypersecretion or so called functionality of the affected patients. medical interference with signal transduction pathways involving tyrosine kinase receptors as such mtor and channel proteins can lead to an inhibition of cellular and tumour growth. these observations have led to the establishment of new therapies, especially for pancreatic nets using especially mtor and tyrosine kinase inhibitors. whereas the tumorigenesis is unknown in the case of sporadic nets, hereditary nets appear to develop via a menin mutation through the intermediate stage of hyplasia before they develop the full metastatic potential. based on the above given tumour biological and histopathological findings, a rather robust classification for nets has been developed by the european neuroendocrine tumor society (enets) using a tnm-classification together with a gradingsystem. furthermore, the formerly used terms such as apudoma, neurocrestoma, carcinoid, etc. have been largely replaced by the meanwhile generally accepted term neuroendocrine tumour. this presentation will focus on the pivotal role of nuclear medicine in the diagnosis and treatment of neuroendocrine tumours (nets). the metabolic and molecular imaging capabilities of both positron emission tomography (pet) and single photon emission tomography (spect) have made a great impact on the clinical management of patients with these tumours. a poster child of molecular imaging in oncology is scintigraphy of the somatostatin receptor (ssr). 111 in-dtpa-octreotide has a substantial value in detection, diagnosis and staging of net and more particularly in gastroenteropancreatic nets. newer ssr-binding radiopharmaceuticals have been developed for pet, mainly with gallium-68 as radiolabel, with higher affinity and more advantageous pharmacokinetics. when used with high-resolution and rapidthroughput multimodal whole body imaging of modern pet/ct cameras, these tracers provide the current state-of-the art ssr imaging. we will also discuss the clinical value of metabolic tracers, such as [ ]5-hydroxytryptophan) for amino acid metabolism imaging. the clinical merits and indications of these tracers will be explained. the continuously evolving quest to develop tracer for other receptor systems expressed on nets will be illustrated, e.g. bombesin, vip, cck and glucagon-like peptide receptor ligands. finally, the role of imaging as selection for metabolic and peptide receptor radionuclide therapy will be discussed. gastroenteropancreatic neuroendocrine tumours (gep-nets) are a heterogeneous group of neoplasms that arise from cells of the diffuse neuroendocrine system and may present with a wide spectrum of clinical presentations. their prognosis is mainly related to their biology, proliferation and differentiation. the main goals of imaging are the diagnosis and the staging of these tumours. the diagnostic challenge is very different in functional tumours where clinical presentation and laboratory parameters are of utmost importance and in nonfunctional tumours where imaging may show characteristic features such as hypervascularisation and calcifications. staging is also essential as locoregional involvement and distant metastases (such as liver metastases) may change the therapeutic approach and are major prognostic factors. multimodal workup included morphological imaging modalities with ct and mr imaging, and endoscopic ultrasound was the most useful and functional imaging. the latter includes somatostatin receptor scintigraphy, fdg pet and more recent functional tools such as pet using 68ga and 18 f-dopa. imaging may also play a role in assessing prognosis in combination with tumour differentiation and tumour proliferation, obtained from pathologic examination. last, imaging is useful in evaluating tumour response after treatment. although surgery remains the only potentially curative therapy for patients with primary gep-nets, other available treatments include chemotherapy, interferon, somatostatin analogues, and targeted therapies. imaging criteria rely not only on changes in tumour size, but also on internal tumour changes. the purpose of this session is to bring the audience up to date with a novel mri method capable of measuring brain perfusion. this method is called arterial spin labelling (asl) and provides a complete non-invasive means to quantitatively assess cerebral blood flow (cbf). as with any mri technique, asl relies on proper setting of many technical parameters to provide an adequate image quality, with minimal influence from potential artefacts. a recent position paper, co-signed by members of the perfusion study group from the international society for magnetic resonance in medicine and the european cost-funded action on 'asl in dementia', has established a series of simple guidelines to help promote this technology in clinical practice. these guidelines will be provided within this session. the created cbf maps will then be analysed, and a simple description of the main features and clinical characteristics of these physiological images will be given to the audience. in particular, a proper difference in the meaning of cbf in several diseases will be highlighted, as it can be either causative, such as e.g. in stroke and cerebrovascular diseases, where a reduced cbf leads to a breakdown in tissue homeostasis, or consequential, as in e.g. dementia, in which a reduction of cbf is the mere reflection of impaired metabolism, combined or not with an underlying brain atrophy. following this session, the radiologist or clinician should be able to better appreciate asl-based sbf maps in several neurological conditions. perfusion is an important parameter to assess the status and liability of organs and tissue. typically, exogenous contrast agents are administered to measure this quantity. arterial spin labelling (asl) is capable of estimating perfusion without the use of exogenous contrast media by labelling inflowing blood magnetically. this labelling process can happen either in a short time over an extended region or over a longer time period, but in a localised area. these techniques are called pulsed asl (pasl) or continuous asl (casl), respectively. for quantification, a critical parameter is the time the labelled blood takes to flow from the region of labelling to the imaging region. this time is typically called bolus arrival time (bat) or arterial transit time (att). it is important to either reduce the influence of this transit time on measured signal intensity or directly estimate it. applying proper bio-physical models, the perfusion-weighted data can then be converted in absolute measures of perfusion. more sophisticated methods allow measuring of the main feeding artery of each imaging voxel (vascular territory mapping) or assessing other parameters beyond perfusion, allowing more detailed assessment of tissue status and function." the use of asl in cerebrovascular disease j. hendrikse; utrecht/nl (j.hendrikse@umcutrecht.nl) obvious applications of arterial spin labelling in clinical mr protocols are cerebral blood flow measurements in patients with acute or chronic cerebrovascular disease. in patients with acute stroke, the cerebral blood flow measurements may indicate the infarct core, with severely decreased perfusion and the infarct penumbra, with decreased perfusion but still viable brain tissue. in chronic cerebrovascular disease, arterial spin labelling cbf measurements show the regionally impaired haemodynamics distal to a carotid obstruction. with adequate collateral blood flow, these areas may be relatively small and with a failure of compensatory mechanism the cerebral blood flow may fall below a critical level. in acute stroke patients, asl mri may show compensatory hyperperfusion in stroke regions after the recanalisation of an occluded artery. other applications of arterial spin labelling are clinical mr protocols in children. in addition to cbf-weighted images, asl mri has also the ability to measure timing parameters: typically, the time it takes for the magnetically labelled arterial blood to flow from the arteries in the neck to the brain tissue, which may be delayed in patients with cerebrovascular disease. furthermore, asl mri has the ability to visualise the (collateral) perfusion territories of the brain feeding arteries in many clinical applications. in patients with cerebrovascular disease, a pitfall may be the absence of label in brain regions due to delayed (collateral) flow, which also may result in high asl signals in (collateral) arteries. learning objectives: 1. to appreciate the different roles of asl in cerebrovascular diseases. 2. to become familiar with the different types of calculated images obtained from multi-time points and selective pulses asl. 3. to become familiar with the limitations and pitfalls of asl. the use of asl in non-vascular brain disease m. smits; rotterdam/nl (marion.smits@erasmusmc.nl) arterial spin labelling (asl) is a non-invasive mri technique with which cerebral blood flow (cbf) can be measured quantitatively. although the first publications of asl mri date over 10 years back, it is only now that asl is commercially available on mri systems from all major vendors and is making its way into clinical practice. the main areas of interest for current and future nonvascular clinical application of asl mri of the brain are dementia and neuro-oncology. asl is proposed as a diagnostic alternative to fluorodeoxy-dglucose (fdg)-pet in the workup of dementia patients. asl has several advantages over fdg-pet. crucially, it can easily be added to the routinely performed structural mri examination. feasibility studies show that asl provides reliable cbf maps in dementia. in patients with established alzheimer's disease and frontotemporal dementia, hypoperfusion patterns are seen that are similar to hypometabolism patterns with fdg-pet. current and future studies in this field will need to demonstrate the validity of asl in the diagnostic workup of the individual patient, early in the disease process. studies on asl in brain tumour imaging indicate a high correlation between areas of increased cbf as measured with asl, and increased cerebral blood volume as measured with dynamic susceptibility contrast-enhanced perfusion imaging. the major advantages of asl for brain tumour imaging are the fact that cbf measurements are not influenced by breakdown of the blood brain barrier, as well as its quantitative nature, facilitating multicentre and longitudinal studies. the analysis of a sinonasal tumour requires mri for differentiation between tumour and secretions or polyps, to assess the local extension and spread into adjacent compartments (skull base, intracranial, orbit, deep facial compartments) and to depict perineural spread. t2, t1 and high-resolution postcontrast series preferably in three, but at least in two different planes, are needed. ct provides additional information of bony structures and serves as a road map for surgical navigation. a fascinating benign sinonasal tumour is inverted papilloma, which has a high recurrence rate if not removed in toto and may harbour carcinoma in < 5% of patients. ct may show the attachment of the tumour as an area of increased sclerosis, which directs the surgeon to plan the operation. in patients with recurrent inverted papilloma, providing information to the radiologist about its presumed localisation is important, the more so in patients suffering from polyposis. malignant tumours are uncommon and of a large histologic variety. about 80% arise in the maxillary sinus; 70% are squamous cell carcinomas. they are often large at diagnosis, because clinical symptoms of nasal obstruction or headache are non-specific. diagnosis is by biopsy. in view of the rapid development of advanced endoscopic techniques, preoperative imaging is extremely important to assess accurately tumour extension. the skull base and dura as well as the lamina papyracea should be scrutinised for tumour locations to foresee an additional cranioendoscopic approach to a standard endonasal endoscopic approach. finally, imaging may play a role in differentiating non-nasal disease, e.g. primary bone tumours, from mucosal disease. to discuss risk/benefit considerations in medical imaging from the perspective of patients and highlight some of the pre-requisites to ensure trust and confidence. this presentation will draw on the work of the european patients' forum on patient safety, quality of care, health literacy, and patient empowerment, to explore what are the key factors to consider in radiation risk analysis, from a patient's perspective, recognising that 'one size does not fit all'. it will examine what constitutes quality information in this environment, effective dialogue between the patient and the radiologist, and the interdisciplinary team, informed consent and transparency of data. it will also highlight some of the particular challenges regarding vulnerable patients, and those requiring on-going treatment due to chronic disease (s). the justification for medical procedures is based on the assumption that the benefit outweighs the risk. this presentation looks at the radiation risk factors from recent high-profile papers (pearce et al., 2012) and publications from international bodies such as beir and icrp. at lower radiation doses (< 100 msv), quantifying, understanding and communicating radiation risk to staff, patients and referring clinicians presents a range of challenges. advances in health information systems will facilitate more precise dose risk relationships. there are a number of approaches to stochastic radiation risk assessment such as organ-/age-based assessment and effective dose equivalent assessment. at-risk groups, such as children and pregnant women, need special focus. eu directives demand special attention for high-dose interventional procedures and ct scans. these techniques, particularly if repeated, require further risk assessment regarding potential deterministic effects such as erythema, hair loss, and radiation-induced cataractogenesis. this paper looks at strategies in consenting, monitoring, and follow-up of such high-dose effects. the practical implications of the new occupational icrp eye dose limits for interventional practice are also examined. with the advent of higher field scanners in clinical practice and the construction of 'mri compatible' implanted devices, the list of the do's and don'ts while performing an mri examination changes constantly. in this presentation basic safety guidelines and rules will be explained regarding static magnetic field effects, time varying magnetic field effects, radiofrequency field effects and acoustic noise effects both with regard to the patient as well as the personnel using the equipment. due to the advances in medical technology the list of possible 'safe' and 'unsafe' items changes almost daily. therefore it is very important to have all the information about the patient's condition and implants prior to the mri procedure in order to asses possible contraindications in advance. while until a couple of years ago cardiac pacemakers and neurostimulators were contraindicated in the mri environment, the advent of 'mri compatible' pacemakers and other implanted devices introduces challenges in patient safety. in fact these devices are only safe in certain configurations and also in a lot of cases specific mri scan sequences and rf antennas are only allowed. following the european emf directive, where the mri part is derogated, the protection of staff working with em fields also became a topic of debate. what are the possible risks for staff working with mri magnets and how can one implement practical rules for the safe use of the mri equipment. the field of image-guided ablation has expended recently with new ablation techniques like micro-wave, irreversible electroporation, cryoablation. nevertheless, after each treatment, whatever the technique used, we will leave in place in the treated organ, a scar instead of the tumour. follow-up of these treated areas are done by radiologists using ct of mr or contrast enhanced ultrasound. standardisation of terms has been done in 2003 by an international committee presided by dr. goldberg. this allows reporting criteria identical from one center and from one country to another. furthermore, it allows a more homogeneous literature and evaluation of success. nevertheless, techniques are not all the same and the cellular and tissue damage in the tumour and around it in the healthy parenchyma are not identical and does not have the same evolution over time. thermal ablation is frequently used to treat liver, lung and bone tumoural lesions because of its safety, efficacy and tolerability. one issue is the lack of reliable imaging modality to assess treatment efficacy and to detect early relapse. several papers have demonstrated that 18 fdg pet/ct is a useful tool to follow-up ablated liver tumour, detecting residual disease easily and earlier than conventional imaging. few reports evaluating the usefulness of 18 fdg-pet/ct in the follow-up of ablated lung lesions are available, but prospective studies show promising results, with a high negative predictive value of this technique. very few data are available on bone lesions and further studies are needed to assess the role of 18 fdg-pet/ct in the follow-up of these lesions. in general, the in vivo typical aspect of completely ablated lesion on 18 fdg-pet/ct is a ring shape, diffuse, peripheral, homogeneous 18 fdg uptake at the treated lesion; on the other hand, the presence of heterogeneous and focal uptake is more frequently related to disease relapse. suvmax (standardised uptake value) is not a reliable indicator. it is higher in case of disease relapse than in completely ablated lesions, but also in case of important inflammatory reaction. finally, the best time point to evaluate ablation efficacy still remains to be defined, but 18 fdg-pet/ct should be performed at least 3 months after treatment to avoid dubious or inconclusive findings due to inflammatory reaction. the aim of thermal ablation treatment is to generate an area of thermocoagulation whose diameter is larger or at least equivalent to that of the tumour. this necrotic scar usually shrinks with time, but most often very slowly. therefore, the criteria of response based on size measurement cannot be applied. the pattern of thermal ablation is similar whatever the thermo-ablation technique used. on ct imaging, thermal ablation areas are well circumscribed and oval shaped. the criterion commonly used to assess the efficacy is the absence of enhancement in the thermal ablation necrosis, which corresponds to tissue devoid of viable tumour. on mr imaging, the thermo-ablation areas are typically hyperintense on unenhanced t1 due to the presence of proteinaceous material, and hypointense on t2, explained by the dehydrating effect of thermal damage. the residual tumour is typically round in shape and located at the periphery of the necrotic area or in contact with large vessels. mr imaging allows earlier detection of residual liver tumour than ct imaging. neurodegenerative diseases, cancer and heart disease perhaps summarise the major challenges to medicine in this century, a challenge in accurate diagnosis and also in treatment. recent technological advances in medical imaging technology mean that these challenges can be dealt with more efficiently. anatomy can be studied faster, safer and with higher spatial resolution and precision. in addition to anatomy, the study of function has become feasible; more sophisticated hardware and software are being used to get the required data to map out the functionality and understand how this relates to anatomy to offer a more comprehensive view of normal development and explain pathological conditions. at the same time, researchers and clinicians are urged to create a platform for reciprocal communication to facilitate translation of the research findings to a graspable clinical benefit for the patients. this translational platform will allow flagging the major clinical questions, inform current and future research experiments and at the same time help utilise recent research findings in the clinical setting. this session will review state-of-the-art mri techniques and document different approaches to translational imaging. it will also allow understanding the obstacles and remedies in implementing translational medicine. many neurological diseases are associated with progressively reduced cognitive function. recent evidence suggests that proficient cognitive function depends on an appropriate interaction between large-scale cognitive control networks in the brain. it is hypothesised that damage to white matter microstructure, as found in many neurological diseases, disrupts the integrated operation of these networks and results in impaired cognitive function. diffusion tensor imaging (dti) has been used to investigate alteration to white matter micro-structure and resting state fmri (rsfmri) has proven to be a useful technique to assess brain function in multiple cortical systems. however, the combined use of these techniques in the clinical setting has not yet taken hold. in this presentation, i will demonstrate the flexibility of these mri techniques in assessing brain structure and function and address their feasibility of use in a clinical setting. imaging in oncology is a growing field within radiology. different tomographic techniques are used either isolated or as multimodality-multivariable imaging, as there is an increasing need to combine morphological and functional information. different cutting-edge modalities, such as pet-ct, dw-mr, ce-mr and mr-spectroscopy, are standard in most clinical scenarios. new images have advantages providing excellent soft-tissue contrast and multidimensional functional, structural and morphological information. the development of new diagnostic imaging research areas, mainly in the field of oncology, cardiology and neuropsychiatry, will impact the way medicine is performed today. both clinical and experimental multimodality studies, in humans and animals, will have to demonstrate an efficient use of the imaging information provided by the modalities to affect the future of medical imaging. we will comment on the impact of continued technological developments in medical imaging on patients with cancer (diagnosis, staging and follow-up) and the challenges of imaging technologies from research into clinical reality. the recent advances and developments in measurements and biomarkers which have led to a greater understanding of cancer will be commented, together with the morphologic, metabolic and functional oncological imaging research and clinical practice. finally, the role of the radiographer in advanced oncological imaging techniques will be evaluated. when imaging the head and neck region with ct or mri, teeth are always present. we frequently encounter radiolucent or radiopaque lesions of the jaw on scans performed for other indications. familiarity with typical dental conditions is necessary to subject the patients to the right therapy. to correctly evaluate and describe those lesions, this special focus session on dental imaging gives the radiologist a tool to report dental lesions. the anatomy of panoramic and ct images will be reviewed in the first talk. technical details as well as pitfalls will be presented. in the second talk, the focus is on pre-and post-surgical imaging with ct where typical lesions of the jaw will be presented. an insight into imaging the teeth with mri will be given by the third speaker. the discussion on the impact of radiologists on dental images will complement this special focus session's theme. panoramic radiography produces a single image of the maxilla, mandible, teeth, temporomandibular joints and maxillary sinuses. during the exposure, the x-ray source and the detector rotate synchronously around the patient producing a curved surface tomography. this horseshoe-shaped zone of sharp image is called the focal trough/image layer. advantages of this technique are a good overview of lower facial hard tissues, the convenience of an extraoral examination, a low patient radiation dose, and low costs. disadvantages are limited width of the sharply imaged layer, variable magnification, and oblique projection, especially in the upper premolar region. patient positioning is most important for obtaining a detailed panoramic radiograph. in addition to patient position errors, patient movement during exposure and metal objects can cause artefacts. also, ghost images caused by structures located between the x-ray source and the rotation centre can hamper diagnostics. cbct is a radiographic imaging method that allows accurate 3d imaging of hard tissues. during a cbct scan, the scanner rotates around the patient's head (180â°-360â°) obtaining multiple sequential planar projection images by a 2d detector. the scanning software collects the data which is processed to create a volumetric data set with isotopic voxels with varying fov. disadvantages of cbct imaging are poor soft tissue contrast and artefacts. in addition to normal panoramic and cbct anatomy, after this presentation the audience will be familiar with the panoramic and cbct techniques as well as common errors and pitfalls of these techniques. pre-surgical and post-surgical imaging with mdct and cone-beam ct a. gahleitner; vienna/at (andre.gahleitner@meduniwien.ac.at) multislice-ct and more recently cone-beam-ct have become an established method for anatomic imaging of the jaws prior to dental implant placement. commonly referred to as "dental-ct", these high-resolution imaging techniques have gained importance in diagnosing dental-associated diseases of the mandible and maxilla. especially in patients with inflammations, cysts, oro-antral fistulas, odontogenous sinusitis, impacted teeth and dental fractures, new indications have emerged. unfortunately, most radiologists have had little experience in this area and many of the dental-ct findings remain undescribed. hence, we will determine the ct appearance of frequent dentalrelated diseases of the jaws and demonstrate typical pre-and postoperative findings. this presentation reflects our experiences from 18 years of performing dental-ct with 36.000 investigations, closely working together with dentists and oral surgeons. learning objectives: 1. to learn about the typical findings from pathological conditions of the jaw, which confront dentists and oral surgeons. 2. to understand these findings in cross-sectional imaging like multislice and cone-beam ct. 3. to learn about the usual treatments for these conditions in order to know how they are used in dental radiology. dental mri s. rohde; dortmund/ de (stefan.rohde@klinikumdo.de) this lecture will discuss the potential of dental mri in the field of inflammatory and neoplastic disease of the periodontal space. experimental and preliminary clinical data from high-field dental mri will be presented with a special focus on the visibility of critical anatomical structures on high-resolution sequences. the results will be compared to high-resolution cone-beam ct. based on representative cases, we will review the main causes of thoracic non-traumatic vascular emergencies (acute aortic syndrome, pulmonary thromboembolism and haemoptysis); mdct angiography has become the firstline imaging test for the diagnosis of these entities. as acute aortic disease is the most common fatal condition in patients with chest pain and prompt recognition and treatment are of paramount importance, we will review the spectrum of acute aortic pathology focusing on the distinctive findings of each entity (classic dissection, intramural haematoma and penetrating aortic ulcer) and upgrading the clues for their diagnosis. acute pulmonary embolism (pe) remains a common clinical challenge. mdct pulmonary angiography has become the first-line imaging study in the diagnosis of pe because of its speed, accuracy, low interobserver variability and ability to provide alternative diagnoses. we will review the role of mdct in the evaluation of acute thrombotic pe: findings of acute pe (including how to evaluate the severity of an episode of pe at ct pulmonary angiography) and some potential pitfalls. massive haemoptysis is a life-threatening condition that is associated with a high mortality rate. haemoptysis usually involves bleeding from the bronchial arteries or, less frequently, from nonbronchial systemic arteries. haemoptysis of pulmonary arterial origin is rare, estimated at less than 10% of haemoptysis cases. mdct angiography permits noninvasive, rapid, and accurate assessment of the cause and consequences of haemorrhage into the airways and helps guide subsequent management. acute respiratory failure can have multiple underlying causes including infection, fluid overload, immunological diseases or exacerbation of preexisting lung disease. since the clinical symptoms are nonspecific, imaging plays an important role. the first imaging method is mostly the chest radiograph, easy to access and to obtain, but non-diagnostic in many cases. (hr)ct offers more possibilities to define the differential diagnosis. the option of this interactive workshop will be to get familiar with the spectrum of diseases that can cause acute respiratory failure and learn about key findings in radiography as well as ct to reduce the differential diagnosis. the interaction between preexisting lung disease, clinical information (e.g. chemotherapy, rheumatoid arthritis, copd) and imaging findings will be discussed using clinical case studies. options and also limitations of imaging findings will be illustrated. the following scenarios will be taken into account: acute cardiac failure and various appearances of oedema; acute immunological-toxic disorders including druginduced lung disease and inhalational injuries; exacerbations of preexisting lung disease including fibrotic and obstructive lung disorders; severe infections causing respiratory failure and their complications. contrast-enhanced ultrasoud (ceus) and elastography are evolving us techniques that have already found their ways into clinical practice (ceus) or will do so in the next few years (elastography). ceus is performed with 2 nd generation us contrast media, but these contrast media are not available worldwide. in many european countries, sonovueâ® (bracco, it) is the only available contrast, consisting of micro-bubbles less than the size of red blood cells. in contrast to ct and mr contrast media, these bubbles are strictly intravascular. for us imaging, low mechanical index us techniques are used to see the resonance of sound by these bubbles. ceus is excellent for the differential diagnosis of focal liver lesions based on vascularisation and specific contrast uptake (imaging the wash-in and wash-out of us contrast over time with excellent temporal resolution) and increases us sensitivity to liver metastases in colorectal cancer patients. however, ceus is only useful when there are excellent us conditions. in pancreatic us, ceus allows to differentiate adenocarcinoma from neuroendocrine tumours based on vascularisation (us contrast uptake). whereas elastography (strain elastography or shear wave elastography) is established for the diagnosis of liver fibrosis, there are no general recommendations for using these various techniques to measure the "hardness of a focal lesion" in focal liver and pancreas lesions. diffusion-weighted mr imaging (dw-mri) provides information on tissue cellularity, extracellular space tortuosity and integrity of cell membranes by measuring the motion of water molecules in tissues modified by flows (blood vessels, glandular ducts,.). and interaction with cellular components. integrated in conventional-mr acquisition protocol, dw-mri increases sensitivity for lesion detection. the apparent diffusion coefficient (adc) can be calculated using a mono-exponential relationship between signal attenuation and b-value. this fitting is influenced by microcapillary perfusion. a more sophisticated approach (intravoxel incoherent motion, ivim) would enable estimation of parameters that separately reflect tissue diffusivity and microcapillary perfusion. using ivim-analysis, the derived quantitative parameters describe tissue diffusivity, perfusion and perfusion fraction. by providing qualitative and quantitative information, dw-mri is applied in oncology to characterise malignancy, including lesion aggressiveness, and to monitor treatment response. perfusion imaging is a useful tool to achieve information concerning tissue vasculature, microvascular permeability and interstitial space characteristics. dynamic contrast-enhanced techniques (dce-ct, dce-mr) are based on the analysis of the contrast agent (tracer) biodistribution in tissues. quantitative parameters are obtained using pharmacokinetic models, as transfer constant ktrans, extracellular-extravascular space fraction ve, vascular tissue fraction vp and the rate constant kep. quantitative dw-mr and dce-mr parameters are increasingly used as imaging biomarkers to predict tumour response and/or to monitor the effects of therapy, especially when anticancer agents with novel models of action are used (anti-angiogenic, tyrosine kinase inhibitors and several others). therefore, these new imaging biomarkers may have a pivotal role in correctly evaluating tumour response and stratify and managing cancer patients. elderly and the young can all present special problems that require a greater depth of understanding to obtain a diagnostic study. this session will help you in your quest for reliable high-quality investigations for all. a. coronary cta in patients with severe arrhythmias and high heart rate c. loewe; vienna/ at (christian.loewe@meduniwien.ac.at) besides all advances in scanner technology, heart rate remains a critical issue for coronary cta, and motion artefacts due to cardiac function represents still the most frequent reason for limited diagnostic image quality in cardiac cta. thus, the target heart rate is defined depending on the scanner system used and ranged between below 60 bpm and below 70 bpm. however, in a number of patients heart rate control is not possible or not successful (i.e. children, emergencies, heart transplant recipients), whereas a relevant proportion of ctas are performed in patients with heart rates higher than the target frequency. during this presentation, the possibilities for heart rate control by beta blocker injection and beyond will be discussed and possible workflows will be presented. furthermore, examination strategies for patients with high heart rates will be presented including reverse dose modulation, high-pitch scanning, systolic scanning and more. finally, tools for reconstruction and assessment of patients scanned at higher heart rate will be introduced. different to high heart rates and even more critical with regard to image quality is arrhythmia. due to the complexity of cardiac synchronisation, a ct suite is not the place for cardiac resynchronisation, whereas the indication to cta has to be reevaluated depending on referring diagnosis and severity of arrhythmia. since there are patients undergoing cta because of arrhythmia including patients prior to ablation treatment, strategies for examination and image reconstruction in case of arrhythmic patients have to be established and will be presented. cardiac computed tomography (ct) has become a widely available diagnostic tool used in a range of heart conditions. the commonest application of this technique is in the evaluation for coronary artery patency (coronary ct angiography) in patients with chest pain. when coronary arteries are heavily calcified, or post-coronary angioplasty with stent implantation, diagnostic problems can occur. in these circumstances, the evaluation of the coronary arteries on ct is hampered by the occurrence of high-density artefacts caused by calcifications and stent struts. these artefacts may preclude the appropriate assessment of the coronary lumen. the presence of motion artefacts in the dataset or image noise in very large patients may exacerbate the problem. in this scenario, accurate patient selection and preparation remain key to ensure that the diagnostic yield of the cardiac ct study is good. optimisation of scan parameters (kv), contrast injection protocol and use of appropriate postprocessing techniques (e.g. dedicated convolution filters) play an important role in daily clinical practice. recent technical developments include dualenergy scan techniques and gemstone spectral detector systems that acquire simultaneously high and low kilovoltage datasets. this is done to achieve tissue differentiation. in principle, by using monochromatic image reconstruction, the effect of high-density artefacts may be decreased. using a similar principle, high-density structures can be subtracted from the image. the introduction of iterative reconstruction algorithms may play a role in that these algorithms are theoretically more accurate in the modeling of physical noise and tissue geometries. lack of movement artefacts is one of the major prerequisites for good image quality in cardiac mr. it is crucial to have the minimum possible image acquisition time. it is important to make both te and tr as short as possible. data acquisition should be synchronised with patient's ecg or pulse. special attention should be paid to good quality of ecg recordings (good contact of electrodes with the skin, electrodes positioning, using of dielectric pad). in patients with arrhythmia, prospective ecg synchronisation should be used instead or a retrospective one, or special protocols may be applied for arrhythmia correction. breathing artefacts are usually not a problem for cardiac mri, because most sequences are acquired during a single breath-hold. using ssfp and parallel imaging allows obtaining a complete set of cine mr images through the whole heart in 1-8 short breath-hold periods. the technique of realtime cardiac mr is a good way to perform successful examinations even in difficult patients, especially the ones with heart failure. other systemic mrartefacts (aliasing, chemical shift, magnetic susceptibility, off-resonance) should be recognised and diminished or eliminated by the operator. these artefacts are more prominent in case of 3 t systems. late-enhancement studies with gd are very dependent on the correct selection of the ti time. phase-contrast mri requires venc calibration in cases of valve stenoses. to meet the challenges and the benefits of cardiac mri, one must balance the constraints of signal-and contrast-to-noise ratios, spatial and temporal resolution, scan time and image quality. scoliosis, a common spinal deformity in teenagers, especially girls, progresses during their growth until the end of puberty. therapeutic choices, which are either medical -with corset -or surgical, depend on this progression. follow-up is mainly clinical. however, radiographs are often indicated to give precise information: ap and lateral views of the spine in standing position remain the basis of this follow-up. obtaining a good image quality at all levels of the spine has been a technical challenge for a long time, and the question of radiation dose is also a main concern, as these radiographs require a high radiation dose. fortunately, radiographic techniques have greatly improved over the past few years: from the conventional 90 or 120 cm film to digital screens and now flat screens, we now obtain better quality images with less radiation. today, eos system using xenon chamber is the best to give good ap and lateral views. it allows 3d reconstructions with minimal radiation dose. on these radiographs, measures can be performed, essentially cobb's angle. it helps in evaluating progression of the curves and making surgical decisions. other imaging techniques are requested only in particular situations as in the presence of neurological symptoms or general disease such as neurofibromatosis, or in young children with malformative scoliosis and sometimes preoperatively. ct is best to study the vertebrae; it objectivates vertebral malformations (agenesis, hypoplasia, blocks). mr will be requested to study the cord, nervous roots, craniospinal junction and the soft tissues. collaboration between the radiologist and spinal surgeon is essential. the key elements in the diagnostic process, as for most bone lesions, are: the age of the patient, the type of bone and bone segment involved, the location within the bone, the presence of signs of aggressiveness (type of osteolysis, limits, presence and type of periosteal reaction). conventional x-rays should never be absent from the initial workup of a focal bone lesion in a child, as they provide essential features for differential diagnosis and, in most cases, eliminate the need for other more costly techniques. the need and priority for other imaging techniques, such as ct, mri and bone scintigraphy, are decided on a case-by-case basis and sometimes a combination of these techniques, which complement each other, is needed. it is the radiologist's responsibility to recommend histological analysis of a lesion via biopsy whenever the imaging aspect is not characteristic or indicates signs of possible malignancy. learning objectives: 1. to recognise the most common benign bone tumours and pseudo-tumours. 2. to understand the differences between benign bone tumours, pseudotumours and malignancies in children. 3. to understand imaging modalities that could help in the differential diagnosis of benign bone tumours and pseudo-tumours in children. a-472 17:00 a.c. offiah; sheffield/uk (amaka.offiah@nhs.net) the 2010 nosology and classification of genetic skeletal disorders subdivides 456 conditions into 40 groups defined by molecular, biochemical and/or radiographic criteria. 316 conditions are associated with mutations in at least one of 226 different genes. some of these conditions are rare or even extremely rare (occurring in fewer than 1 in 100,000 of the population). clearly, the general paediatric radiologist cannot be expected to correctly recognise and diagnose all of these conditions. the approach is to perform a set of radiographic images dependent on the patient's age/size and to develop a standard system for reviewing these images. the standard set of images for a patient over 2 to 3 years of age consists of ap and lateral skull, ap chest, ap pelvis, lateral thoracolumbar spine, ap one upper limb, ap one lower limb and dp left hand. variations on this routine dysplasia skeletal survey will be discussed and a standard system for interpreting the images will be presented using radiographs of the commoner skeletal dysplasias as examples. in the last few years, interest in body composition (bc) analysis, which is the quantification and characterisation of relative amounts of muscle, fat, bone, and other vital parts composing the human body, has grown rapidly for clinical, research and epidemiological purposes. studying body composition has gained great importance for the comprehension and decoding of a multitude of patho-physiological processes (e.g. obesity, diabetes and endocrine diseases and also gastrointestinal, renal, nervous, infectious diseases, etc). and physiological and para-physiological conditions as in athletes or growth and ageing processes. although the main imaging techniques, which include dualenergy x-ray absorptiometry (dexa), computed tomography (ct), and magnetic resonance imaging (mri), offer a differentiated and attractive analysis of bc, they still need to find a definite position in clinical practice. through 'programming' low birth weight is associated with increased rates of coronary heart disease, stroke, hypertension & non-insulin dependent diabetes. prediction of morbidity and mortality from body composition, particularly fat, stimulates the importance and application of accurate and precise methods for quantitative assessment of body composition; the gold standard for which is cadaver analysis, but other methods have to be implemented in vivo. body composition alters in many chronic diseases, starvation cases, metabolic syndromes, and senescence stages, and is a key component of health. several techniques are available which vary in simplicity and complexity of use. each make assumptions and may not measure body composition directly, but make predictions from other measurements made. skinfold thickness measurements assess regional fat and are quick and simple to perform at all ages. reproducibility is good, but less so in obesity. there is some limitation of reference data to express results as standard deviation scores (sds). body mass index (bmi; weight/height 2 ) is widely used as an index of relative weight expressed as sds for gender, age and ethnicity. waist circumference (wc) is a measure of central fat, and can also be expressed as a ratio to hip circumference. bioelectric impedance analysis (bia) measures body impedance to a small electric current, which estimates total body water (tbw) from which can be derived fat free mass (ffm). tbw can also be measured by neutron activation. air displacement plethysmography (bod pod) is a new method for body composition assessment. learning objectives: 1. to understand normal body composition in children and adults. 2. to learn how body composition can be altered by disease. 3. to appreciate the clinical relevance of assessing body composition. 4. to understand the non-imaging methods available for measuring body composition, with their advantages and limitations. computed tomography: what does it measure and how? j. damilakis; iraklion/ gr (damilaki@med.uoc.gr) ct allows measurement of total body fat and enables differentiation of subcutaneous from visceral adipose tissue. body fat can be estimated using the conventional technique of manual planimetry. using planimetry, the user delineates manually the boundaries of subcutaneous and visceral fat in each ct image. however, this method is labour intensive, time-consuming, and, therefore, not easily applicable in routine clinical practice. another ct method used for the estimation of abdominal fat is the semiautomatic measurement of adipose tissue area. abdominal fat is assessed in a ct slice by using a fixed range of hounsfield units to define the area of adipose tissue. a limitation of this method is that the attenuation range of fat may vary among individuals. the stereological volume estimation method is based on the cavalieri's principle. according to this principle, the volume of an object can be measured by cutting it into equally spaced slices and measuring the area of the object on each slice. to measure body fat using stereology, a square grid of test points is randomly superimposed on each ct section. all points lying inside the fat tissue region are selected by the user and the software automatically calculates the total number of points hitting the fat. stereology provides the possibility for efficient fat volume assessment. however, research studies are needed to optimise the stereological estimation of fat and compare stereological measurements with those from other adipose tissue measurement ct techniques. learning objectives: 1. to appreciate the role of ct imaging in body composition analysis. 2. to learn how to measure visceral and subcutaneous adipose tissue using ct. 3. to understand the advantages and limitations of ct techniques (planimetry, thresholding, stereology) in evaluating adipose tissue. mri: current and future applications d.c. karampinos; munich/ de (dimitrios.karampinos@tum.de) mri has been emerging as an ionising radiation-free imaging modality to measure fat distribution in the human body and fat content in different organs. the present talk will first introduce mri methods to measure fat distribution, including the well-established t1-weighted imaging and the emerging dixon imaging approaches. the challenges related to the data acquisition and image post-processing of the two imaging approaches in the study of fat distribution will be reviewed. examples will be shown from the current use of mri in investigating adipose tissue distribution alterations or differences in patients with metabolic disorders, including obesity and diabetes. quantitative mri methods enabling the measurement of fat content with high spatial resolution will be then presented, with a focus on water-fat separation methods. the technical challenges associated with the establishment of mri-based fat content, as an accurate and reproducible imaging biomarker will be discussed. the selection of pulse sequence parameters and image reconstruction algorithm in a state-of-the-art water-fat separation experiment will be explained. applications will be shown from the growing literature of mri-based fat quantification in abdominal organs (e.g. liver) and in skeletal muscles, aiming to show the great premise of quantitative water-fat mri in quantifying fat content with high spatial resolution in different body parts. at the end of the talk, the potential of quantitative water-fat mri will be discussed in the emerging application of measuring bone marrow fat content and its association with bone health and metabolic disorders. the key role of dual-energy x-ray absorptiometry (dxa) in the management of metabolic bone diseases is well known. the role of dxa in the study of body composition and in the clinical evaluation of disorders which directly or indirectly involve the whole metabolism as they may induce changes in body mass and fat percentage is less known or less understood. dxa has a range of clinical applications in this field, from assessing associations between adipose or lean mass and the risk of disease to understanding and measuring the effects of pathophysiological processes or therapeutic interventions, in both adult and paediatric human populations as well as in pre-clinical settings. dxa analyses body composition at the molecular level that is basically translated into a clinical model made up of fat mass, non-bone lean mass, and bone mineral content. dxa allows total and regional assessment of the three abovementioned compartments, usually by a whole body scan. since body composition is a hot topic today, manufacturers have steered the development of dxa technology and methodology towards this. new dxa machines have been designed to accommodate heavier and larger patients and to scan wider areas. new strategies, such as half-body assessment, permit accurate body scan and analysis of individuals exceeding scan field limits. although dxa is a projective imaging technique, new solutions have recently allowed the differential estimate of subcutaneous and intra-abdominal visceral fat. the transition to narrow fan-beam densitometers has led to faster scan times and better resolution; however, inter-or intra-device variation exists depending on several factors. in cancer patients, disease-free survival is a good indicator for tumour response, but for many common cancers, treatment of disseminated disease is often noncurative. the increased duration of survival is related to changes in tumour size after treatment. however, the anatomical determination of tumour response has some limitations, especially when non-cytotoxic targeted therapies are used. with these new treatments options, the lack of progression may be associated with a good improvement in outcome, even in the absence of major shrinkage of tumours. new imaging biomarkers are therefore needed to assess therapeutic response. molecular imaging is now playing a prominent role in the monitoring of cytostatic targeted therapies. pet-ct, dynamic contrast enhancement studies or diffusion-weighted imaging are the most promising ones. the aim of this session is to present the state of the art in tumour response assessment with regard to new therapeutic regimens. in early oncologic times, treatments of different malignancies were reported in different ways. c. gordon zubrod and others first articulated the model of multicentre clinical trials and argued for standards to be agreed for included and excluded subjects, the method of assigning treatment and in measuring response. nowadays, we have better knowledge of tumour biology; however, we continue using the classical response criteria (who and recist) and overall survival as a primary goal for effective treatment in most of the malignancies. in the last few years, different criteria for responses have been reported to evaluate the disease and a lot of discussions between authors have been reported. now, we can use the recist criteria v1.1, implement the percist criteria and also forget the immunotherapy criteria. furthermore in the last few years, different treatments such as vaccines, antiangiogenics and targeted therapies have increased our arsenal in the treatment of different malignancies such as kidney cancer, prostate cancer, breast cancer and so on. another problem for our patients is that those diseases have a long evolution after the first-line treatment. we have to be able to define in each disease the treatment line and type of treatment to determine which evaluation criteria are necessary and which is the objective of treatment, pfs or os. we have to be aware that if we are not able to define such topics, we may be losing active treatments. recist 1.1 are the criteria most often used in studies to evaluate response to treatment in solid tumors. on each follow-up examination, response is defined by a combination of unidimensional measurement of 'target lesions', qualitative evaluation of 'non-target' lesions, and presence/absence of 'new lesions'. ct and mri are the preferred modalities for recist evaluation, and evaluations must be performed using the same modality, in the same plane. we will review anatomic locations which should be avoided, and how to deal with intercurrent events resulting in the impossibility of measurement. cases when recist seems inadequate will be discussed, including evaluation of bone metastases, and focal therapy. finally, though these criteria were developed for drug trials, they may provide a frame for reading examinations and writing reports in routine practice. reproducible, objective and quantitative criteria help to define or in the obese patient. ct is especially helpful in those with suspected retroperitoneal pathology, in the investigation of immunocompromised patients and those with complex post-operative problems. ct guidance may be required to facilitate percutaneous abscess drainage, particularly for deep pelvic collections. in addition, ct plays a vital role as a 'problem-solver' when ultrasound has failed to fully answer the clinical question posed. this short presentation will utilise clinical studies to illustrate the benefits of ct in the investigation of the acute abdomen, both as the initial imaging modality and as a second line tool following ultrasound. learning objectives: 1. to understand the advantages of ct as a primary imaging modality for children with acute abdomen. 2. to learn about clinical scenarios in which ct is relevant. 3. to appreciate the use of ct as an adjunct to ultrasound. abdominal trauma: us is better v. miele; rome/it (vmiele@sirm.org) ultrasonography (us) is a reliable technique whose advantages are rapidity, portability and accuracy in depicting intraperitoneal fluid without interrupting resuscitation and without radiation exposure. in the haemodynamically unstable paediatric patients, it represents the first line together with the x-ray evaluation. us for trauma has become more standardised and is worldwide known with the acronym of fast (focused abdominal sonography for trauma) or e-fast (extended-fast) used in depicting also pleural and pericardial effusions and pneumothorax. nevertheless, many parenchymal injuries are not correctly visualised at baseline us and some traumatic solid organ lesions can occur without hemoperitoneum. in case of haemodynamically stable patients, who have suffered a low-energy trauma, the greater time available allows the use of specific us contrast agents, enabling a better identification of traumatic organ injuries. contrast-enhanced ultrasonography (ceus) has a greater sensibility and specificity in the identification of parenchymal traumatic lesions, both in the first evaluation and follow-up, and could avoid unnecessary radiation and iodinated contrast medium exposure. in case of haemodynamically stable paediatric patients, who have suffered a high-energy trauma, us is not recommended as first-line investigation, because ce-mdct should be performed first. only in the follow-up, ceus can be considered an alternative to ct. in conclusion, e-fast and ceus should be considered as a useful tool in the assessment and monitoring of paediatric trauma. this examination can be performed at the patient's bedside, representing a useful alternative to ct in the paediatric traumatised patients and in the follow-up of a known abdominal injury. learning objectives: 1. to understand the differences in the diagnostic paths of paediatric patients. 2. to learn about the diagnostic efficacy and limitations of ultrasonography. 3. to become familiar with the use of the contrast-enhanced ultrasonography (ceus). abdominal trauma: ct is better m. raissaki; iraklion/gr (mraissaki@yahoo.gr) ct has been considered a sensitive, specific, and accurate test in the identification and grading of injuries, especially in the severely injured child. it should be overemphasised that traumatised children differ from adults: haemodynamically stable children may actually be actively bleeding and rapidly deteriorate. conversely, children have smaller calibre vessels, stronger vasoconstriction, and stronger solid organ capsules; bleeding may stop spontaneously, organ rupture is more difficult and delayed rupture is rare. this is why few children will undergo laparotomy or trans-arterial embolisation. the goal of imaging is to clear the abdomen in multi-traumatised children, identify those that may rapidly deteriorate because of clinically silent active bleeding, increase the surgeon's confidence level and define short-and long-term medical management. due to children's increased radiosensitivity, all ct scans should be indicated based on appropriate early clinical evaluation, assessment of risk factors for abdominal injuries and evaluation of the closely monitored child. alara includes the availability of outside scans upon admission, avoiding non-contrast scans and multiple phases and applying age-and weight-dependent exposure parameters. ct should not be performed as follow-up unless there is clinical deterioration. ct has the advantage of rapidly identifying and delineating with high resolution solid organ, vascular, mesenteric, bowel injuries and pending oligaemic collapse (hypoperfusion complex or shock bowel). important fractures and thoracic injuries may be simultaneously revealed with ct. the objective documentation of intraabdominal injuries is extremely important in suspected child abuse. evaluation of mr imaging in a patient with an intramedullary lesion should focus on key features: a) the location of the lesion on the cross-sectional area of the cord, best evaluated on axial images, b) the length of the lesion evaluated on sagittal images, c) the presence of cavitation and cysts, d) signal intensity on t2-wi, e) the presence of enhancement and enhancement type, and f) associated leptomeningeal enhancement. the knowledge of the presence or absence of the brain lesions is important information for narrowing the differential diagnosis. the clinical picture and the onset of symptoms will help the differentiation between the neoplastic and inflammatory and vascular lesions. in this lecture, the imaging characteristics and typical patterns of intramedullary lesions will be presented. a diagnostic algorithm, which includes imaging, clinics and csf analysis, will be discussed. a common clinico-radiological situation is the differentiation between spinal infection, degenerative changes and osteopaenia, and spinal tumour. in most cases, conventional ct and/or mri will allow a certain differentiation, and additional biopsies are mainly used to obtain tissue for bacteriological or histopathological classification. advanced mr techniques such as dwi may sometimes help in increasing diagnostic certainty, but are seldomly used in day-to-day practice. spinal infections typically present around the intervertebral disc, but may also present as isoloated spondylitis without disc involvement, and sometimes the infection quickly spreads to the epidural space. degenerative changes my sometimes mimic infection due to strong gadolinium enhancement. the main differential diagnosis of spinal tumorous processes is osteopaenic changes (oedema), and ct may be helpful in such cases, for example to demonstrate degenerative gas in the vertebral body. rare causes of spinal abnormalities such as atypical pathogens and rare tumours may cause diagnostic problems; often the fastest road to a diagnosis is biopsy in those cases. the correct clinical diagnostic approach to spine disease is mandatory in the selection of patients to be treated. the anatomy and the relationship between different structures must be known in detail to understand the source of the pain and so to treat it percutaneously. mr, ct, dynamic x-ray and nm bone scan in selected cases can be used to understand the reason for the pain. mr with t2 stir sequence or t2 fat supp technique is mandatory to show bone marrow oedema and to decide on which metamer to perform the treatment. ct is often necessary after mr in primary and secondary spine tumours. disk disease can be seen either on ct or mr. two major treatments must be considered: discogenic pain and vertebrogenic pain, and for this reason disk treatment and vertebral treatment. disk treatment includes many mini-invasive systems to use; however, no treatment has been shown to be superior to the others, with good clinical results in 75-80% of the cases, even at long-term follow-up. vp and assisted techniques are available for the treatment of not within a few minutes following ablation, ct of the ablation zone will demonstrate an extensive area of ground glass opacity (ggo). a ggo of at least 4.5 mm peripheral to the tumour is predictive of complete ablation. as early as 24 hours post-treatment, the entire ablated region usually appeared as a well-demarcated homogeneous dense opacity on ct that corresponded to necrotic tissue and its surrounding rim of granulation tissue. this zone of ablation is the "baseline post-ablation imaging" for follow-up. then, a relatively slow involution of the ablation zone will occur with various patterns, including nodular, fibrosis, disappearance, cavitation and atelectasis. morphologic features of local tumor progression are an increase in the overall size or a change in the shape of the ablation zone (even without enhancement). it is generally considered that an ablation volume that does not increase in size on subsequent imaging after the baseline post-ablation imaging is a complete ablation. the relatively slow decrease in size of the ablation zone renders ct morphologic evaluation responsible for late discovery of local tumour progression. pet/ct is able to discover incomplete ablation earlier than ct at a stage the disease remains small. patients who have very early evaluation with pet/ct are at risk of either false-positive result due to early inflammation process, or false-negative result due to early inflammation masking active tumor foci. 3 or 6 months after ablation can be a reasonable time for pet/ct. learning objectives: 1. to consolidate knowledge on the imaging aspects of successful ablation. 2. to become familiar with the main pitfalls of post-ablation imaging. 3 . to learn about the imaging aspects of most common complications. a-503 17:00 c. follow-up imaging of thermal ablative therapies for kidney tumours d.j. breen; southampton/uk (david.breen@uhs.nhs.uk) image-guided ablation of kidney tumours has been increasingly set to become the standard of care treatment for smaller (< 5 cm) renal tumours, yet ablation remains a non-extirpative technique and is therefore paramount, in this curative setting, that imaging follow-up should reliably confirm complete tumour eradication. early on in radiofrequency ablation (rfa), control remained problematic and inadequate treatment was evidenced by residual marginal crescents of viable, enhancing disease. in the current era of more definitive ablation with multipolar techniques, cryo-and microwave ablation (mwa), this pattern of treatment failure should rarely, if ever, be encountered. typically following adequate ablation imaging should confirm a completely nonenhancing tumour and a related cortical ablation zone. whilst nonenhancement is an accepted surrogate of tumour non-viability, most practitioners look for additional collateral features such as the 'halo' sign, appearing as a soft tissue ring in the adjacent peri-renal fat, usually a sound marker of complete tumour eradication. follow-up data have shown that cryoablation (cra) can yield robust outcomes, but often incurs notable haemorrhagic change and a 'rind-like' feature around the ablation zone. cra also appears to induce faster involution of the treated tumour, whereas rfa and mwa can induce a persistent granulomatous mass which only very slowly involutes over a number of years. late local recurrence is increasingly rare at around 2-3%, but can occur as nodules of enhancing disease as late as 3-6 years after the initial treatment. subtraction mr can be useful, but to date pet and perfusion techniques still lack resolution and specificity. multiple percutaneous image-guided therapies are currently available for thermal ablation of bone tumours. thermal sources for these treatment modalities include high-intensity ultrasound, laser, microwave, radiofrequency, and cryotherapy. the predictability of thermal ablation is adequate to limit collateral damage and complications, however, is limited by biologic and anatomic variability of tissue. clinical evaluation is essential in symptomatic tumours. close imaging follow-up with ct, mri, bone scan, and pet plays a vital role in the management of the post-thermal ablation patient and detection of complications. recurrences or regrowth can be considered for repeated thermal ablation if the lesion is discovered early, before the tumour geometry, location, or distribution become unfavourable. the imaging features could vary with the different ablation method. the radiologist reporting the follow-up imaging should be familiar with different ablation methods. mri with dynamic contrast enhanced imaging and subtraction allows to detect recurrences in hypervascular tumour. contrast enhancement on t1-weighted mri imaging seems to be predictive of clinically unsuccessful ablation. on ct scan, bone reconstruction can be visualised but is a slow process, particularly in adults. pet scan is an excellent morphologic and metabolic image to follow-up the tumours. however, the inflammation produce after ablation can be misleading, particularly during the first three months. imaging follow-up plays an essential role in the management of the post-thermal ablation patient and detection of complications. interventional radiology (ir) is an evolution of radiology that treats many diseases, originally treated by traditional surgery. the clinical importance of ir has been demonstrated over the years by performing procedures that offer the benefit of therapeutic treatments, competitive from the point of view of a shorter hospitalisation time. indeed, thanks to ir, patients are treated in a less invasive manner, hospitalisation is limited and thus promotes the containment of social costs. to maintain standards clinical oversight needs to focus upon correct organisational, functional and technological appropriateness of practice. to achieve correct ir performance, it is necessary to guarantee that all the instrumental guides (fluoroscopy, ultrasound, computed tomography equipment) function optimally, the procedural equipment including guides/catheters/stents, etc. are chosen according to their technical features and their characteristics are appropriate for use, incorporating cost considerations. as the complexity and variety of interventional procedures grow, there is an increasing need to ensure the appropriate training of specialised ir staff. consideration of dedicated education and continued professional development options for radiographers working in ir is of priority. the italian association of interventional radiographers (aitri) is very important in sharing guidelines in a multidisciplinary environment to standardise and harmonise the knowledge and skills of the team in hybrid theatre and interventional suites. interventional radiology technology is rapidly expanding and, to maintain safe and efficient practice, careful consideration of current and potential future organisational needs and the training of staff within an ir suite require detailed consideration. the lecture will discuss where new and current knowledge about radiation risk and effects are coming from. a brief overview of the different sources of knowledge, including hiroshima and nagasaki life span study, will be given. the most important stakeholders involved in research and formulating guidelines for radiation protection, with special emphasis on the new main publication from the international committee on radiological protection (icrp), and the impact on radiographic practice will be discussed. new tissue weighting factors for breast glandule gives a significant higher risk for females today, especially in the pubertal age. on the other hand, they have the risk for hereditary effects significantly decreased. estimation of risk, both in general and in the individual, will be discussed. regarding staff protection, there is a new recommendation for annual dose limit for the eye lens. the previous annual dose limit was 150 msv, and this is now recommended to be decreased to 20 msv averaged over five years with no single year exceeding 50 msv. the new recommendation can be a limiting factor in interventional radiology and cardiology, if sufficient protection is not used. learning objectives: 1. to understand the importance of radiation protection in interventional radiology for patients and staff. 2. to appreciate the latest recommendations for staff radiation protection in interventional radiology. 3. to appreciate the important role of the interventional radiographer in radiation protection. a-506 17:00 the improvement of patient care and aims for the highest possible levels of service are to the forefront of the modern "interventional suite". role development experiences will be explored, considering need, effect and management of development. service demands, the need to extend those provided, the limited number of radiologists, financial constraints and the requirement for continuous professional development at state level provide much stimulus for professional radiographic role development. increased job satisfaction, reduced waiting lists and improved patient experience all provide largely positive results it appears. resistance from radiologists, multidisciplinary team members and radiographers themselves however, can provide unnecessary barriers to change. once abridged the blurring of professional lines and insecurity within multidisciplinary team members may also occur. various experiences would suggest that only by allowing ownership of change by all the clinical stakeholders involved, thus empowering them, leads to successful development. on examination clear guidelines and distinct protocols must be established, taking account of current workload, to create the ideal scenario for good multidisciplinary team ethos, where members have overlapping yet clearly defined roles. professional accountability, responsibility and an understanding of those role's are all key, but without correct training, including support and resources, no regime for role development can be achieved successfully. clinical audit not only ensures the delivery of high quality and effective care in line with best practice, whilst ensuring cost effectiveness, but also provides the confidence for all involved, especially the interventional patient. learning objectives: 1. to understand the factors influencing change in professional roles within interventional radiology. 2. to learn about the potential impact of enhanced professional roles and a multidisciplinary team approach on service delivery and patient outcomes. 3. to understand the need for clear protocols and guidelines along with appropriate training and audit of practice when implementing such changes. there have been many attempts to develop gene reporters for mri, however these give relatively modest image contrast that can be difficult to detect. i will describe in this talk a reporter that gives intense and positive contrast in mr images (up to ~8x increase in signal), which can also be used with radionuclide imaging, thus combining the sensitivity of radionuclide imaging with the spatial resolution of mri. the contrast obtained is directly related to the degree of gene expression and is readily reversible, thus allowing longitudinal studies of changes in expression. the transplantation of pancreatic islet into the liver is an excellent example of successful cell therapy. transplanted islet visualisation in vivo using a noninvasive imaging method, for example mri, is necessary to prove technical success. monitoring of transplanted islets in vivo and long-term tracking their fate using mri requires their labelling by a suitable contrast agent in vitro prior to transplantation. under encite project we successfully performed animal experiments, which proved therapy potential of labelled pancreatic islets. labelled islets implanted into the rat liver were viable and induced long-term normoglycemia in diabetic rats. mri proved their viability and even distribution in the host tissue. these results allowed performing a clinical study on a group of 12 patients, which were transplanted by iron labelled pancreatic islets from cadaver donors. the successful pilot experiment enabled introducing of transplantation of native islets into routine clinical practice. search for better alternative sites, improved immunosuppression and alternative insulinproducing cells require multimodal and multifunctional molecular probes. currently we test polymer meshes as artificial transplant sites, effect of mesenchymal stem cells as a supportive net for beta cells, and novel cellular probes combing 1h, 19 f labels and fluorescent ones. optical imaging in the clinic j. dijkstra; leiden/nl (j.dijkstra@lumc.nl) recently a lot of developments have been done in the field of optical imaging. new sensitive devices made it possible to use both visible and near infrared light as diagnostic tool and guidance tool. the advantage of near infrared is that the penetration depth in tissue is much better than for visible light, allowing to see deeper. by using techniques like augmented reality, the data from infrared, both anatomical and functional, can be presented to the operator in real-time. optical imaging is used e.g. as an evaluation tools for mammography where the optical spectral properties of the tumor cells is used to monitor the effectiveness of chemo treatment. the spectral properties of the breast are measured using a laser at different wavelengths and a camera to create tomographically a 3d volume. dedicated near infrared probes which bind to certain tissue types make it possible to look for e.g. remaining tumor tissue in resection margins during surgery. this techniques also allow to visualise structures which should be avoided during procedures like nerves. by adding multispectral imaging, the endogenous contrast can be used. different tissues have their own absorption spectrum which can be shown as additional information, for instance the ration hb/hbo2. optical imaging also allows for acquiring images at near microscopic resolution real time in-vivo by using optical coherence tomography. this modality is being tested to provide information about the presence of certain cell types very fast where otherwise histology is needed. mesenchymal stem cells constructs for image-guided cell therapy in myocardial ischemia and digestive fistulas o. clã©ment, e. blondiaux, g. rahmi, l. pidial, a. silva, f. gazeau, c. wilhelm, g. autret; paris/fr (olivier.clement@inserm.fr) regenerative medicine has recently emerged as a potential therapeutic tool. a number of preclinical and clinical trials have been conducted in many diseases ranging from diabetes to myocardial infarction and neuro-regenerative diseases that assess the feasibility and benefits of injecting stem cells. however, outcomes relating to graft survival remain generally unsatisfactory, whether the process of injection is direct, intravenous or catheter-guided. to overcome such issues, tissue engineering has potential to improve cell engraftment and therapeutic response including functional parameters. this work aimed to evaluate mesenchymal stem cell constructs for image-guided cell therapy in myocardial ischemia and digestive fistulas. we tried to options: 1. fibrin patches based on fibrinogen monomers polymerised with thrombin and seeded with cells. 2. constructs based on 3d multilayers of confluent cells sheets. tissue constructs were labelled with iron oxide particles and evaluated in a model a myocardial infarction for the fibrin patches or digestive fistula for the 3d constructs. mri at 4.7 was performed at various time points after treatments using a high resolution coil. fibrin patches could induce a therapeutic effect by increasing the left ventricular ejection fraction compared to sham. 3d constructs induced an increased number of fistula healing and enhanced micro-vasculature density compared to controls. mri of labelled stem cell constructs allowed a good evaluation of the models and showed increased therapeutic efficacy. the proposed paracrine mechanisms will be discussed. is cell imaging relevant for the clinic? lessons to be learned from preclinical research u. himmelreich; leuven/be (uwe.himmelreich@med.kuleuven.be) non-invasive imaging of therapeutic cells has become a popular field of research over the last decade. this interest was mainly based on the hope that the location, migration but also function of immune, stem and other cells can be visualised over time in individuals. the development of novel contrast agents and mechanisms for mri but also other imaging methods has resulted in exciting basic research findings. in particular, the application of relatively biotolerant iron oxide based nanoparticles has fostered the hope for direct translation into clinical research and general practice. however, pre-clinical research has also highlighted several limitations of nanoparticle based cell imaging by using mri including the generation of unspecific contrast, difficulties to quantitatively image engrafted cells, unambiguous contrast, adverse effects on cell biology, limitations for longitudinal follow-up or the lack of functional information. such shortcomings are traditionally overcome in preclinical research by combining mri with other imaging modalities like bioluminescence imaging or positron emission tomography. our research focuses on the optimisation of cell labeling strategies for robust, sensitive and potentially quantitative visualisation of stem and progenitor cells in therapy models in vivo to assess cell behavior after engraftment. the sensitivity, stability, toxicity and adverse effects on the cell biology by the labeling procedure were studied for iron oxide based particles. the potential of gdchelates and 19 f labeled compounds for cell labeling has been assessed in vitro and in vivo. based on our preclinical research finding the potential of future applications in patients will be explored. cardiac ct is becoming the imaging modality of choice for an increasing number of clinical indications, not only to rule out coronary artery disease but also to evaluate cardiac morphology and function, and to determine patient outcome after coronary artery revascularisation. however, as with any other imaging tools, appropriate interpretation of cardiac ct examinations is required to assess the clinical value of this newly established diagnostic imaging modality. this process requires performance of thorough cardiac ct acquisition protocols, detailed knowledge of standard cardiac anatomic and physiologic terminology, as well as appropriate postprocessing, reading and reporting. in particular, radiologists need to recognise and be aware of the imaging findings that may confound and lead to interpretation errors. this lecture will summarise the practical aspects of postprocessing, reading and reporting of non-invasive cardiac ct examinations. the value and limitations of every available ct postprocessing technique including two-dimensional multiplanar reformations, curved multiplanar reformats, maximum intensity projection (mip) and volume rendered images will be explained. moreover, hints for improving reading results by recognising technical causes for various artefacts in cardiac ct will be elucidated and reading approaches to diminish false positives, false negatives and inaccuracies when assessing coronary artery stenosis will be suggested. cardiac magnetic resonance (cmr) is a complex imaging technique due to the intrinsic anatomical and technical peculiarities of the exam. these include the non-orthogonal cardiac orientation within the chest cavity requiring dedicated acquisition planes and the complex respiratory and cardiac motion to which the heart is subject and requiring a combination of ecg-gated and breath-hold sequences. potential additional anatomical pitfalls also include normal structures and variants like the moderator band, papillary muscles, and the presence of prominent crista terminalis or myocardial trabeculations, whose recognition is mandatory and may mimic in some cases a pathological condition. technical issues of cmr concern the continuous intracavitary inflow of protons and the associated "slow-flow" artifacts (limiting visualisation of endomyocardial border in some cases) pitfalls related to ecg gating, like inadequate synchronisation or the t-wave swell phenomenon; and finally a series of specific artifacts intrinsically related to the use of different pulse sequences that may interfere with image quality. an additional, more complex issue to consider is also the widespread diffusion of high-field magnets which have further enhanced those aspects. knowledge of the spectrum of those cmr peculiarities is mandatory to approaching and providing a correct diagnosis according to the main clinical request. the present lecture will review the most important anatomical and technical pitfalls of cmr examination and offer, when possible, practical solutions to overcome those limitations. shoulder imaging and intervention are becoming increasingly important in clinical practice. this session considers the indications, techniques, imaging findings and relative merits of diagnostic ultrasound and mri of the shoulder. the indications, techniques and results of us-guided interventional procedures are also considered. a panel discussion will deal with controversies in shoulder imaging such as the accuracy of us and mri in assessing rotator cuff tears, tendinosis, impingement and muscle atrophy, and the efficacy of us-guided interventions. audience participation in the discussion will be welcome. the shoulder is an anatomic area that is very commonly evaluated with musculoskeletal ultrasound. ultrasonography is widely recognised as a reliable means of assessing rotator cuff disease with accuracies reaching 100% for fullthickness tears and 90-95 % for partial-thickness tears. diagnostic accuracy depends mostly on the skills and experience of the examiner. a comprehensive ultrasound (us) examination requires, first of all, sound knowledge of the anatomy. a specific scanning protocol must be adopted in every us examination in patients with shoulder disease, because focal symptoms do not correlate with the location of the disease. the greatest importance of ultrasonography in rotator cuff assessment lies in its dynamic character. several dynamic manoeuvres can reveal pathologies such as subacromial impingement. last, but not least there are several scanning pitfalls such as anisotropy. anatomy key structures as well as the us technique and scanning protocol will be presented in this lecture. dynamic manoeuvres will be described and demonstrated with videos. scanning pitfalls will be emphasised. advantages and disadvantages of the us examination compared to other imaging modalities will be discussed. guidelines concerning the mr examination technique of the rotator cuff will be presented in this session. on intermediate-weighted mr images, tendinopathy and partial and complete tears of the rotator can be differentiated with high diagnostic accuracy. indications for mr arthrography, especially for the detection of small articular sided partial tears in athletes, will be presented as well. established classification systems for the description of rotator cuff tears will be discussed. besides characterisation of rotator cuff lesions, especially in view of therapeutic decision-making, recognition of the underlying pathomechanism is necessary. therefore, the role of imaging is to detect different structural findings that are suggestive of a possibly underlying impingement syndrome. in primary impingement syndromes imaging abnormalities of the rotator cuff, the overlying bursa and the coracohumeral arch represent the centre of imaging findings. primary extrinsic impingement is caused by structural abnormalities of the coracoacromial arch, whereas secondary extrinsic impingement is related to glenohumeral instability. types of internal impingement (posterosuperior and anterosuperior impingement) are secondary to rotator cuff and/or capsular dysfunction. posterosuperior impingement can be diagnosed on mr arthrograms by identification of the socalled "kissing lesion" pattern, with corresponding lesions of the undersurface of the rotator cuff, posterosuperior labrum, greater tuberosity and superior glenoid. imaging abnormalities of this condition will be discussed. the shoulder is one of the joints in the human body that is most subject to a number of pathologic conditions, both in young and in elderly subjects, such as subacromial-subdeltoid bursitis, calcific tendinopathy, and degenerative conditions. being inexpensive, readily available, and radiation-free, ultrasound is the imaging modality of choice to guide interventional procedures around the shoulder. thanks to its high resolution and multiplanar capabilities, ultrasound can be used to guide needles precisely in the tendons of the rotator cuff or within the joint space, both gleno-humeral and acromio-clavicular. this approach can be used to perform a number of different procedures. when dealing with bursitis, a needle can be guided within the subacromial bursa to aspirate fluid and to inject anti-inflammatory drugs. in case of calcific tendinopathy, one or two needles can be used to dissolve calcium deposit and drain it, providing patients prompt relief. in selected patients with overuse tendinopathy, ultrasound can be used to guide intratendinous injection of platelet-rich plasma that has been reported to be helpful in stimulating tendon healing. although minimally invasive, these procedures should be performed in an ultrasound ward with a high degree of sterility, as risk of infection can be concrete. multi-detector computed tomography (ct) offers new opportunities in the imaging of the gastrointestinal tract. its ability to cover a large volume in a very short scan time, and in a single breath-hold with thin collimation and isotropic voxels, allows the imaging of the entire oesophagus, stomach, and the whole chest and abdomen with high-quality multiplanar reformation and threedimensional reconstruction. preparation of the patients by fasting from solid food approximately 6 hours prior the examination is important. proper distention of the oesophagus and stomach by oral administration of effervescent granules and water, and optimally timed administration of intravenous contrast material are required to detect and characterise the disease. preoperative staging of oesophageal and gastric carcinoma appears to be the main indication for mdct and may replace endoluminal ultrasound (eus) in the staging of advanced cancers. the use of various reconstruction techniques, including virtual gastroscopy (vg) using a volume-rendering (vr) technique, is promising for the detection of early gastric cancer. the application of the texture analysis technique to distinguish between the different types of gastric and esophageal tumors is still evolving. finally, the introduction of fdg pet, in combination with mdct, has resulted in further optimisation of the diagnostic workup of oesophageal cancer, as well as specific types of cases of gastric cancer. by providing morphologic and functional information in the same setting, this technique has come to be the modality of choice, when available. the diagnosis of oesophageal and gastric cancer is usually based on endoscopic findings accompanied by biopsy. however, staging is a matter for diagnostic imaging and is the major determinant of disease management. this should be discussed within a multidisciplinary forum (multidisciplinary team [mdt] meeting) in which the radiologist plays a crucial part. accurate stagingusually based on the tnm staging criteria -is essential and the radiologist's report should reflect this pivotal role. the tnm staging of oesophageal cancer and gastric cancer will be discussed in detail. the phases in staging is essentially a filtering process which seeks to initially exclude distant metastasis and/or advanced local disease, initially by optimally protocolled ct scanning, if ct shows advanced disease, treatment is palliative, but even under these circumstances imaging will help determine the method of palliation. conversely, if ct demonstrates localised disease, 18 f fdg-pet scanning for oesophageal cancer and for selected cases of gastric cancer is indicated. if this, too, shows no nodal or distant metastasis, accurate t staging with eus will help determine whether the patient proceeds directly to surgery or undergoes neo-adjuvant chemo/radiotherapy prior to surgery, or in the case of oesophageal cancer may be suitable for emr. the role of staging laparoscopy in gastric cancer will also be discussed. in summary, the radiologist and nuclear medicine physician are crucial in determining treatment. their reports are lynch pins in the mdt discussion of patient management. it is therefore essential that the imaging report should optimally inform this discussion. learning objectives: 1. to learn about the latest tmn staging in oesophageal and gastric cancer. 2. to appreciate the imaging criteria for local, nodal and metastatic disease, and understand the accuracy of imaging staging. 3. to become familiar with the structure of a perfect imaging report. a-520 09:10 c. assessment after treatment a.m. riddell; london/uk (angela. riddell@rmh.nhs.uk) it is now established that for the majority of patients with oesophageal and advanced gastric cancer, there is survival benefit from the use of neoadjuvant therapy. therefore, there is a requirement for imaging to accurately restage the tumour and to assess the response to neoadjuvant therapy, to provide prognostic information and to direct future management. restaging following therapy is challenging, as differentiating treatment-related fibrosis/oedema from viable tumour is problematic with both ct and endoscopic ultrasound. the t and n staging accuracy for both modalities falls following neoadjuvant therapy. inconsistencies in measurements due to alterations in the degree of gastric/oesophageal distension can also limit the accuracy of recist criteria to determine the response. functional imaging techniques such as pet-ct offer an improved method for assessing response. alterations in the standardised uptake value (suv) occur much earlier than changes in size; therefore a metabolic response can be detected sooner, allowing for more rapid alterations in treatment strategies. acute complications following oesophagogastrectomy generally occur within the thorax and are either related to a leak at the anastomosis/mediastinitis or respiratory complications such as pneumonia or a pleural effusion. intra-abdominal collections may develop following oesophagogastrectomy and gastrectomy. late complications following both procedures are often due to tumour recurrence: locoregional such as lymph node recurrence or at the anastomosis; metastatic spread such as haematogenous spread or via the peritoneum or pleura. currently, there is no consensus on the most appropriate timing or frequency of postoperative imaging. a. an overview of pulmonary artery hypertension n.j. screaton; cambridge/uk (nicholas.screaton@papworth.nhs.uk) pulmonary hypertension is defined by increased mean pulmonary arterial pressure > 25 mmhg at rest or > 30 mmhg during exercise. ph causes significant mortality and morbidity, but commonly presents with non-specific clinical signs and symptoms resulting in significant delay in accurate diagnosis and specific treatment. untreated ph is progressive with increased pulmonary vascular resistance leading to right ventricular failure and ultimately death. the current dana point classification of pulmonary hypertension is clinically based. it groups diseases with similar pathophysiological mechanisms and therapeutic approaches. groupings include conditions characterised by diffuse small vessel narrowing (group 1 and group 1'), ph secondary to left sided cardiac disease (group 2), chronic hypoxic pleuro-parenchymal disease (group 3), chronic thrombo-embolic pulmonary hypertension cteph (group 4), and a miscellaneous group of diseases with either unclear or multi-factorial aetiologies (group 5). in the dana point classification, small vessel diseases are subdivided into group 1 which primarily affect the pulmonary arterioles and group 1' affecting the capillary/venous pulmonary circulation (pulmonary capillary haemangiomatosis and pulmonary veno-occlusive disease). the differentiation of group 1 from group 1' diseases is important since in group 1' arteriolar dilatation treatments can cause life-threatening pulmonary oedema. group 4 is synonymous with cteph with other causes of large vessel obstruction (vasculitis and pulmonary artery tumour) being considered as group 5 disorders. recent advances include an increased understanding of molecular mechanisms underpinning pah, facilitating targeted therapy development, a rapidly expanding role of surgical pulmonary endarterectomy in proximal cteph, and recognition of imaging as a potential therapeutic end point. ct allows depicting pulmonary hypertension (ph) and helps identifying its cause, therefore playing a crucial role in the diagnostic workup. ct features of pulmonary arterial hypertension include dilatation of the pulmonary artery trunk, with a diameter greater than or equal to 29 mm, a ratio to the aortic diameter greater than 1:1 and a segmental artery-to-bronchus ratio greater than 1:1 in at least three pulmonary lobes. on ecg-gated ct, right pulmonary artery distensibility shows the best diagnostic value with 86% sensitivity and 96% specificity for a cutoff value of 16.5%. among the various causes of secondary ph, ct is especially useful for detecting signs of chronic thromboembolic pulmonary hypertension, including wall-adherent thrombi, bands, webs or chronic arterial occlusion, mosaic lung attenuation and systemic collateral supply. ct shows signs of pulmonary edema, such as thickening of the interlobular septa, centrilobular ground glass opacities, mediastinal lymph node enlargement and pleural effusion in ph caused by pulmonary veno-occlusive disease, left heart diseases or mediastinal fibrosis. signs of lung parenchyma diseases may be indentified on ct; ph is a late complication in patients with pulmonary fibrosis, sarcoidosis or chronic obstructive lung disease, but may affect systemic sclerosis patients with limited lung parenchyma involvement. congenital cardiac abnormalities with untreated right-to-left shunting resulting in eisenmenger syndrome, such as ventricular or atrial septal defect and patent ductus arteriosus are easily recognised on ct. conversely, signs of peripheral pulmonary arteriovenous shunting in portopulmonary hypertension and ph caused by hepatopulmonary syndrome are more difficult to assess. learning objectives: 1. to learn about the ct diagnosis of pulmonary artery hypertension. 2. to become familiar with the causes of pulmonary artery hypertension on ct. a-524 09:30 c. mri in pulmonary artery hypertension j. biederer; heidelberg/ de (juergen.biederer@med.uni-heidelberg.de) for the assessment of pulmonary arterial hypertension (pah), the dedicated 30 min mri protocol would comprise a free breathing and noncontrastenhanced examination, short t2-w sequences, dynamic contrast-enhanced perfusion imaging, a high-resolution angiogram, a 3d breath-hold acquisition, dynamic steady-state free precession or gradient echo sequences of the heart and a study of myocardial late enhancement. the morphologic sequences show typical features of pah: right atrial/ventricular dilatation, enlargement of the pulmonary trunk/main pulmonary arteries and peripherally attenuated pulmonary vessels. incidental infiltrates, nodules or masses of the lung, mediastinum and chest wall would be covered. the first pass contrastenhanced perfusion imaging demonstrates an increased mean transit time/decreased pulmonary blood flow, but a relatively homogeneous lung perfusion (important to differentiate from cteph, where multiple segmental perfusion defects would be expected). the cardiac part shows right ventricular mass, wall thickness and functional changes correlating with elevation of pulmonary arterial pressure: distortion of the interventricular septum, area change of the pulmonary trunk, right ventricular volume/stroke volume as well as pathologic right/left ventricular end-diastolic volume indexes. late enhancement of the right ventricular wall would correlate with myocardial fibrosis. furthermore, optional experimental velocity-encoded sequences (ideally for multidirectional flow visualisation, "4d flow") show a decreased pulmonary artery blood flow velocity, increased retrograde flow and inhomogeneous velocity profiles. in conclusion for the near future, given the availability of scanner time and appropriate experience of the team, thoracic mri is probably the most comprehensive and effective single examination for the diagnosis and follow-up of pah. in the era of organ-based radiology, the group of diseases known as multisystemic malignancies represents an obvious challenge to both radiologists and oncologists. the necessity to match the growing possibilities of different imaging modalities with widespread multisystemic pathology and clinical sufficiency resulted in upgrading well-known diagnostic algorithms. the precise knowledge of clinical staging systems and classification, and the pathologic and physiologic mechanisms of the disease pathways are important for planning imaging modalities and specific protocols. perfect imaging of multisystemic malignancies now includes not only traditional anatomic-based modalities, but also much more often different types of whole body scanning such as ct, mri, pet and their combination in spect/ct, pet/ct and now even pet/mri. new imaging modalities and growing possibilities of traditional imaging techniques obviously influence the current clinical guidelines for this disclosure: c. heussel: consultant boehringer ingelheim, grifols, novartis. a common language between radiologists and clinicians, so that the latter can make an informed treatment decision based on sound conclusions to become familiar with the conditions necessary to implement them to understand the limits of their application to learn useful lessons from these criteria for routine clinical practice chairman's introduction a. palko this requires a thorough knowledge of the relevant brain anatomy, choice of appropriate structural and molecular imaging modalities and interpretation of mri and pet/spect in the most prevalent disorders in a structured fashion the presentation has the objective of giving the audience a synthesised panorama of our country situated in north america, with more than 110 million inhabitants and a large prehispanic history based on the aztec, toltec and maya cultures, and also of interesting facts related to the three centuries of colonial existence under the spain influence and dominium until the 1810 war of independence. after 1880, mexico has never had an international war; the last was against the northern border country, the united states. also, we will give important data on how in 1910 the mexicans rebelled against a 30-year dictator, general porfirio diaz. the mexican revolution was a long and cruel war, but later opened the doors to democracy and a complex developmental era began that is still in process. some demographic and contributions to health, science and culture issues will be mentioned and also the works of mexican scientists, writers and philosophers who have been presented awards including the nobel prize. in relation to well-known mexican artists such as diego rivera and frida khalo, some facts of their works will be presented. interventional radiology in oncologic patients g. elizondo-riojas; monterrey/ mx (elizondoguillermo@hotmail.com) interventional radiology (ir) is becoming an increasingly prominent subspecialty in the care of oncologic patients. its role extends from initial diagnosis to minimally invasive treatment of the malignancy and its complications. image-guided biopsies are increasingly performed using minimally invasive techniques. also, an integral part of care of these patients is vascular access as a means of medication, chemotherapy or parenteral nutrition, and interventional radiologists can place required the devices with well-established safety and efficacy. ir also plays a substantial role in the therapy of oncologic patients, through local tumor treatments such as transarterial chemo-embolisation and locoregional control with radiofrequency/cryo ablation, as well as management of complications of malignancy such as pain, obstruction (biliary, ureteral, etc) ., venous thrombosis and drainage of thoracic and abdominal collections. in mexico, ir is a growing subspecialty, and more medical students nowadays want to be radiologists and eventually become interventional radiologists. this is a paradigm shift. more and more radiologist wants to be involved with patient management and to be more than just "observers" in the process of patient care. we have to be prepared to offer this opportunity to our residents; otherwise other specialties will "have to fill the empty space" that we have left. interventional oncology has all the advantages to fulfil this opportunity. it is our chance to contribute to the advancement of medical care. learning objectives: 1. to appreciate the role of interventional radiology in the management of oncologic patients. 2. to learn how interventional radiology changes the quality of life for patients with cancer. 3. to understand the impact of interventional radiology procedures in the outcome of some neoplastic diseases. interlude: origins and development of radiology in mexico m.e. stoopen-rometti; mexico/mx (mstoopen@clinicalomas.com.mx) mexican radiology started in 1896, just a few months after the discovery of xrays. during the last few decades, as well as in other countries, there has been a great development both in public and private sectors, which will be described in this interlude. learning objectives: 1. to learn about the history of radiology in mexico. 2. to learn about the development of radiology in mexico. 3 . to learn about the present and future of radiology in mexico. modern issues in oncologic ultrasound j. mexico/mx (jtanus59@hotmail.com) advances in ultrasound (us) technology allow confident characterisation of masses. these include harmonic imaging, compound imaging, power doppler, faster frame rates, higher resolution transducers, three-dimensional (3d) us, us contrast agents and, more recently, elastography and fusion imaging. highfrequency transducers provide superb spatial and soft-tissue resolution, permitting substantially improved differentiation of subtle lesion, margin resolution, and lesion conspicuity in the background of normal tissue. elastography features such as size ratios, shape, homogeneity, and maximum lesion stiffness complement conventional us in the analysis of lesions. ultrasound contrast agents have overcome some of the limitations of doppler ultrasound techniques with demonstration of irregular branching central or penetrating vascularity within a solid mass raising suspicion of malignant neovascularity (neoangiogenesis). ultrasound contrast agents can provide important information in the assessment of lesions to be treated by locoregional therapies, which include ablation (feeding vessels), trans-arterial chemo/radio-embolisation, detecting viable tumour persistence following this treatment; facilitation of needle positioning in cases of poor lesion delineation, and assessment of local tumour progression. it facilitates needle positioning in cases of incomplete or poor lesion delineation on unenhanced ultrasound. us contrast agents are an important key during the evaluation of the immediate treatment effect of ablation and guidance for immediate re-treatment of residual tumour. learning objectives: 1. to understand the role of ultrasound in the management of oncology patients. 2. to learn how ultrasound is used in large oncology centers. 3 . to learn about the modern concepts of ultrasound in oncology patients. the aim of this lecture is to give an overview of the techniques for imaging inflammatory bowel disease (ibd) of the small bowel and the colon with either ultrasound (us), multidetector row computed tomography (mdct) or with magnetic resonance imaging (mri) and compare the different modalities for its strength and weakness. optimal imaging of the bowel begins with the preparation phase. the small bowel has to be distended for a concise examination. this is mainly done orally, which is named enterography. a solution of 2.5% mannitol seems to be the one preparation technique mostly used for small bowel distension. another technique is the enteroclysis, application of contrast after intubation of the small bowel. the comparative advatages and disatvantages of the two preparation methods will be discussed. this intraluminal contrast gives a neutral contrast in ct and a biphasic signal in mr. the colon can be prepared in a fashion similar to colonoscopy meaning total cleansing. another possibility is the so called fecal tagging whereas the stool will be contrasted with an additive to standardised food. therefore no cleansing is needed for preparation. imaging parameters will be discussed for mr and ct. the aim of imaging for the bowel should be to establish the following: 1) presence, severity, and extent of disease; 2) activity of the disease and 3) extra-intestinal complications. us, mr and mdct have proven to be a good tool to evaluate the extent, the activity of the disease and the presence of extraluminal complications. pros and cons will be discussed when to use which technique. learning objectives: 1. to understand state-of-the-art mri, ct and us protocols for imaging ibd. 2. to appreciate the comparative advantages and disadvantages of enterography and enteroclysis protocols. 3 . to learn about protocol modifications when evaluating the colon.a-393 10:50 b. small bowel disease j. stoker; amsterdam/nl (j.stoker@amc.uva.nl) classification of small bowel crohn's disease is helpful for assessing disease activity and treatment monitoring. similar to clinically based classification, also imaging-based classification systems have been developed, of which some have been externally validated. important imaging features for determining disease activity include bowel wall thickness and vascularity/enhancement; at mri, also wall oedema plays a role. stenoses, fistulas and abscesses are important sequels. for assessment and monitoring of small bowel disease the breast imaging reporting and data system (bi-radsâ®) for mammography of the american college of radiology (acrâ®) consists of several components, a standardised lexicon of terms to be used during reporting, a 4-step coding system for the mammographic density as a surrogate parameter for the mammographic sensitivity, and a group of assessment categories ranging from 0 to 6 for structured communication regarding the recommended further management. the goal of bi-radsâ® is to improve the quality of breast imaging reporting and communication. in addition, by providing structured reports it facilitates regular quality assurance measures. the bi-radsâ® atlas for mammography is currently in its fourth edition and was released in 2003. the upcoming 5 th edition is expected soon and will be incorporated into the course as it becomes available. the breast imaging reporting and data system (bi-rads) was first developed by the american college of radiology for standardising the reporting of mammography. since its first publication in 1993, new editions have also addressed breast ultrasound (us) and mr imaging examination. the new (fifth) edition will be published soon. on the form, this new version was designed to include a web-based format. substance includes updates in lexicon descriptors, e.g. masses, calcifications, associated features (now comprising surrounding tissue with stiffness assessment), and special cases. us descriptors will be reviewed in the lecture. of note, guidance on how to link bi-rads descriptors with management recommendations has been added in the report section. a new approach to outcome assessment (audit section) is being proposed for screening us. the appropriate use of descriptors is expected to increase the accuracy of imaging interpretation. for relevant patient management, us analysis is to be integrated with other available imaging, as well as with clinical data. learning objectives: 1. to learn about the bi-rads lexicon. 2. to understand the usefulness of bi-rads system. a-434 15:00 c. mri k. pinker-domenig, p.a.t. baltzer; vienna/at (katja.pinker@meduniwien.ac.at) dynamic contrast-enhanced magnetic resonance imaging (dce-mri) of the breast is a well-established non-invasive imaging technique. it has clinical application in the screening of high-risk patients, diagnosis and staging of breast cancer, monitoring neoadjuvant chemotherapy and post-treatment follow-up. to standardise the reporting of dce-mri of the breast and minimise false-positive results without compromising sensitivity, the american college of radiology (acr) introduced the breast imaging-reporting and data system (bi-radsâ®) mri lexicon in 2003. bi-rads relies on the combined analysis of morphological appearance and lesion enhancement kinetics. it is widely used for reporting dce-mri of the breast and is applicable at any given field strength. it aims to provide an up-date report on the bi-radsâ® lexicon and instill confidence in using bi-radsâ® descriptors. the bi-radsâ® system may be placed in a broader clinical context to highlight its value for standardised reporting of dce-mri of the breast. mr-guided focused ultrasound is a new therapeutic modality which can allow selective destruction and or heating of tissues in deep body areas under close image guidance control. these talks will introduce the field and allow you to understand the areas of current work and areas of future development in this rapidly expanding field. session objectives: 1. to become familiar with mr-guided focused ultrasound. 2. to understand the advantages of focused ultrasound. 3. to learn in which areas focused ultrasound is evolving successfully. description of technique c. moonen; utrecht/nl (c.moonen@umcutrecht.nl)high-intensity focused ultrasound (hifu) is the only clinically viable technology that can be used to achieve a local temperature increase deep inside the human body in a non-invasive way. mri guidance of the procedure allows in situ target definition and identification of nearby healthy tissue to be spared. in addition, mri can be used to provide continuous temperature mapping during hifu for spatial and temporal control of the heating procedure and prediction of the final lesion based on the received thermal dose. the primary purpose of the development of mr-guided hifu was to achieve safe non-invasive tissue ablation. the technique has been tested extensively and is now accepted in the clinic for ablation of uterine fibroids. mr-guided hifu for ablation shows conceptual similarities with radiation therapy. however, thermal damage generally shows threshold-like behaviour with necrosis above the critical thermal dose and full recovery below. mr-guided hifu is being clinically evaluated in the cancer field. this presentation will cover the basic technologies for treatment of stationary tissues, and some advances towards treatment of mobile abdominal organs. for state-of-the-art mr liver and pancreatic imaging, a field strength of at least 1.5t is required. all non-blood pool gadolinium chelate-based contrast agents are suitable for dynamic liver and pancreatic mri. all gadolinium chelates should be routinely administered at a rate of 1-2 ml/s followed by a 20 ml saline flush at 1-2 ml/s using a power injector. to obtain hepatobiliary phase imaging in addition to dynamic phase imaging, the use of liver-specific contrast agents is required. gd-eob provides the highest hepatocyte enhancement, but an overlap between delayed phase and hepatocyte phase has to be considered during dynamic evaluation. the hepatocyte phase can be considered adequate when contrast is detected in the intrahepatic bile ducts. hepatobiliary phase imaging benefits from a gradient echo high flip angle, depending on magnet field strength. in the absence of liver function impairment and biliary obstruction, contrast-enhanced mr cholangiography can be obtained with gd-eob at 20-40 minutes, and with gd-bopta at 60-120 minutes. when the differential diagnosis is primarily between solid benign lesion vs. metastasis, the use of a liver-specific ca is recommended, due to the ability to diagnose fnh confidently. the combined interpretation of dynamic and hepatobiliary phase improves diagnostic accuracy of mr imaging for the detection of hcc.hemangiomas and intrahepatic ccc result in relative hypointensity in the late vascular phase after gd-eob administration. when combined with t2weighted mrcp, contrast-enhanced mrc allows morphologic and functional assessment of the biliary system. gastrointestinal stromal tumours (gist) are rare malignant tumours arising within the wall of the gut from the interstitial cells of cajal, which act as pacemaker cells controlling peristalsis. the crude annual incidence of clinically detected gists is approximately 10 cases per million in europe. the median age at diagnosis is approximately 63 years, and 80% of patients are older than 50 years. however, a small number of cases do occur in younger people and children, and these are usually syndromic gists. gists can occur at any site of the gut from the oesophagus to rectum, although they can also arise in the extra-gastrointestinal abdominal and pelvic locations, so-called e-gists. the commonest location is the stomach (55%), followed by the small intestine (35%) and rectum (5%). diagnosis is by biopsy, with spindle cell or epithelioid morphology, and immunohistochemical staining for cd117 (the protein product of the kit gene) and/or dog-1 receptors. approximately, 80% of gists have mutations in the kit gene, 10% have mutations of the pdgfra gene, and the remaining 10% have no mutation (wild-type) or rare gene mutations. early stage disease is managed by surgery, followed by 3 years of adjuvant imatinib (a tyrosine kinase inhibitor with activity against kit and pdgfra receptors) for cases at high risk of relapse. advanced metastatic disease is treated with imatinib, with a median duration of response of approximately 2 years. at disease progression, second-line treatment is with sunitinib, with a median duration of response of approximately 6 months. imaging plays a major role in the detection, characterisation and staging of gastrointestinal tumours (gists). imaging of gists depends on the mode of presentation and the local availability. endoscopic ultrasound and computed tomography (ct) are the most widely used imaging methods. gists have a spectrum of radiological appearances depending on tumour size and site of origin, but often show certain key radiological features. multiphase multidetector row ct is necessary to detect and stage gists and multiplanar imaging is important so as to define the likely organ of origin of the mass, which may be a challenging task. the clinical diagnosis of a gist is based mainly on imaging, as biopsy runs the risk of tumour rupture or seeding of the biopsy tract. in patients with an unresectable primary tumour or metastatic disease at presentation, biopsy confirmation is important before starting medical treatment. ct or/and mri are used to assess primary tumour extension, local invasion and the presence of metastases, with main sites of metastasis being the liver and the omentum. gastrointestinal stromal tumours (gists) are treated with targeted therapy regimes. these treatment strategies are based on the suppression of tumour vasculature using the tyrosine kinase inhibition pathway. drugs like imatinib and sunitinib exhibit specific changes in tumours and metastases that can be detected on cross-sectional imaging. these changes differ significantly from standard treatment effects of cytotoxic chemotherapy. while the latter leads to destruction of tumour cells and thereby to a reduction of tumour size, the former will cause a decrease in vascularity and thereby in attenuation and enhancement of lesions while the size may remain unchanged. radiologists have to be aware of these specific patterns of response to treatment. this presentation will include a review of the choi criteria which have been developed for the assessment of gist lesions under treatment. also, current imaging strategies focusing on time-resolved ct imaging (ct perfusion imaging) will be presented. the aim of this lecture is to provide a practical approach to response imaging in gist patients integrating both existing and novel strategies. radiological response evaluation using anatomical imaging was developed in the 1980s in early phase ii clinical trials. potential new anti-cancer agents were assessed by measuring tumour size before and during therapy and a predetermined reduction in size constituted response. radiological response represents an objective surrogate for patient benefit and was the primary end point in early phase ii studies. if a pre-defined percentage of patients achieved the required response, then the agent proceeded to large phase ii and iii studies where clinical time to progression or progression-free survival comprised the primary end point. between 1980 and 2000, there were extraordinary advances in cross-sectional imaging techniques which became widely available. different imaging techniques were introduced piecemeal with different co-operative groups adding different requirements, so meaningful comparisons from one trial to another could not be made. in 2000, the recist criteria were introduced requiring specific imaging stipulations and a minimum baseline tumour size to unify the different criteria and enable meaningful comparisons from one study to another. further advances continue to be made regarding anatomical and functional imaging. not all anti-cancer agents are cytocidal and many studies now use time to progression or progression-free survival defined by radiological imaging as the primary end point. certain tumour types respond in a unique manner requiring the employment of specific response criteria in these tumour types to adequately demonstrate response. some of these tumour types and their specific response criteria will be discussed. learning objectives: 1. to learn about the role of radiological response evaluation in clinical trials. 2. to understand how radiological response evaluation has evolved and continues to evolve. 3. to understand which response criteria are utilised in specific tumour types. emerging biomarkers for response assessment: pros and cons m.c. roethke; heidelberg/ de (m.roethke@dkfz.de) non-invasive response assessment of new specific anti-cancer therapies is an emerging field of oncologic imaging. in the past few years, large efforts were undertaken to develop new functional biomarkers to enable an earlier diagnosis, improved risk stratification and treatment monitoring of oncological diseases. imaging biomarkers reflect changes in tumour biology, which can be differentiated into certain categories (e.g. cell density, tumour heterogeneity, iron concentration, elastic properties, or cellular receptors). in a first step, alternative qualitative and quantitative imaging biomarkers for the different modalities (mri, ct, pet) are elucidated. for magnetic resonance imaging, new techniques with potential for treatment response monitoring such as diffusion-weighted imaging, susceptibility weighted imaging, and elastography will be assessed. then, quantification of iodine uptake of contrast-enhanced ct as an imaging biomarker will be addressed. novel pet imaging strategies for therapy monitoring will be mentioned with focus on receptor targeting tracers (e.g. psma, dotatoc). furthermore, the role of pet-ct/mri is mentioned to facilitate functional techniques in oncological imaging with imaging biomarkers. the potential clinical use of prior introduced biomarkers is demonstrated for several cancer entities (e.g. hcc, prostate cancer, malign melanoma, multiple myeloma, glioblastoma). advantages and disadvantages of the illustrated imaging biomarkers are discussed during this part of the lecture. the goal is to image the right patient, at the right time, using the right test and with the right interpretation so that patients will be advised on the right therapy. ultimately, the aim is to maximise patient outcomes at an affordable cost. this session will cover the state of the art in ebr, cer, and hta and demonstrate how the results are used in imaging decisions. the application of evidence-based medicine to medical imaging was relatively delayed in comparison to other specialties. radiologists should be aware of the necessity to justify radiological examinations and imaging-based interventional procedures on the basis of the best available evidence. diagnostic tests can be evaluated with studies exploring their value in terms of: 1. technical performance; 2. diagnostic performance; 3. diagnostic impact; 4. therapeutic impact; 5. patient outcome; 6. societal impact. notably, this is a one-way logic chain. while improvement at the upper levels implies improvement at some of the lower levels, the vice versa is not always true (e.g., a better diagnostic performance does not always imply a therapeutic impact or a better patient outcome). moreover, different degrees of recommendations are based on different levels of evidence, with experts' opinion as the lowest level of evidence and meta-analyses of high-quality homogeneous studies and multicentre studies being the best level of evidence. the quality of studies needs to be evaluated in terms of internal and external validity, the former regarding study implementation (protocol violations, reference standard, measurements, and readers' independence), the latter regarding study planning (study design, subjects selection, methods, and statistical analysis). biases influencing the internal validity limit the intrinsic value of study results, while those influencing external validity limit the generalisability of study results to clinical practice. finally, high-quality research must be planned to build the evidence in favour of radiological procedures, especially for new technologies which tend to enter the market without any preliminary demonstration of efficacy. state-of-the-art methods in ebr, cer, and hta relevant to imaging u. siebert; hall i. tirol/at more and more, clinical guideline developers and reimbursement decision makers need to base their work and decisions on solid evidence. this presentation will introduce the key concepts and principles of evidence-based medicine (ebm), comparative effectiveness research (cer), and health technology assessment (hta) and their application to the field of radiology. in particular, it will be discussed which role observational studies, clinical trials, and decision-analytic modeling play in ebr, cer, and hta and when each of these study types is needed to assess imaging technologies. specific topics include the assessment of bias, optimising cutoffs and multiple test strategies, making causal inferences, explicitly weighing benefits, risks and costs, and considering ethical, legal and social implications (elsi). the excitement generated by the discovery of x-rays led to the early adoption of this technology in many hospitals around europe. over the last three decades, the explosion of new medical imaging technologies together with the recognition by clinicians of the value of these for their patients has meant that imaging budgets have increased exponentially. evidence based radiology (ebr) is a relatively new approach designed to inform clinicians of the most appropriate technique to use in a given clinical scenario. the comparative effectiveness research (cer) is used by healthcare systems to develop a strategic approach to rationalise the availability of imaging investigations. the health technology assessment (hta) funding approach is a mechanism to assess new and emerging imaging technologies in a systematic timely manner. the uk has a nationally funded healthcare system which is designed to deliver equitable care for the population free at the point of delivery. the challenge for the uk has been to ensure the highest quality service by delivering the most appropriate technology and care for patients in a timely manner. the national institute for clinical excellence (nice) is an independent body which gives guidance on new drugs and medical devices. this body requires robust scientific evidence on which to base their decisions. to create the evidence base, the imaging studies need to be of a certain standard to be included (consort, stard, etc). an example from oncologic imaging will be used to show how ebr influences daily practice. acute abdomen and abdominal trauma are both emergencies with potential fatal sequela when under/ misdiagnosed. imaging plays a crucial role in the diagnosis and management. us is the imaging technique of choice in most cases, as it is rapid, portable, lacks radiation and there is no need for sedation in young infants. us accuracy can be enhanced by iv contrast agents administration. however, limitations may occur in obese children, in deep structures, or because of gas filled bowel loops. on the other hand, ct provides excellent visualisation without limitations by obesity, gas, or deep lesions. however, there is always the radiation exposure risk of the radiosensitive paediatric patient, while sedation is required in non co-operative young children. the aim of this session is to understand "which" is the modality of choice and "why", for the most common paediatric abdominal emergencies. the acute abdomen: ct is the answer a. paterson; belfast/uk (anniezunz@gmail.com)abdominal pain is a common symptom in children, and whilst the majority will have a self-limiting condition, in some the pain may indicate an acute medical or surgical condition that requires prompt investigation and treatment. in the paediatric setting, the primary imaging modality for those with an acute abdomen is ultrasound. however, there are certain patient groups -often older children or adolescents -in whom ct plays an important role. it is well acknowledged that ct is non-operator dependent: an important factor for children presenting to emergency departments outside children's hospitals. the speed of a ct exam is valuable in the acute setting, as is the capability to obtain images without having to touch the tender abdomen of a distressed child. ct offers a global perspective of the abdomen, and image quality is not hindered by the presence of excessive bowel gas, an abnormal body habitus only porotic fragility fractures, but also of primary and secondary spine tumours such as traumatic fractures. a wide variety of lesions in and around the orbita can impair eye movement. ct and mr imaging is frequently used to confirm or exclude lesions in and around the orbit in patients with impaired eye movement. first of all, it is very important to know the exact clinical history of the patients. ct is excellent for confirming a mass; however mri is more sensitive and arrives often at a single most likely diagnosis. characteristic imaging features may help distinguish among lesions that have overlapping clinical presentations. this review focuses on some of the common orbital masses. in this lecture common benign and malignant lesions will be discussed. vascular lesions include capillary (infantile) haemangioma, cavernous haemangioma, and lymphangioma. benign tumours include optic nerve sheath meningioma, schwannoma, and neurofibroma. malignancies that are reviewed include: lymphoma, metastasis, rhabdomyosarcoma, and optic glioma. in addition, benign and malignant lesions affecting the eye movement from outside of the orbit (e.g. from the paranasal sinuses, nasopharynx and skull base) will be discussed. trigeminal neuralgia is a unique form of facial pain, defined by the international association for the study of pain as a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more trigeminal nerve branches, triggered by a specific event. additional diagnostic criteria of the international headache society include paroxysmal, stereotypic pain attacks and absence of associated neurological deficits. it is due to trigeminal nerve compression at the root entry zone, a transitional zone between central and peripheral myelination, where the myelin sheath is thinner and more prone to compression and electrical stimulation. the most common cause is vascular compression, by aberrant loops of the sca, aica, pica or vertebro-basilar dolichoectasia, leading to a neurovascular conflict. small size of the prepontine and cpa cisterns has been identified as a predisposing factor. occasionally, expansile lesions of the skull base or cns compress the root entry zone and lead to atypical trigeminal neuralgia. mr imaging is the modality of choice to evaluate these patients and requires specific tailored protocols to depict its causes, including 3d heavily t2w images reconstructed in the three planes and an angiographic sequence for the depiction of neurovascular conflicts. as neurovascular contacts are quite common in the general population, strict imaging criteria for the diagnosis of nvc have emerged. the offending vessel needs to cross the nerve perpendicularly and deviate or indent its course at the rez. a pictorial review of the most common causes of trigeminal neuralgia and trigeminal neuropathy will be presented. learning objectives: 1. to understand the causes of trigeminal neuralgia and its clinical symptoms. 2. to learn about the relevant anatomy and appropriate imaging methods. 3. to become familiar with the relevant radiological images, differential diagnosis and limitations of the method. c. facing problems of the face: facial pain, tics and palsy b. verbist; leiden/nl (b.m.verbist@lumc.nl) facial impairments may be due to neuropathies of the trigeminal and facial nerve. this lecture will focus on the seventh cranial nerve. this nerve is a complex, mixed nerve with motor fibres, parasympathetic fibres, sensory fibres to the external auditory canal and special sensory (taste) fibres to the tongue. the most common presentation of facial nerve dysfunction is facial palsy. the paresis or paralysis of facial muscles may be caused by several conditions such as developmental abnormalities, infectious or inflammatory disease or tumoural lesions. other presentations of facial nerve dysfunction are facial tics or hemifacial spasm and pain. the indications for imaging, choice of imaging modality and possible imaging findings in case of facial palsy, facial tics and facial nerve-related pain will be discussed. in this presentation, the procedures used to create the standard will be reviewed and some of the most recent changes discussed. as a collaboration of professional societies and companies, integrating the healthcare enterprise (ihe, www.ihe.net) seeks to establish methods wherein health computer systems can communicate to achieve specific functional objectives. these involve development of methodologies to implement standards such as dicom, hl7, etc. in this presentation, the procedures used to create the ihe profiles will be reviewed. patient dose tracking is rapidly growing in the usa as a large number of commercial products are available in response to user demand. these products leverage the work that has gone into the development of the dicom dose structured report and the proliferation of digital imaging systems. medical physicists are crucial team members as they are most capable of performing patient dose measurements and calculations. noteworthy is that the 'toolbox' of the medical physicist is expanding. informatics with patient dose tracking tools invariably includes familiarity at some detail with dicom structure and tags, dose structured reports (sr), sr readers, ris content and orders, modality work list broker content, modality (imaging) specific content as well as pacs, archive rules for storage/retrieval and emr. patient-specific information and the highly detailed specifics of the individual dose prescription are necessary for advanced estimates of information. a dose tracking system (a qa tool outside of the normal imaging device that uses content provided by dose sr and other information systems) usually strives to elevate the quality of the dose estimate, using informatics tools such as patient and organ models, dosimetry engines, and predictive statistics. general use cases for dose tracking will be presented including advanced dose estimations for individual patient exams and qa review for both ct and fluoroscopy. examples of tracking of prescriptions by patient, protocol/procedure and operator for determination of patient dose history, 'outliers', continuous improvement (using dmaic tools) or for meeting regulatory or accrediting bodies will be included. with the introduction of digital radiology, it is possible to have automatic systems to collect and archive patient dose data individually, in addition to demographic, geometric, and other procedural parameters, as part of the dicom header or through other dicom services. these automatic systems mean significant benefits for patient dosimetry and quality control. different approaches were used, depending on the availability and level of implementation of the dicom standard, including extracting the technical information from the headers, using the radiation dose structured reports (which contain accumulated dose over several irradiation events), analysing the mpps messages sent by the modalities to the radiology information system, and implementing optical character recognition techniques on saved screen images. before issuing a formal patient dose report, the medical physicists should verify and correct all patient dose data. all these approaches allow managing more information and provide better capacity to audit the full imaging procedure and to help with the optimisation. the current level of technology allows doing so at a reasonable cost and with a great benefit for the clinical practice. automatic detection of abnormal patient doses or mistakes in the technical parameters used and their prompt correction is possible. diagnostic reference levels will be effortlessly reviewed with such systems. some examples of pitfalls and possible optimisation actions will be presented. pathology. finally, the perfect assessment of clinical course of the disease and possible outcomes, the understanding of tumor response criteria and therapyinduced changes are significant for image interpretation in patients with multisystemic malignancies. multiple myeloma is a haematologic disorder characterised by the infiltration and proliferation of monoclonal plasma cells mainly in the bone marrow. the main symptoms are hypercalcaemia, renal impairment, cytopaenia/anaemia and bone disease -summarised as crab-criteria. symptomatic multiple myeloma is consistently preceded by asymptomatic premalignant stages called monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. these stages also present with detectable monoclonal protein and/or monoclonal plasma cells in bone marrow, but do not show any end organ impairment. staging of multiple myeloma is based on the measurement of the monoclonal protein in serum and urine as well as the assessment of impairment of haematopoiesis, renal function and mineralised bone. in the last decade, the development of novel therapeutic agents has led to an increase in response rates and survival time of patients with multiple myeloma, which further stresses the value of response assessment by imaging. cross-sectional imaging like mri, ct and pet-ct is currently replacing conventional radiological surveys in the initial workup and follow-up of patients with monoclonal plasma cell diseases. recent studies demonstrate the added value of mri in improving initial staging by unravelling a diffuse infiltration of bone marrow by plasma cells, a focal pattern or a combination of both. also, pet-ct can detect response to therapy earlier than conventional response criteria. furthermore, recent studies revealed that a complete remission of myeloma confirmed by mri or pet-ct goes along with a better prognosis compared to a complete response based only on serological parameters. learning objectives:1. to learn about the role of clinical staging systems and imaging in work-up and classification of plasma cell disorders with a focus on multiple myeloma and to learn about parameters of disease activity. 2. to understand the pathophysiologic mechanisms of multiple myeloma and to learn about the effects of abnormal plasma cells on bone remodeling cells.3. to become familiar with response criteria and therapy-induced changes and to compare the significance of imaging and serological markers for response evaluation in multiple myeloma. 4. to learn about recent studies on imaging based response assessment and prognostic significance.a-527 08:58over the last 40 years, there have been numerous efforts to classify lymphoid malignancies, culminating in the who classification introduced in 2008. so it is clear that malignant lymphomas require a sophisticated diagnostic approach based on clinical features, morphology, immunophenotyping and genetic analysis. it is essential that such an approach underpins the clinical management of these diseases, many of which are amenable to cure. the same situation is present in radiology staging procedures -it has a multidisciplinary approach. a wide range of staging procedures can include all radiology methods from cxr and chest and abdominopelvic computed tomograph to whole body mri, scintigraphy and pet-ct scans. lesions of the regional lymph node system. distant spread of mm is thought to transpire intra-and extravascularly (along the external vessel lattices) supported by specific mechanisms of extravasation and protection of mm cells against the local immune system. to date, many imaging methods, such as ultrasound, computed tomography (ct), magnetic resonance imaging, and positron emission tomography/ct, are used in the diagnosis of mm and its metastases, whereas lymphoscintigraphy has become an important tool for workup of the lymph node drainage patterns. radiological challenges include improved staging and re-staging of multi-systemic mm. accordingly, current imaging guidelines and the role and applications of the different imaging modalities in advanced mm (stage iii / iv) are reviewed with regard to their usefulness in patient management. however, standardised imaging protocols and integration of functional information to morphological imaging are needed in the future to allow for improved detection and guidance of treatment in patients with mm. the original atlanta classification of acute pancreatitis established in 1992 is outdated. in 2012, an international working group has modified the atlanta classification for acute pancreatitis to update the terminology and provide new morphologic classifications.the revised classification of acute pancreatitis identified two phases of the disease: early (first week) and late (after the first week). acute pancreatitis is subdivided into two types: interstitial oedematous pancreatitis and necrotising pancreatitis. if the diagnosis of acute pancreatitis is established by abdominal pain and by increases in the serum pancreatic enzyme activities, a contrast-enhanced ct is not usually required for diagnosis in the early phase. this revised classification introduces new terminology for pancreatic fluid collections. depending on the presence or absence of necrosis, acute collections in the first 4 weeks are called acute necrotic collections or acute peripancreatic fluid collections. once an enhancing capsule develops, persistent acute peripancreatic fluid collections are referred to as pseudocysts and acute necrotic collections, as walled-off necroses. all can be sterile or infected. this classification of acute pancreatitis allows a consistent, worldwide classification and should avoid confusion in the terminology of pancreatic fluid collections. the role of diagnostic imaging in chronic and inflammatory pancreatitis and ipmns is to detect structural changes of the ducts and of pancreatic parenchyma, assess the functional integrity of the gland, detect associated complications, and assist in management. these goals are generally fully achieved using mdct and mr imaging. in this lecture, the advantages and limitations of each technique will be discussed and illustrated. key features allowing differential diagnosis of both entities will be underlined. autoimmune pancreatitis (aip) was first described in 1961 and represents a rare form of immune mediated chronic pancreatitis which is characterised by a marked infiltration of lymphocytes and plasma cells into pancreatic tissue. whilst the majority of cases present with diffuse gland involvement, approximately 30% of patients demonstrate either segmental or focal involvement of the pancreas. clinical presentation is very variable with patients describing a range of symptoms; severe pain however is uncommon. imaging plays a central role in the diagnosis and management of aip and knowledge of the radiological appearances, which can vary significantly due to the various degrees of fibrosis and inflammatory infiltrate, is critical. cardinal features include focal or diffuse pancreatic enlargement with the loss of normal lobular architecture. in addition, pancreatic duct involvement as demonstrated by single or multiple focal strictures with limited more proximal dilatation is common. whilst these appearances may suggest a diagnosis of aip correlation with clinical history, serology and histopathology is mandatory to accurately diagnose atypical cases. in contrast, paraduodenal pancreatitis is a specific and rare form of segmental chronic inflammation characterised by fibrous tissue formation in the "groove" area between the duodenum, head of pancreas and lower common bile duct. the pathology was first described in 1973 and has since been subdivided into pure, segmental and non-segmental forms. whilst the radiological diagnosis of both aip and paraduodenal pancreatitis remains challenging, the presentation will emphasise relevant imaging strategies as well as provide tips and tricks for accurate diagnosis. bone scintigraphy is often used in combination with ct and clinical information for staging and therapy response evaluation of bone metastases. magnetic resonance (mr) imaging is a technique that is known to be valuable both for detection of bone metastases and for evaluation of their response to treatment. integrated positron emission tomography with computed tomography (pet/ct) combines the functional data from pet with anatomic information of ct in a single examination. 18 f-fluoride is a non-specific pet tracer that has recently shown very high sensitivity for bone metastases. for accurate response evaluation, it is important to recognise not only changes in bone metastases, but also the effects of treatment on unaffected, normal parts of the bone marrow. these latter therapy-related benign changes could otherwise be misinterpreted as disseminated disease or vice versa. despite the fact that the methods mentioned above, alone or in combination, have improved the assessment of bone metastases, they often remain non-specific. a specific diagnosis can in many cases only be achieved with a bone biopsy. this refresher course will give you an overview of the present imaging methods for detection and characterisation of bone lesions. indications for, and how to perform, ablation and cementoplasty of bone metastases will be presented. optimal algorithms for treatment follow-up of bone metastases and advantages and disadvantages with different imaging methods will be reviewed. also, future development of diagnostic and therapeutic methods will be included in the presentations, e.g. potential role of emerging pet imaging probes for assessing bone malignancies. author disclosure: h. ahlstrã¶m: research/grant support; astrazeneca. a. diagnostic approach: the role of hybrid imaging k. herrmann; wã¼rzburg/ this presentation will include a short review of the epidemiology of primary and metastatic bone disease, its classification and staging definitions. then we discuss the role of radionuclide imaging in initial and subsequent treatment strategy considerations. another aim is to provide guidelines for the appropriate use and applications of diagnostic radionuclide approaches for the assessment of bone diseases. the focus of this presentation will be on the role of radionuclide imaging in metastatic prostate, breast and lung cancer in the context of other available diagnostic imaging approaches. the ability of hybrid imaging technologies to achieve improved diagnostic accuracy will be emphasised and when appropriate the potential role of emerging pet imaging probes for assessing bone malignancies discussed. if feasible, the availability and effectiveness of radionuclide-based therapeutic approaches for malignant bone diseases will be reviewed. skeletal metastases are associated with significant morbidity and have high impact on health costs. effective palliative treatments are available, but less than 50% of patients respond in terms of tumour markers, pain or quality of life and all treatments are associated with some toxicity. it is generally accepted that the current imaging techniques are inadequate for measuring treatment response in a clinically relevant time frame such that skeletal metastases are usually considered as non-measurable disease in clinical routine and trials. there is therefore a need for non-invasive, objective methods to evaluate treatment response of skeletal metastases at earlier time points to guide clinical care. in addition to imaging structural changes in bone (e.g. x-ray, ct), it is now possible to image a number of biological characteristics of bone metastases including tumour metabolism, tumour cellularity, and osteoblast and osteoclast activity. methods currently available, or being actively investigated, include 99m tc-mdp spect/ct, 18 f-fluoride pet/ct, 18 f-fdg pet/ct, 11 c/ 18 f-choline pet/ct, rgd-spect/pet and dw-mri. some of the tracer methodologies will potentially be applicable for and complementary to pet/mri. the timing of follow-up imaging after commencing treatment is still under investigation. it is likely that tumour-specific methodologies may reflect response/non-response earlier than bone-specific methods due to a prolonged flare in reactive bone in responding metastatic sites. learning objectives: 1. to understand the techniques and quantitative parameters used for treatment response evaluation. 2. to learn the optimal timing for follow-up imaging after treatment. 3. to become familiar with common pitfalls in the interpretation of posttreatment mri and pet. panel discussion: how to differentiate between bone metastases and chronic inflammatory or treatment-induced changes 09:44 structured reporting is an opportunity and a challenge at the same time. expert speakers of this session will present and discuss their views on the subject, contributing to the clear vision of the members of audience on this complicated subject, convincing us to take this technique as an opportunity to improve and standardise the quality of our reporting activities. even though structured reporting (sr) has been appreciated as one of the effective methods of electronic reporting, there are not that many real applications to facilitate utilisation of this technique in practice. why it is so?the radiologists want a flexible tool to create clear, concise reports in a reasonably short time. like all template-based reporting systems, the application must be tailored to preferences of multiple users in a radiology department. the report templates should also be flexible in terms of length to avoid inappropriately detailed reports. the final appearance of the report is critical for acceptance by clinicians. accordingly, the technical challenges of development of sr systems may be grouped as: "user interface", "database structure", and "output file/document" problems. flexibility to comply with different user preferences will lead to both user interface design and database structure challenges. one of the major technical challenges is the transformation of structured data to a final text to be acceptable and applicable for the referring physician. also, exporting of reports to dicom format using dicom-sr concepts is still a challenge. multi-media formats are becoming more and more popular specially in sr reports. effective communication of radiology results is critical to high-quality health care. to that end, the radiological society of north america (rsna) has developed a library with more than 200 best-practice radiology reporting templates. the templates are freely available online (www.radreport.org) and have been accessed more than 750,000 times. the new ihe "management of radiology reporting templates" (mrrt) profile builds upon the web's hypertext markup language version 5 (html5) to provide an international standard for describing and exchanging reporting templates. this presentation will describe the rsna report template library, introduce the international mrrt standard for report templates, and describe opportunities for esr members and affiliated societies to participate. the broad goals of this initiative are to improve the quality of radiology reports, increase the productivity of radiologists, promote the use of practice guidelines, and advance data-driven health care.learning objectives:1. to explore a library of 'best practices' radiology reporting templates. 2. to become familiar with international standards for radiology reporting templates.3. to understand how structured reporting will promote the use of practice guidelines and will advance data-driven health-care. structured reporting in europe: the esr initiative o. ratib; geneva/chthe rsna has initiated a new initiative called radreport with the aim of helping promote standard reporting and improve reporting practices by creating a library of clear and consistent report templates (http://reportingwiki.rsna.org/). this project also supported in part by the national institute of biomedical imaging and bioengineering (nibib) has already gained the participation of numerous countries around the world, contributing with reports in different languages. these report templates are "structured" in the sense that they incorporate reusable knowledge, or meaning, to the clinical reporting process. structured interpretation and reporting for detecting significant prostate cancer is crucial, as it allows comparing inter-observer interpretation variability, reduces this variability by stimulating discussion of the individual scores, enhances communication with the clinicians in a uniform way, facilitates quality assurance plus research, and in this way improves patient outcome. in this presentation, the pi-rads scoring system will be shown and discussed, and fast effective structured reporting using computer software will be presented. in a rapidly ageing society, dementia prevalences are sharply increasing. furthermore, knowledge about disease mechanisms is constantly evolving. a more nosologic approach in the workup of dementia is required to improve prognostication, patient management as well as select appropriate treatment. a. anatomy of the limbic system t.a. yousry; london/uk (t.yousry@ucl.ac.uk)the term "limbic" has been used in many different connotations. to understand the anatomy, we have to define the term first. the clearest definition stems from broca: "le grand lobe limbic". defined as such, the limbic lobe is composed of 2 main structures: the limbic and the intralimbic gyri. 1. the limbic gyrus is composed of the subcallosoal gyrus anteriorly, followed in an arc by the cingulate gyrus, isthmus and parahippocampal gyrus. the latter is composed of 2 parts: i) a posterior narrow segment, the superior surface of which is called subiculum, and ii) a more voluminous anterior segment, also known as the piriform lobe. the latter consists of the anterior part of the uncus and the entorhinal area. 2. the intralimbic gyrus arches within the limbic gyrus. it is divided into 3 parts: i) anterior (prehippocampal rudiment); ii) superior (indusium griseum); and iii) inferior (hippocampus). the latter consists of 2 lamina rolled inside each other: the cornu ammonis and the dentate gyrus, with the cornu ammonis consisting of 4 neuronal fields (ca1-4). to understand the function, we have to understand the connections that define this function. the interplay with the insula is of particular importance. in summary, we will review the mri characteristics of the components of the limbic lobe, their connections, and their function, using 1.5 t, 3 t and 9.4 t high field imaging. at the end of this lecture, you will know definition (s) of the limbic lobe, its major subdivisions, connections and functions. structural neuroimaging is increasingly used in the diagnosis of neurodegenerative diseases. in a memory clinic setting, computed tomography (ct) and magnetic resonance imaging (mri) have become the most important paraclinical diagnostic tools. recent guidelines on the diagnosis and management of disorders associated with dementia state that neuroimaging should be performed at least once during the diagnostic workup. in the past, neuroimaging had been performed to exclude potentially treatable causes of dementia. however, this exclusionary approach of neuroimaging in the diagnosis of dementia has been replaced by an inclusionary approach driven by conclusive evidence that ct and mri can substantially support the clinical diagnosis by the demonstration of a distinct atrophy pattern and the assessment of vascular (co)morbidity. for these purposes, the use of visual rating scales allows a fast and reproducible assessment of global/regional cortical atrophy and vascular white matter pathology. more recently, new imaging markers such as cerebral microbleeds and superficial siderosis haven been identified and linked to alzheimer pathology. in addition, next to structural mri, advanced and quantitative mri methods have been introduced in the clinical setting. mri perfusion techniques such as arterial spin labelling (asl) demonstrated a diagnostic value in memory clinic patients, particularly in those showing no or inconclusive pathology on structural mri. de (horst.urbach@uniklinik-freiburg.de) cognitive decline is a clinical symptom in many neurodegenerative disorders. mri is typically performed in the initial diagnostic workup of these patients. as a structural imaging modality, mri is often unrevealing while several molecular imaging modalities show disease-associated alterations: 18 f-fdg-pet shows reduced glucose metabolism in neocortical association cortices, mainly in the posterior cingulate, precuneus and temporoparietal regions. since glucose metabolism is normally higher in the posterior cingulate and precuneus, reduced glucose metabolism must be specifically sought for or highlighted by voxel-based analysis. dynamic imaging of swallowing from the mouth to the duodenum is the only clinical test providing a fast and accurate diagnostic overview of the upper gi function. swallowing disorders are divided into those with dysphagia that means problems during eating or drinking, with suspicion of aspiration as an important subgroup and those with sensations like the globus syndrome or noncardiac retrosternal pain. oropharyngeal dysphagia in patients with neuromuscular diseases or postoperative conditions can be evaluated precisely and within the same session as oesophageal motility disorders, stenoses or postoperative problems are detected and in a complementary fashion to endoscopy, ph monitoring and manometry. the exclusive ability of dynamic imaging of swallowing is to diagnose combined disorders of the pharynx and the oesophagus, to detect and localise subtle and multiple benign stenoses of the upper gi tract and to combine visualisation of pathophysiology and bolus transport as well. radiologic evaluation concentrates on 7 functional units, which represent the visible "moving areas" of deglutition, where evident pathologic conditions can be found: 1) oral cavity and tongue, 2) soft palate, 3) epiglottis, 4) hyoid and larynx, 5) pharyngeal constrictors, 6) pharyngoesophageal segment, 7) oesophagus and stomach. this lecture intends to explain the common causes of dysphagia, the approach to a tailored examination and the use of an advanced imaging technique. further, the basics of taking the swallowing history and the structure of reporting swallowing disorders along the seven functional units will be provided. hoarseness is defined as a rough or noisy quality of voice. the possible causes of hoarseness are manifold, ranging from benign diseases such as the common cold to malignant tumours. therefore, hoarseness as a symptom should always be taken seriously. evaluation of a patient with hoarseness by a head and neck specialist will always starts with a history and a physical examination including laryngoscopy. after these examinations, a diagnosis can be established in most patients without additional imaging. the aetiologies of hoarseness are: 1) inflammation/infection, 2) trauma, 3) neoplasms, 4) others (including medical conditions, e.g. hypothyroidism) and 5) vocal cord paralysis. this presentation will focus on imaging of vocal cord paralysis. vocal cord paralysis should not be considered a diagnosis, but as a symptom of (possible) underlying disease. when vocal cord palsy is discovered, this is frequently a reason to perform cross-sectional imaging. the radiological workup needs to include the full course of the vagus nerve. moreover, reporting radiologists need to be able to recognise the radiological signs of vocal cord palsy in the absence of hoarseness, since many patients with cord palsy are asymptomatic (up to 30%). the anatomy of the vagus nerve and its laryngeal branches that innervate the intrinsic muscles of the larynx will be discussed. then the (expected) course of the vagus nerve and recurrent laryngeal nerve will be shown. finally, radiological signs of vocal cord palsy will be discussed using examples from daily practice. in contemporary medicine, endovascular techniques often replace conventional methods of treatment, including surgery, in the management of an increasing range of diseases. this requires development of specific methods assessing the effectiveness of treatment and able to detect complications that may be much different from those occurring in conventional therapy. this is first of all seen in the endovascular treatment of patients suffering from vascular lesions and neoplastic diseases. commonly, there is a high initial technical success of endovascular treatment, but the durability is not always satisfactory and needs to be further examined. endovascular treatment is bound to the risk of specific complications, often without clinical symptoms. therefore, there is a need to use imaging follow-up of these patients.interventional radiologists are aware of the importance of those issues and should play an important role in developing and deciding about the follow-up scheme and choice of the best imaging methods for these patients. besides indepth knowledge of the treatment, radiologists are also familiar with the possible complications and can offer an optimal, minimally invasive and cost effective diagnosis and treatment. the potential imaging methods for follow-up after angioplasty (pta) and/or stenting include doppler ultrasound, cta and mra. although excellent images can be obtained by cta and mra, the drawbacks of these studies for routine follow-up are obvious. (access to ct and mr equipment, cost, contrast medium, ionising radiation, etc). in the uk, the most common imaging method is duplex ultrasound. there is no established role for the use of ultrasound contrast agents. ultrasound is freely available in the majority of centres, is inexpensive and complication free. follow-up by ultrasound may be undertaken by radiologists, although more usually by technologists in vascular laboratories. in practice, few patients are followed up by any imaging study at all unless they develop symptoms. the main category of patients who undergo some form of imaging follow-up after pta/stenting are patients with surgical bypass grafts, who are usually routinely followed up whether they have undergone angioplasty/stenting or not. in view of the fact that this is a lecture on follow-up after intervention, procedural complications are excluded from the discussion. the complications of angioplasty and stenting are similar. the main early complications are restenosis or reocclusion. other early complications are related to the arterial puncture site and include haematoma, dissection, occlusion and pseudoaneurysms. the main late complications are restenosis and reocclusion. treatment of restenosis and reocclusion usually involves additional angioplasty or stents using conventional or drug-eluting balloons or stents. cutting balloons, atherectomy and cryotherapy have a controversial role based on limited evidence. imaging follow-up of oncologic patients after embolisation procedures j.i. bilbao; pamplona/es (jibilbao@unav.es)the term "embolisation" groups different procedures in which imaging guidance is fundamental for both performing the procedure and for the early detection of complications. it has been demonstrated by several studies that "tumoural response" is tightly associated with survival, thus it is of major interest to measure accurately how the tumour is modified by the treatment. the "world health organisation" -who -first published the objective criteria for the evaluation of response. these criteria were slightly modified in 2000 and named as "response evaluation criteria for solid tumors"-recist. accordingly, "complete response" (cr) corresponds to the disappearance of the tumour, "partial response" (pr) is defined when there is a decrease in the tumour size equal to or higher than 30% and "progressive disease" (pd) is applied when there is an increase equal to or higher than 20%. "stabilisation of the disease" (sd) corresponds to measurements in between > 30% (pr) and < 20% (pd). tumours (until five nodules in the same viscera), no matter if necrotic or viable, were evaluated with one measure (its largest diameter). a new version ("1.1 recist) has introduced modifications, among which is the number of nodules (2 instead of 5) that needs to be evaluated. in some circumstances, when morphologic criteria (recist and who) fail to predict the outcome, then new functional criteria have been recently established. "mrecist" (which only measures the tumour that uptakes contrast) is an accurate classification for hcc. new methods "beyond recist" have been established for some specific treatments such as targeted therapies. in this session, the audience will have a comprehensive overview of the elastography, its principles and current state-of-the-art clinical applications. the session will deliver an overview of currently available methods of both ultrasound elastography (use) and magnetic resonance elastography (mre), their physical principles, technical and equipment requirements as well as the influence of various factors for obtained results. following this session, the audience will have insight into clinical applications of elastography in liver, prostate and brain diagnostics. the strengths and weaknesses of elastographic modalities will be compared and discussed under consideration of more established imaging modalities. the session will present potential developments of use and mre and possible future clinical applications. panel discussion will aim at defining the place of elastography in current and future diagnostic algorithms. the well-known sensitivity of the palpating hand for detecting lesions is related to the incredibly wide range of values of the shear modulus in the body, spanning over eight orders of magnitude. elastography was invented to exploit this high variability of constants by introducing the shear modulus into the image contrast of medical ultrasound or magnetic resonance imaging. today, both ultrasound elastography (use) and magnetic resonance elastography (mre) are in clinical use, predominantly for staging liver fibrosis or discriminating tumours in the breast, liver, and prostate. the talk reviews the physical principles, technical requirements and current methods of both use and mre. furthermore, the strengths and weaknesses of elastographic modalities are compared and discussed under consideration of more established imaging modalities. an outlook of elastography is given, highlighting the real-time feasibility of use and the sensitivity of mre to tissue pressure. suspicion of prostate cancer (pca) exists in the case of elevated psa serum values and/or suspicious findings on digital rectal examination (dre). systematic biopsy (sb) will be done to confirm or rule out pca. unfortunately, an elevation of psa serum values often is caused by benign changes, e.g. prostatitis or adenomyomatosis and not every cancer is palpable on dre. furthermore, sb may miss clinically significant disease in up to 35%. therefore, a more targeted approach would be desirable and imaging of pca is currently under strong effort. one possibility for visualisation of pca is the representation of tissue elasticity. usually, cancers have higher cell and vessel density than the normal surrounding tissue and therefore are associated with increased stiffness. in contrast to dre, where only the posterior parts of the prostate can be reached, rte does not have this problem, since all anatomical regions can be evaluated. furthermore, this noninvasive technique is time-and cost-effective and targeted biopsy or focal therapy of the prostate can be done under real-time conditions. another important issue is that rte can be performed by both urologists and radiologists. nevertheless, rte is of limited value in the detection of small cancer lesions and there may be problems in visualising pca with predominantly gleason pattern 3. the lack of data about inter-and intraobserver variability and of multicentre studies (now in process) are probably the reasons why rte has not been included in the guidelines of urological societies so far. cerebral tissue structure is altered in many neurodegenerative diseases, but also during physiological processes like maturation or ageing. structural changes directly affect the mechanical tissue properties. magnetic resonance elastography (mre) is an imaging technique capable of assessing biomechanical brain parenchymal properties non-invasively. viscoelasticity can be quantified by analysing the propagation of mechanically elicited shear waves in the investigated tissue. thus, mre could be a helpful tool to detect physiological or pathological processes influencing the cerebral tissue integrity. learning objectives: 1. to appreciate the advantages and limitations of a virtual palpation of the brain. 2. to become familiar with mechanical wave induction and detection in cerebral measurements. 3 . to learn about current and potential clinical applications. 4 . to learn about the relationship between microscopic and macroscopic, as well as focal and globally diffuse biomechanical brain parenchymal alterations. are based on the generation of shear waves inside the liver tissue with specific mr liver drivers and ultrasound probes. subsequently, phase images revealing the displacement of the waves will be investigated for healthy and pathological (alcoholic fibrosis) livers. moreover, the development of phantoms mimicking the stiffness of biological soft tissues (liver, muscle, â�¦) will be also presented. the viscoelastic (elasticity and viscosity) properties of healthy and fibrotic livers were measured, and the relevance of these parameters, used as a liver diagnostic marker, was analysed. in parallel, an increase of the wavelength as a function of the stiffness was obtained for the developed set of phantoms. the characterisation of the elastic properties is an excellent marker to differentiate minor and major fibrosis. a summary of the advantages and disadvantages of us and mr elastography techniques will be presented. a-558 09:00 the breast lesion excision system (bles) has evolved as a breast radiological technology over the last decade and is now in widespread use in europe and across the world. it was designed as a large biopsy device, but more recently due to its unique capability to obtain a single large breast tissue specimen in only a few seconds by utilising a radiofrequency cutting and cauterising wave, it has increasingly been explored in the therapeutic setting. it is easy to use under ultrasound or mammographic guidance with procedures taking a similar length of time to that of a vacuum biopsy, and with patient preparation and anaesthetic essentially identical. the technical aspects of performing these procedures will be detailed as well as its use specifically to perform excisional biopsies. this is limited by patient and lesional factors, all of which will be discussed in more detail. following a bles, the post-procedure appearances need to be considered so that follow-up imaging can be interpreted accurately. the risks and complications of this procedure are outlined as well as a discussion made of the latest papers in this field that may suggest future applications and developments. learning objectives: 1. to understand the mechanism of the bles technique. 2. to become familiar with the post-bles aspects of various types of imaging. during the past few years, it has been shown that there is not a single disease entity called "breast cancer". there are different subtypes that entail diverse recurrence risks. this is the first issue to take into account, and patients will be stratified accordingly before any follow-up is planned. imaging findings in a patient treated for breast cancer will depend on the type of treatment: breast conserving therapy (bct), mastectomy (and all the reconstructive techniques), radiotherapy and minimally invasive techniques. to differentiate between fat necrosis and other common post-treatment changes from relapse, it is important to know the timeline when all these changes take place and also schedule the follow-up imaging procedures accordingly. other important issues to take into account are the limitations and indications of the different modalities (mammography, ultrasound and mri). although ultrasound and mammography have traditionally been used in the follow-up of these patients, mri is being used more and more often due to its superior multiplanar capabilities and the functional information not supplied by the other techniques. blood clot formation in the veins is referred to as venous thrombosis (vt). vt is most common in the deep veins of the legs and pelvis. if the thrombus dislocates to the pulmonary arteries this is referred to as pulmonary embolism (pe). the combination of deep vein thrombosis (dvt) and pe is referred to as venous thromboembolism (vte). the diagnosis of dvt and vte is essential, as vte is potentially fatal. furthermore, undiagnosed, non-fatal dvt may result in negative long-term pathologies (e.g. post-thrombotic syndrome). major risk factors for the development of vte are thrombophilia, history of dvt, age > 60, surgery, obesity, long travel, cancer, immobility and pregnancy. in addition, underlying congenital abnormalities or compression syndromes (may-thurner syndrome) are also important to diagnose. diagnosis of vte is not always easy. primary diagnosis includes clinical (wells score) and lab testing (d-dimer). first line imaging testing is done by leg ultrasound (us). if pe is suspected ct is indicated immediately. ct of the pulmonary arteries (ctpa) may be combined with indirect ct venography (ctv). the question of when to combine ctpa and ctv still remains. a favourable approach is to add ctv in a negative ctpa. recently mr venography (mrv) is emerging as comprehensive imaging tool especially in patients with chronic dvt to assess the extent and underlying causes. in this respect imaging without radiation dose with high spatial delineation of vascular abnormalities facilitates intervention for thrombolysis or interventional therapy including recanalisation and stenting. alternatively, intravenous unfractionated heparin is used in situations when a quick reversal is necessary. b) non-medication: early mobilisation has been widely adopted to activate the muscle pump. if early mobilisation is not possible, compression stockings and/or pneumatic compression boots are applied to better empty the veins. 3. treatment: a) anticoagulation: the main goal of anticoagulation is to prevent progression and recurrence of dvt. typically, anticoagulation is started with lmh, followed by vitamin k antagonists (coumadin). the first dvt is generally treated for 3-6 months; recurrent dvt for 12 months. b) compression therapy: compression stockings ameliorate pain and leg swelling of acute dvt. in addition, the development of a post-thrombotic syndrome (pts) should be reduced. c) thrombolysis: the main goal of thrombus removal is prevention of pts. in addition, thrombolysis is used for severe ilio-femoral dvt, especially with phlegmasia coerulea dolens. there are different ways of thrombolysis: systemic thrombolysis was abandoned because of high bleeding complications. catheter-based thrombolysis has shown to reduce the bleeding risk, but it is quite time and resource consuming. the latest development is pharmaco-mechanical catheter thrombus removal which combines thrombolytic drugs with a mechanical maceration. recent studies (cavent,torpedo) have shown a reduction of pts compared to anticoagulation. the use of inferior vena cava filters (ivcfs) is a controversial method for the prevention of pulmonary emboli. there are large variations in their usage; often with ten to one hundredfold differences in placement between different countries. ideally, ivcf usage is based on sensible protocols derived from clinical experience and trials. in practice, this is less frequently the case. indications, contraindications and questionable indications (mainly during venous thrombolysis) will be discussed. familiarity with ultrasound guidance will be stressed. the key technical steps in the insertion and removal of ivcfs will be discussed. the question that this refresher course is aimed to answer is whether novel it tools may actually help in improving quality and workflow efficiency in daily radiological practice. in fact, since the early installations of pacs, it tools have often been considered as mere productivity tools rather than enabling technologies for fostering quality in medical care. the three distinguished lecturers in this course will address the following topics: improving quality and efficiency of computerised order entry through decision support, improving quality and efficiency of reporting through structure and templates, and improving quality and efficiency of dose management through exchange between modalities and registries. they will cover all aspects of the radiological workflow: from the selection of the most appropriate diagnostic procedure, to the efficient reporting of diagnostic and non-diagnostic data (such as radiation dose information and contrast media information). they will demonstrate how newly adapted it tools may provide assistance throughout the radiological workflow, with potentially enormous gains in terms of patients' safety and total quality management. session objectives: 1. to appreciate the need for it tools to ensure quality control. 2. to understand how to collect data concerning radiation dose. a. improving the quality and efficiency of computerised order entry through decision support p. mildenberger; mainz/ de (peter.mildenberger@unimedizin-mainz.de) electronic communication of requests for radiological procedures is a logical and relevant extension to integrated information systems in health care. this communication of orders and the entry (oe) into ris improve the workflows. but, quality improvements require additional efforts to link order-entry-solutions with health knowledge for ordering the appropriate imaging procedure. these clinical decision support (cds) tools should be based on generally accepted and implemented criteria, e.g. evidence-based medicine. it is known that the acceptance of such systems, if successful and efficient implementations are given, is very good. it concepts for cds are well known and standards for classifications are available, but semantic interoperability is still a developing area. actually, clinical information systems provide different levels of integration of oe and cds. further developments could be an implementation of interoperability profiles and the representation of cds knowledge in webbased services of non-commercial organisations. b. improving quality and efficiency of reporting through structure and templates e. neri; pisa/it (emanueleneri1@gmail.com)the report represents the final stage of the diagnostic imaging process, for which the radiologist is responsible. this process is driven by an accurate selection of the diagnostic tests, based on the clinical question. therefore, the report should be an expression of this path, depending on the question asked by the clinician. the structure of a radiology report for the same clinical problem and the same method of investigation varies from country to country and between different radiologists. this diversity can be a problem in the global world where a patient can have imaging tests from different places with different reporting languages, or when patient data is transmitted and shared between different centres. there is, therefore, the need to standardise the report as much as possible; finalising its structure and contents to a specific clinical problem, and possibly using a standard terminology. an attempt to solve this problem is in progress with the joint initiative on structured report esr-rsna (http://www.rsna.org/reporting_initiative.aspx), aimed at improving reporting practises by creating a library of clear and consistent report templates. the main expected benefits of structured reporting templates are report uniformity and improvement of communication between referring physicians. literature evidences that structured reporting can also quicken report turnaround, and reduce costs and lexical errors; thereby improving the quality and safety of radiological practise. the european directive on medical exposures requires the assessment and evaluation of patient doses, especially in procedures involving high doses to the patient. in the current draft of the new directive on basic safety standards, some requirements on patient dosimetry in diagnostic and interventional radiology have been reinforced: x-ray systems should provide dosimetric information with the capability of being transferred to the examination report (for all ct and interventional systems). diagnostic reference levels (drls) shall be reviewed regularly. these requirements will push the industry and the users to develop better strategies to evaluate patient doses, transfer these values to patient reports (contributing to the patient exposure tracking system) and also use available software to process these dosimetric data and perform some automatic analysis. this analysis should: a) include periodic calibration factors for patient dose quantities, b) include automatic detection of high dose values (especially relevant for interventional procedures), c) include statistical analysis to update drls and compare with the existing ones and d) suggest corrective actions to fulfil the quality assurance programmes and the clinical audit requirements. dicom radiation dose structured reports represent a significant advantage, but more efforts will be necessary for the automatic process of the relevant data contained in the report to verify that the radiological risk is acceptable and to suggest, if appropriate, corrective actions to improve clinical practice. without these last steps, patient dosimetry efforts and european regulations for radiation safety could only have a moderate impact. gastrointestinal tumors include a variety of lesions, with the most frequent being adenocarcinoma of the small and large intestine, small bowel lymphoma, neuroendocrine tumours (nets) and gastrointestinal stromal tumours (gists). according to histology, location and initial imaging staging, those lesions may require completely different therapies: surgery alone, adjuvant chemotherapy (cht), neoadjuvant cht followed by surgery or a combination of neoadjuvant chemoradiotherapy (crt) followed by surgery. after treatment, imaging follow-up is mandatory. the most common post-operative findings after small bowel or colonic resections will be presented, together with clues for early detection of recurrence. in those cases which underwent adjuvant cht, imaging findings and diagnostic criteria related to the use of either cytotoxic or cytostatic drugs will be shown, to facilitate the interpretation of radiologists in assessing response to therapy. finally, tissue changes following neoadjuvant crt will be discussed, particularly in rectal cancer. the possibilities of different imaging modalities in assessing either complete or partial response to therapy will be presented, with a critical analysis of different imaging findings. unlike infectious enteritis, in patients with crohn's disease (cd) the changes in clinical activity have poor correlation with changes in inflammatory lesions after medical treatment. mucosal healing (mh) and improvement in patient's symptomatology are usually considered the main objectives of medical treatment. however, improvement in clinical symptoms is not always associated with mucosal healing and the persistence of severe inflammatory lesions augurs a more aggressive disease course in terms of flare-ups, hospitalisation requirements and the need for surgery. endoscopy is the gold standard for the assessment of luminal lesions in cd, but given the good correlation shown between endoscopy and cross-sectional imaging in assessing the activity and severity, imaging is increasingly introduced as a tool to monitor medical treatment. there is some evidence indicating that crosssectional imaging can be considered a responsive and reliable tool as it detects meaningful changes in patients' status over time after therapeutic interventions. besides this, cross-sectional imaging is capable of monitoring the colon and the small bowel and penetrating lesions that cannot always be assessed by endoscopy. becoming familiar with the radiological changes during and after treatment will be key in the decision-making process. degeneration is routinely defined as a morbid change of cells, tissues and even organs. in the msk system degeneration occurs in bones, joints (synarthrosis and diarthrosis), muscles and tendons. primary degeneration implies ageing as well as overuse, based on mircrotrauma. the latter may be related to constitutional, professional or sports-related factors. a distinction between ageing and overuse is not possible with the use of histology and imaging. only the intensity of the changes, which may be inadequate in relation to the age of the patient, may give a hint. on the contrary, the term "secondary degeneration" should be used for clearly defined events or diseases, which finally will result in the degeneration of tissues. the causes are inflammation (ra, infection), metabolic disease (e.g. cppd) or trauma. other ways to classify degeneration of the msk system are related to the anatomy. accordingly, degeneration of the particular parts of the peripheral or axial skeleton, muscles and tendons has to be discussed. one has to have in mind that bones, cartilage, muscles and tendons form a complex unit. the single elements of these complex units jointly undergo degenerative deterioration, e.g. bone, cartilage, fibrocartilage and capsule are jointly involved in case of oa of the knee joint. the same holds true for the synchondroses of the spine. at the rotator cuff not only the tendons, but also the underlying bone and the muscle tissue are changed. (o.m.vandelden@amc.uva.nl) there are many different types of embolisation, but all share many basic principles. the specific approach, technique, materials and equipment used may differ depending upon many variables such as the type of vascular territory involved (venous, arterial, small vessels, large vessels), clinical setting (elective or emergent procedure), and type of underlying disease to be treated (e.g. tumor embolisation, acute haemorrhage, vascular malformation, arteriovenous fistula, etc). pre-procedural imaging and planning are essential for most embolisation procedures and intra-procedural navigation can be done with fluoroscopy, dsa, and new 3d-techniques. with proper imaging workup prior to embolisation procedure time, radiation dose and contrast load can be significantly reduced. embolisation materials can be roughly divided into liquid agents (alcohol, glue, polymers), particulate agents (pva, calibrate microspheres, drug-eluting beads) and coils (detachable, non-detachable) and plugs (amplatzerâ®-plugs). plugs and coils are deployed at the exact site of destination and usually easy and safe to use. particles and liquid agents reach their site of destination by flow guidance and can be more difficult and unpredictable in their use. complications include puncture-site complications (thrombosis, dissection, haematoma), systemic complications (contrastinduced nephropathy, allergic reactions) and specific embolisation-related complications (non-target organ embolisation, end-organ ischaemia, postembolisation syndrome). when used with expertise and proper experience, most types of embolisation have good results with acceptable complication rates. although there has been advancement in imaging techniques, several pitfalls in the assessment of diseases of the pancreas, small bowel and rectum remain. the differentiation and the correct characterisation of tumours and inflammatory disease in some cases may be difficult. also, atypical presentation of common tumours or uncommon tumours persists and is a challenge. problematic situations are constantly represented as intestinal bleeding and unexpected findings. in this session, we point out the procedure of the best imaging modality and protocols of challenging cases. a. pancreas c. triantopoulou; athens/gr (ctriantopoulou@gmail.com)pancreatic imaging and interpretation of focal lesions remains a challenging issue. despite the advances in imaging techniques and the dedicated protocols that are now in use, a possibility for pitfalls remains. these pitfalls are related either to the inability of the early recognition of a lesion, or to the wrong characterisation of a "mass". both pitfalls are of great importance, taking into account the lethal pancreatic cancer and the possible complications that may follow an unnecessary pancreatic surgery. there are many variants of the pancreatic parenchyma, the ducts or even vessels, and deep knowledge of the pancreatic anatomy and embryology is needed, to be able to recognise these variations in imaging. a pancreatic variant may not only be misinterpreted as a severe pancreatic disease (e.g. ectopic spleen vs neuroendocrine tumour), but may also be the underlying cause of pancreatic inflammatory lesions (e.g. ectopic pancreas on the duodenal wall causing groove pancreatitis). other pitfalls are related to the atypical presentation of a common lesion (e.g. isoattenuating pancreatic adenocarcinoma), the presence of uncommon tumours, diffuse or multifocal diseases, the co-existence of two different entities and the heterogeneous or overlapping appearance of cystic lesions. in any challenging case, a focused methodology should be applied and the diagnostic procedure based on predefined imaging parameters, taking also into consideration the clinical and laboratory findings. excluding pancreatic cancer should be the first goal and every attempt should be made to differentiate between surgical and non-surgical cases. endoscopy is the gold standard in small bowel diseases, but it is a challenging technique: the pillcam is a commonly used tool and multidetector ct is a diffuse investigation technique. ct enteroclysis/enterography is a worldwide tool in intestinal exploration. throughout the investigation of the small bowel, morphologic anomalies or embryonal development defects may be present (meckel's diverticulum, duplications of intestinal tracts). artefacts may be determined and there may be misunderstanding. mdct is the first tool in emergency diagnosis; imaging pitfalls are possible. unsuspected diseases may be revealed: we will see a case of gist in a patient affected by intestinal bleeding of an obscure origin. ct enteroclysis may find unknown or unsuspected diseases: correct technical parameters have to be respected, as artefacts may be derived from an improper acquisition technique, such as a limited distension or poor intravenous enhancement. in follow-up, mr is preferred to investigate the intestine, mainly in the young population. unexpected findings may be due to rare pathology: we met a case of endometriosis, with ambiguous presentations; patients affected by autoimmune pathologies (pyoderma gangrenosum or lupus erythematosus), with unknown inflammatory intestinal chronic diseases. in oncology, pet-ct imaging is the main diagnostic tool, but there are abdominal pitfalls that limit its effectiveness (intestinal hot spots, artefacts from peristalsis): the small bowel may frequently obstruct an easy diagnosis. in case of emergency, if the radiological diagnosis is not clear, the surgeon determines the management of the patient. in case of a defective study technique, a correct examination may be repeated. endoscopy or pillcam may help to detect mucosal lesions invisible at ct. mri plays a key role in the assessment of disease of the rectum and in particular for the staging (and restaging) of rectal cancer. in this session, the relevant mr anatomy of the rectum will be discussed. furthermore, the strengths and weaknesses of mri in the assessment of rectal cancer during primary staging and restaging after chemoradiotherapy will be highlighted using various rectal cancer cases. finally, we will discuss some rare tumours of the rectum (including gist and carcinoid). optimisation of ct and mr techniques has provided new challenges for imaging in the assessment of airway and lung diseases. phenotypic abnormalities which can be recognised on visual and quantitative evaluation of ct images in copd patients may improve the diagnostic accuracy, help optimise treatment and provide a framework for clinical trials. although expiratory ct helps assess air trapping due to small airway obstruction and excessive dynamic collapse of large airways, potential tricks in technique and interpretation of ct images must be known. owing to multiple and successive improvements over years, functional and morphologic evaluation of the lung using mri has become reality for clinical practice. already regarded as a favoured cross-sectional imaging in paediatric chest radiology, mri of the lung is gaining new indications also in lung diseases occurring in adults. the potential for high-resolution computed tomography (hrct) to uncover several morphological subtypes that come under the umbrella term chronic obstructive pulmonary disease (copd) is now more familiar to both radiologists and specialist respiratory physicians. a complete approach to the classification of copd would ideally assimilate several parameters through a combined visual-quantitative hrct analysis. the insight that some subjects given the label of copd have "pure" airways diseases or emphysema can be readily provided by a simple visual evaluation. the subtypes -centrilobular, panlobular, and paraseptal emphysema -can be reliably distinguished on hrct images. the visual assessment of bronchial abnormalities and accompanying smoking-related interstitial lung disease may also complete the phenotypic classification of copd. furthermore, it is now possible to objectively quantify the global extent of emphysema, gas-trapping, and bronchial metrics by two types of softwares which are now increasingly available on latest ct workstations. learning objectives:1. to learn about the classification of copd. 2. to appreciate the role of hrct in the classification of copd. a-578 16:28 this presentation will examine the role of expiratory ct in the diagnosis of small and large airways diseases. small airways disease or air trapping may be a feature of asthma, copd and hypersensitivity pneumonitis, and is typically characterised by a mosaic attenuation pattern on ct. tracheobronchomalacia and excessive dynamic airway collapse (edac) are large airways conditions that may be recognised by tracheal narrowing on inspiratory and/or expiratory ct. the typical clinical and ct manifestations of these diseases will be reviewed. additionally, a number of important caveats with regard to ct in small and large airways disease will be discussed: 1) the comparative strengths and limitations of ct, bronchoscopy and lung function testing in making the diagnosis; 2) the overlap in appearances that exists between diseased and healthy individuals; 3) the variability in definitions of conditions such as tracheobronchomalacia. the optimal ct technique for imaging of airways disease, including the role of dynamic expiratory ct, will also be reviewed. for routine clinical applications, a standardised mri protocol has been widely implemented. it addresses the major challenges of mri of the lung, i.e. low proton density, susceptibility artefacts as well as respiratory and cardiac motion. beyond visualisation of lung morphology, which is done in an inspiratory breath-hold, functional imaging has become an integral part of the routine protocols: perfusion, blood flow, ventilation, respiratory motion, diffusion. for perfusion imaging, inspiratory or expiratory scans can be used, blood flow measurement should be performed during shallow breathing, and ventilation and diffusion are mainly assessed in inspiration. respiratory motion is best assessed by dynamic image acquisitions. continuous breathing can also be combined with triggering or navigators to improve image quality or derive functional maps. mri is recommended as the first-line cross-sectional imaging modality in paediatric chest radiology, including cystic fibrosis, complicated pneumonia, any pulmonary or cardiovascular anomaly, as well as the assessment of mediastinal masses in children and adults. mri is also challenging pet/ct in the staging of lung cancer (tnm) as well as ct and echocardiography in the assessment of pulmonary arterial hypertension. mrieven without contrast -is an alternative in the diagnosis of acute pulmonary embolism if iodinated contrast medium is contraindicated or in pregnant women. mri should also be used in complicated pneumonia, e.g. in immunocompromised patients as well as for the functional assessment of chronic obstructive pulmonary disease (copd) or severe asthma. the role of mri in interstitial lung disease stills needs to be determined. unlike the simple forms of cranisynostosis whose modalities and timing of surgical correction are well established, the management of faciocraniosynostoses requires a multispecialistic and repeated evaluation of the single patients. their evolution, in fact, depends on the specific genetic anomalies but also on the phenotype, which can vary in time, of their clinical expression which may lead to different degrees in severity of the associated functional disturbances (csf dynamics impairment, visual deficits, respiratory anomalies, etc). consequently these conditions may require several surgical steps the timing of which are dictated by the exact clinical diagnosis and the evaluation of the functional status at different ages. current management of faciocraniostenoses is thus based not only on the radiological studies but also on the functional assessment of the brain function (e.g. mri imaging studies, metabolic and cerebral blood circulation investigations, respiratory pathways volume evaluation, sleep recording). today's surgical multidisciplinary management may benefit a large variety of techniques which extend from free bone cranioplasty with intraoperative active fixed expansion to more dynamic and less invasive methods which exploit the physiological brain expansion in infants or the gradual cranial vault expansion mechanically stimulated by springs or distractors. in the present report, we will review the decision making process and the rationale on which, at the necker-enfants malades, we base the use of the currently available techniques for skull expansion and correction of cranial malformations according to the accurate dynamic radiological and functional evaluation at different stages of the disease. learning objectives: 1. to learn about the imaging patterns of faciocraniosynostoses. 2. to learn how and when to image. 3. to become familiar with associated brain anomalies. b. all about the paediatric pituitary gland m.i. argyropoulou; ioannina/ gr (margyrop@cc.uoi.gr) mr is the imaging modality of choice for the assessment of the pituitary gland (pg) and the hypothalamus. the normal adenohypophysis is bright during the first two months of life and appears isosignal to the brain parenchyma afterwards. the neurohypophysis is bright, provided that the child is well hydrated. the pg height decreases during the first year of life and then increases until puberty. adenohypophyseal deficiency has been associated with a small pituitary size, an ectopic neurohypophysis, a hypoplastic or absent pituitary stalk, hypothalamic gliomas, craniopharyngiomas and iron overload states. precocious puberty may be idiopathic, but it has also has been associated with hypothalamic hamartomas, craniopharyngiomas and hydrocephalus. diabetes insipidus may be secondary to histiocytosis x, germinomas and trauma causing pituitary stalk interruption. the hypothalamopituitary axis is evaluated by using sagittal and coronal t1-weighted images without and with contrast administration. dynamic contrast enhancement may be useful in the evaluation of disorders responsible of diabetes insipidus. magnetisation transfer imaging may be useful in the evaluation of pituitary deficiencies or precocious puberty. familiarity with orbital and ocular anatomy is crucial to the understanding of disease processes of the orbit. lesions of the orbit may be divided into those which are intraocular and those which are extraocular. the underlying aetiology and geneses of many different lesions that can occur in the orbits vary depending on the location of the lesions and sometimes on additional nonorbital conditions. ct and mri play crucial roles in the evaluation of orbital pathology where often mri still is a complement to ct examination in the evaluation of orbital lesions familiarity with the radiologic appearance of common orbital lesions is important, as many of these lesions will not be seen on physical examination. after a very brief anatomic overview, most of this lecture will focus on the more common benign and malignant lesions as well as differential diagnosis involving the orbit and lachrymal gland in both the paediatric and adult population. the lecture will also present suggested imaging protocol and standard of care with respect to imaging. learning objectives: 1. to understand the embryology and imaging findings of the most common malformations.2. to learn about space-occupying lesions and the differential diagnosis of tumours and inflammatory conditions. 3. to be aware of the role of conventional and advanced mr sequences in the diagnostic approach to lesions in the orbit. room e1 the hand and wrist injury to the wrist and hand is an important clinical problem. first, such injury is relatively common. second, the spectrum of abnormalities is complicated. the purpose of this presentation will be to learn more about the imaging appearances of soft tissue and osteoarticular injury of the wrist and hand using multiple imaging techniques. emphasis will be placed upon pathomechanics and characterisation of greater and lesser arc injury patterns of the wrist. the various posttraumatic instability patterns of the wrist will be also discussed. rheumatoid arthritis (ra), psoriatic arthritis (psa) and other inflammatory disease can be diagnosed and sometimes differentiated in the early stages of the disease on the basis of mri and/or pdus features of the hand and wrist. rheumatoid arthritis (ra) activity is closely correlated with inflammation. the synovial membrane is the principal site of inflammation in which the inflammatory process enhances capillary perfusion and permeability. doppler ultrasonography (dus), using the amount of colour pixels in the region of interest, and dynamic magnetic resonance imaging (de-mri) are both able to detect this inflammation in the wrist and hand. although these techniques are both capable of monitoring synovium inflammation modifications after ra treatment, pdus has become an essential tool for ra joint monitoring in routine practice in view of its sensitivity in the detection of synovitis, feasibility in outpatient clinics, and low cost. (ellopis@hospital-ribera.com) radiological study of the wrist and hand is challenging due to its complex anatomy with many small structures and the number of normal bone and soft tissue variants that might mimic injuries. moreover, many findings can be asymptomatic. their knowledge is important to avoid misdiagnosis. during this lecture we will also review the role of the different imaging modalities, such as plain films for wrist alignment and bone structures as well as the important role of us and mr in differentiating tumour from tumour-like conditions. we will become familiar with some specific radiological findings that allow us to make accurate diagnoses of soft tissue and bone lesions. learning objectives: 1. to learn more about the spectrum of intra and para-articular soft tissue tumours, and soft tissue tumour-like lesions. 2. to become familiar with us and mri findings of specific soft tissue lesions. room e2oncologic imaging chairman's introduction c. pfannenberg; tã¼bingen/ de (christina.pfannenberg@med.uni-tuebingen.de) with recent advances in cross-sectional imaging, the frequency of detecting "incidental findings" has markedly increased. incidental findings (=incidentaloma) are defined as unexpected, asymptomatic abnormalities detected by imaging performed for an unrelated reason. these incidentalomas have created a management dilemma for both radiologists and clinicians, particularly in the cancer patient in whom any mass warrants further evaluation. discovery of incidental findings often leads to a cascade of additional tests that is costly, provokes anxiety and exposes patients to the risk of unnecessary radiation and intervention. the workup of incidentalomas varies widely by physicians, and strategies for optimising patient management are only beginning to emerge. in this course, guidelines concerning a rational approach to some of the more common incidental abnormalities in cancer patients are presented. basic principles and tools for interpretation of incidental findings, common pitfalls and protocol issues regarding the differentiation of benign and malignant lesions as well as treatment-induced abnormalities will be addressed with a focus on the liver, lung and skeletal system. at the end of the session, the speakers will discuss the role of functional imaging techniques for characterisation of incidental lesions. session objectives: 1. to become familiar with basic principles and common pitfalls in interpretation of incidental findings in the lung, abdomen and skeletal system. 2. to learn how functional imaging (dwi, pet/ct, bs) can help in lesion characterisation.3. to provide attendees with clear and practical messages for the management of the most common incidental findings in cancer patients. a. abdomen: common pitfalls and protocol issues a. ba-ssalamah; vienna/ at (ahmed.ba-ssalamah@meduniwien.ac.at) an incidentaloma is quite a frequent diagnosis in medicine, in general, and in radiology, in particular. by definition, an incidentaloma is an abnormality or a tumour found by coincidence without clinical symptoms or suspicion. these incidental findings have long posed challenges to physicians, and particularly to radiologists as well as health-care providers due to the resulting high costs. the scope and scale of these challenges have increased with the introduction of new technologies, in particular cross-sectional imaging, such as mdct and mri using sub-millimetre thin slices. incidentalomas still cause a management dilemma for clinicians, radiologists and even for the patients themselves. this dilemma is particularly pertinent to oncology patients. therefore, a precise knowledge of the broad spectrum of incidental findings is crucial. based on this knowledge, we can choose the appropriate radiologic examination that will provide a confident diagnosis. this way, needless uncertainty, for both the patient and the physician in charge, is avoided. furthermore, invasive procedures, such as biopsies, with the potential for complications, as well as cost-intensive follow-up examinations, can be reduced. furthermore, mri is usually used to detect the side effects of chemotherapy of the liver. simple steatosis is usually reversible, unless the liver receives a 'second hit' of damage from other causes leading to other manifestations, including chemotherapy-associated steatosis, sinusoidal obstructive syndrome, nodular regenerative hyperplasia, veno-occlusive disease, peliosis, pseudo-cirrhosis, and sclerosing cholangitis largely due to microvascular injury. finally, the effects of chemotherapy on peritoneal and mesenteric structures after performing intraperitoneal chemotherapy will be discussed. this presentation will discuss the complex topic of incidental findings in thoracic imaging of oncological patients. incidental findings will be presented with respect to their respective organs and anatomical regions. the presentation will emphasise the clinical relevancy of the findings as well as the specific of risk estimation in oncological patients. finally, the presentation will discuss the usefulness (or lack thereof) of current management guidelines for incidental findings, as designed for the general population. illustrative clinical scenarios will be discussed. radiographs and ct often detect incidental observations in bones, corresponding either to normal variants or benign conditions, which require additional imaging to rule out malignant conditions. mri most often provides nonambiguous explanation for these observations. beside this, mri, targeting either the whole body or only the axial skeleton, often including diffusionweighted (dwi) sequences, is increasingly used for bone tumour detection in many "osteophilic" cancers and haematologic malignancies, without need for contrast material injection and without irradiation, with unparallelled sensitivity to bone lesions. an important advantage and also a challenge for musculoskeletal radiologists are the all organ screening capabilities of dwi, demanding careful study of the huge information provided and knowledge extending far beyond bones in terms of organs and metastatic spread of different cancers. a second major advantage is its ability to detect lesion changes under therapy. however, benign lesions and non-neoplastic conditions, as well as artefacts may also lead to confusing observations on mri, and particularly on dwi. anatomical mr sequences as well as other imaging modalities are of utmost help to recognise these pitfalls. whole body mri including dwi sequences has to position itself among other diagnostic tools, bone scan, spect, and especially pet with its variety of tracers, in the currently evolving strategy of bone screening techniques, which will most likely vary according to the primary cancer. learning objectives: 1. to present most frequent x-ray and ct pseudo lesions and benign conditions and show how mri often enables straightforward interpretation of these abormalities. 2. to highlight the strengths of mri with diffusion weighted imaging (dwi) for malignant lesion detection and characterisation within bones, but also beyond bones. 3. to highlight the typical appearance of malignant lesions on projectional and cross-sectional imaging. 4. to learn to differentiate these lesions from normal marrow variations, stress lesions, bony pseudo-lesions and other benign conditions, and to become familiar with treatment induced changes within lesions and their environment. 5. to situate mri amongst other functional imaging techniques (pet, spect, ). colorectal cancer is the 3 rd most commonly diagnosed cancer in the world with 60% of cases diagnosed in the developed world. with an estimated 1.3 million new cases clinically diagnosed and over 600,000 people killed worldwide by this disease on an annual basis, colorectal cancer is a true public health concern. survival of colorectal cancer is directly related to the extent of disease and specifically presence of liver metastases. imaging plays a key role in the initial staging of colorectal cancer and is the gold standard in evaluating extra colonic disease, primarily liver metastases. imaging is also widely used for therapy monitoring and staging. ct, mri, pet/ct and pet/mri are the key imaging modalities. in addition, tumour response therapy assessed with morphological and functional biomarkers is increasingly used by advanced gastrointestinal oncologic programs. furthermore, image-guided therapy is widely used for patients with unresectable lesions. liver colorectal metastases were the first liver metastases to be treated with image-guided ablation techniques. a gamut of ablative techniques exists ranging from transarterial embolisation, radiofrequency ablation, highly intensified focused ultrasound, brachitherapy etc. in short, diagnosing, characterising and finally assessing tumour response after neoadjuvant and image-guided therapy are all functions where imaging plays a pivotal role. this course is divided into three logical segments dealing with current treatment options, morphological and finally functional biomarkers and it is followed by a panel discussion which includes audience participation. a. current treatment options t.k. helmberger; munich/de (thomas.helmberger@klinikum-muenchen.de) hepatic metastases in colorectal cancer may occur in 20% to 80% of the cases. considering the general oncological (isolated hepatic tumour load; prognostic benefit), and technical (size, number, location of hepatic metastases; expected hepatic functional reserve) framework, surgical resection is still considered to be the method of choice -even if this statement never had been verified by rtcs. nevertheless, in clinical reality only 20-30% of patients with liver metastases may qualify for resection. in consequence, the majority of patients need other or at least modified therapeutical pathways including adjuvant or neoadjuvant chemotherapy and more and more image-guided local ablative therapies. the latter encompass chemo-(transarterial chemoperfusion/-embolisation), thermo-(radiofrequency-, laser-, microwave ablation, high intensified focused ultrasound), and radio-ablative (radio embolisation, interstitial brachytherapy, etc). techniques. particularly, thermalablative techniques gained wide acceptance over the last years, since ample evidence could be presented showing that this method can be applied as primary and also complementary therapies in resectable and non-resectable metastatic disease. furthermore, recent data confirm that in multimodality therapy concepts, progression free survival and overall survival in patients with primarily unresectable and with unfavourable prognosis is comparable to surgery with 5-year survival rates more than 50%. minimally invasive, imageguided therapies will not replace surgical resection; however, these therapy modalities are eligible in a large number of cases and should be implemented consequently in multimodality treatment regimens according to the interdisciplinary consensus of oncologists, interventional radiologists, and surgeons. colorectal liver metastases are typically identified as low attenuation lesions on portal venous phase ct. planning of optimal therapy depends on accurate localisation and characterisation of all focal liver lesions and this is best achieved with mri, which should include diffusion-weighted imaging and use of hepatocyte-specific contrast medium. the typical mri signature of colorectal metastases includes low signal on t1w, moderately increased signal on t2w, irregular peripheral arterial phase enhancement with low signal on portal venous phase, restricted diffusion and absent hepatocytes. morphological tumour response can be assessed with either modality. size-based systems for assessing tumour response are widely applied, with recist 1.1 the most widely used at present. recist 1.1 includes several modifications that make it more user friendly than recist 1.1. more advanced morphological criteria have been described for new targeted and molecular therapies, including overall attenuation, the tumour-liver interface and the appearance of the peripheral rim of enhancement. as hepatic surgeons become more aggressive in their approach to resection in patients with liver metastases, it is important to understand that disappearance or calcification of liver metastases after treatment does not necessarily equate to a complete pathological response. the timing of imaging is therefore critical in assisting the surgeon to remove all previously affected hepatic segments after chemotherapy. learning objectives: 1. to learn about the algorithm for detecting and characterising liver metastases. 2. to understand conventional imaging criteria for assessing tumour response. 3 . to learn about the rationale for monitoring patients after radical and palliative treatments. conventional size measurement criteria remain the most widely used method to determine the response of colorectal liver metastases to treatment. however, tumour size reduction is assessed relatively late (e.g. 12 weeks after treatment) and new targeted treatment may be effective without reducing tumour size. new functional imaging techniques can be applied to quantify different aspects of tumour biology and to develop response, and predictive and prognostic biomarkers. we discuss the use of diffusion-weighted mr imaging, dynamic contrast-enhanced mr imaging and fdg-pet imaging in the evaluation of treatment response in patients with colorectal liver metastases. digital breast tomosynthesis (dbt) is a promising technique for breast imaging based on a full-field digital mammography (ffdm) platform. the x-ray tube moves through a proscribed arc, and several low-dose projection images are acquired. images are reconstructed into a stack of 1 mm slices. the radiation dose is about the same or slightly higher than for ffdm. the most important advantage of dbt is the elimination of superimposed tissue, which improves detection of lesions otherwise hidden by dense breast parenchyma and reduces the interpretation problems caused by overlapping tissue. dbt is suggested to improve sensitivity as well as specificity in women with dense breast. dbt is superior to ffdm in tumour size assessment and for mass visibility and cancer conspicuity. dbt is comparable to ffdm for evaluation of microcalcifications. dbt is superior for the detection of spiculated masses and architectural distortion. the potential to improve sensitivity and specificity is of interest for screening. an open question is whether dbt should be applied in one or two views. two-view dbt would mean a doubling of radiation dose, but a solution is the implementation of synthetic 2d images reconstructed from the 3d dataset of dbt. the synthesised images are created by summing and filtering the stack of reconstructed dbt slices. using synthetic 2d allows "combo mode" to be implemented in screening with the same radiation dose as for conventional 2d. results using dbt in breast cancer screening are very promising. different study design of published studies may explain the variations of results. magnetic resonance imaging of the breast provides a multitude of techniques for detection of breast cancer and differentiation of benign from malignant lesions. in the last few years, significant improvements of scanner hardware and equipment in terms of coils as well as sequence software have been achieved. to date, multiparametric quantitative measurement of perfusion, diffusion and tissue chemistry is possible at field strengths up to 7 tesla. although higher field strengths and improved sequence protocols provide higher signal and allow faster imaging, specific technical issues have to be considered to avoid artefacts and pitfalls. this talk aims to demonstrate the possibilities and limitations of multiparametric and (ultra-)/high-field mri. furthermore, these new techniques are put into the broader clinical context to determine the potential value for breast lesion detection and differentiation. positron emission mammography is a recently developed imaging device using positron emission technology. after injection of a positron-emitting radiotracer, the radiation is detected by a dedicated high-resolution camera, providing high spatial resolution. commercially available systems include cameras where the breast is compressed and which display a 2d image similar in its layout to a mammogram and hanging breast devices where a 3d image similar in its layout to mri is produced. these devices have been compared to pet/ct and have shown higher spatial resolution, accuracy and sensitivity in detecting malignant breast lesions. the most widely studied tracer in pet/ct and in pem is fluorodeoxyglucose (fdg). fdg is a glucose analogue and has had a major impact on oncology imaging with pet/ct. breast carcinomas demonstrate increased glucose consumption and the intensity of the uptake has been correlated with prognosis, hormonal receptor and her2 status, ki67 and nodal involvement. current potential indications for pem are detection and characterisation of breast lesions, local staging in patients with known breast cancer and baseline assessment prior to neoadjuvant chemotherapy. future developments of pem will involve new tracers and fusion with other breast imaging modalities. fluorothymidine is a proliferation tracer that seems promising in early assessment of response to chemotherapy. fluoroestradiol has the potential to image oestrogen receptor status in vivo. the possibility of pem-guided biopsy is a very exciting development and has the potential to select lesions with the highest intensity of uptake. fusion with mri, us and mammography will increase the diagnostic accuracy. the presentation will focus on two frequent findings on mri with increasing incidence during ageing, notably "unspecific" hyperintense lesions on t2/flair and cerebral mircobleeds (cmbs) on t2* or swi images. clinicoradiologic studies suggest that these t2/flair lesions are associated with increased risk of cognitive decline, stroke and death. the clinical relevance of these lesions probably depends on periventricular versus deep white matter location. radiologic-histopathologic studies correspondingly indicate that the degree of histopathologically confirmed demyelination also depends on the location of these t2/flair lesions. cerebral mircobleeds (cmbs) are punctate hypointense lesions on t2* or swi images. while multiple cmbs are associated with diseases such as cerebral amyloid angiopathy (caa), clinicoradiologic studies demonstrate increased incidence of sporadic cmbs in mild cognitive impairment (mci) and alzheimer dementia, indicating a degrading effect of cmbs on cognition. on the other hand, radiologic-histopathologic studies show that not all black spots on t2* or swi correspond to cmbs. cmb mimics include micro-calcifications. the presentation will demonstrate typical manifestations of these "unspecific" t2/flair lesions and cmbs during ageing and provide tips for the interpretation of these lesions during daily clinical routine. with the increasing use of mri, it has become more common to discover incidental brain findings. these findings may be non-specific or have some morphological characteristics and geographical distribution highly suggestive of a demyelinating disease. the term "radiologically isolated syndrome" (ris) was introduced by okuda in 2009 to describe those asymptomatic patients with radiographic abnormalities highly suggestive of multiple sclerosis (ms). sometimes, these lesions may even meet the mri criteria for dissemination in space, which are currently used to predict future development or conversion to ms in patients presenting a clinically isolated syndrome (cis). however, we must not forget that these radiological criteria should be applied only when the patient had experienced any clinical manifestations suggestive of a demyelinating disease. therefore, what happens in those patients in whom we found highly suggestive lesions but have never had symptoms? due to lack of knowledge about the natural history or evolution of this new syndrome, clinical and therapeutic management of these patients is not well established, nor is the risk of conversion to ms. recent data, however, indicate that the presence of gadolinium-enhancing cervical cord and cortical lesions significantly increases the risk of conversion to cis or ms. all these data have improved the characterisation of ris subjects and in our understanding of risk factors for initial symptom development. incidental findings on brain imaging are defined as previously undetected abnormalities of potential clinical relevance that are unexpectedly discovered and unrelated to the purpose of the imaging. incidental findings are increasingly detected in clinical practice, with screening, and in the research setting. data on the prevalence of these abnormalities are scarce, the clinical course of the findings is often unknown, and the management of such lesions is not clear. the prevalence of incidental findings can be expected to vary depending on the purpose of the imaging exams. with improvements in imaging technology (higher field scanners, new pulse sequences), the number of detected incidental findings will increase dramatically. another important point is the advent of imaging biomarkers. advanced techniques for postprocessing and analysis, such as automated segmentation of brain structures or voxel based morphometry, will lead to the discovery of imaging biomarkers. once the predictive value of these markers has been established, most mri studies of the brain, both in the clinical and research setting, will reveal information that might be relevant for the well-being of patients or participants. although still incidental, these findings can unfortunately no longer be considered unexpected. we will soon face large medical, ethical, and practical problems as a result of technical improvements. in this lecture, the most important incidental findings and their prevalence will be reported. the management of incidental findings in the clinical and research setting will be discussed. finally, recommendations for follow-up will be provided. the primary assessment of laryngeal cancer is provided by endoscopy, which is accurate in delineating both the superficial extent and functional impairment. imaging techniques are recommended to grade submucosal invasion, local and distant spread. in the last few decades, open and endolaryngeal surgical procedures as well highly sophisticated rt techniques have been developed to treat the tumour while preserving critical laryngeal functions. for example, early glottic tumours (tis-t2) can be treated by endoscopic laser excision or rt. the integration of information acquired by endoscopy and imaging is essential for proper treatment planning. the radiologist has to know that the site of origin (supraglottis vs glottis or subglottis) and local extent (superficial and submucosal) are the key tumour-related factors in planning the type of treatment. submucosal invasion has a variable impact depending on the location of the primary tumour. the 5 key issues in glottic cancers include the invasion of: the posterior paraglottic space, crico-arytenoid joint, and anterior commissure and contralateral true vocal cord, and vertical spread towards supra and/or subglottis, thyroid or cricoid cartilage. the 5 key issues in supraglottic cancers encompass the invasion of: base of the tongue, preepiglottic space, piriform sinus, vertical spread into glottis and subsequent cartilage invasion (observed exclusively in transglottic cancers). functionsparing surgical techniques -as supracricoid laryngectomies -can be applied in advanced cancers when sparing of the posterior commissure, the ipsilateral crico-arytenoid joint, the mucosa investing the upper cricoid and the outer perichondrium of the thyroid cartilage is demonstrated by endoscopic and imaging mapping. the detection of recurrent laryngeal carcinoma is often challenging. to better appraise the expected findings after initial surgery of laryngeal cancer, the classical partial laryngectomy and laser laryngeal surgery are briefly presented.(chemo)radiotherapy has become an important treatment modality for laryngeal carcinoma. the recurrence rate in t2-t4 laryngeal carcinoma is reported to be between 25% and 50%. the difficulty in differentiation between radiation reaction (such as oedema, fibrosis and soft tissue and cartilage necrosis) and recurrent disease is discussed. a histologic study on wholeorgan sections of 29 recurrent glottic carcinomas is also presented: recurrent disease presents with different tumour spread than does a primary carcinoma, resulting in difficulties in estimating the extent of tumour recurrence. currently, selected recurrences of early glottic carcinoma are, whenever possible, treated by larynx-preserving salvage surgery. in those cases, a precise evaluation of the recurrent tumour extent is mandatory for planning larynx-preserving salvage surgery. this is especially true in critical regions such as the preepiglottic space, infiltration into cartilage, contralateral tumour spread and subglottic tumour extension. the accuracy of crt-classification is relatively low: many patients with signs and symptoms suggesting tumour recurrence present with post-radiotherapy changes; small tumor foci, often localised in the subglottic region, are undetectable by imaging studies. tissue changes in the neck treated by surgery and/or radiotherapy (rt) make the detection of residual or recurrent tumour more difficult. clinical evaluation of the neck is also hampered by these changes. rt-induced fibrosis and postsurgical scar tissue make palpation of the neck very difficult. endoscopy is hampered by endolaryngeal oedema which can persist for many months post-rt. therefore, any (non-invasive) method helping in the detection of recurrence is welcome. patients at risk for local failure after rt can be successfully identified by a post-rt ct (or mr) study between 1 to 6 months after rt. the optimal time point to perform such a 'baseline study' seems to be about 3 to 4 months post-rt. patients with indeterminate findings are candidates for 'imaging surveillance'; i.e. follow-up imaging every 3 to 4 months up to a period of 2 years after rt. however, ongoing studies suggest that metabolic imaging (fdg-pet) may detect local recurrences with a higher accuracy than 'conventional' anatomically based imaging techniques, such as ct and mr. ct and/or mr-findings in the treated neck are frequently inconclusive. at present, new techniques are available to detect recurrent cancer. pet-ct is widely applied in the post-treatment setting. also, advanced mr-techniques such as diffusion weighted imaging (dwi) and dynamic contrast-enhanced mr (dce-mr) can be applied. focusing on the larynx, the advantages of these techniques as well as the limitations will be shown using imaging examples from daily practice. during the last 10 years, several hundred new radiotracers for pet imaging of cancer have been developed and tested preclinically. these tracers are based on proteins (e.g. antibodies and antibody fragments), peptides (e.g. g proteincoupled receptor ligands) or small molecules (e.g. radiolabelled protein kinase inhibitors or metabolic substrates). using these radiotracers, the expression and function of a variety of proteins can be studied in patients, including for example glutamine/glutamate metabolism, neutral amino acid transport, psma, grpr, sstr, cxcr4, folate and alpha-v beta-3 integrin expression. some of these radiopharmaceuticals are potential companion diagnostics and may allow selection of patients for treatment with radiopharmaceuticals or targeted drug conjugates. preclinical and initial clinical data are promising for several new radiotracers, but the key challenge is the clinical validation and dissemination of these compounds. validation and dissemination have been hampered so far by regulatory hurdles as well as by the lack of standardised trial designs for the validation of imaging agents and the lack of accepted and appropriate end points to prove clinical utility. addressing these issues will be critical for the future clinical use of pet and other molecular imaging technologies. imaging targets in cancer range from simple size measurements to more specific biomarkers on functional, cellular, metabolic and molecular levels. as our understanding of basic tumour biology has advanced, techniques have been developed to exploit this information to produce increasingly specific molecular imaging tools. the biodistribution of these molecular imaging probes should be more specific in diagnosing and assessing cancer than the morphological information acquired using anatomical imaging alone. this lecture will discuss current and emerging functional and molecular imaging techniques using mri and their applications in oncology. functional measures of tumour blood flow and vascular permeability can be made using dynamic contrast-enhanced mri. diffusion-weighted imaging is a surrogate for the cellular content of the tumour and emerging methods can be used to probe features of the extracellular space such as tumour ph and stromal content. on the molecular level, cell surface expression of specific proteins and enzyme activity within the cell can be imaged; labelled probes have been developed which bind to these proteins and a new mr technique is being developed for assessing tumour glucose in a similar way to pet. hyperpolarisation methods are emerging to overcome the major limitation of mr: low sensitivity. one such approach is dynamic nuclear polarisation, which can probe carbon metabolism non-invasively in patients with cancer. functional and molecular imaging techniques with mri will increasingly be used in radiology in conjunction with anatomical imaging methods to improve diagnosis and prognosis, target biopsies, as well as predict and detect response to treatment. with mr-spectroscopy, diffusion-weighted imaging, pet-and spect-ct, as well as pet-mri, molecular imaging has already become part of clinical routine diagnosis. also, some contrast agents such as spio for mps-labelling and scavenger-receptor binding gadolinium chelates are clinically applied for liver and lymph node imaging. however, there are still a number of highly promising novel tools that are expected to emerge clinically in the near future. in this context, the first part of the talk will give an overview on how optical imaging basically works and which future clinical applications can be expected. in this context, raman spectroscopy, fluorescence optical reflectance imaging, fluorescence mediated tomography, photoacoustic imaging and cerenkov luminescence imaging will be addressed. the second part of the talk introduces molecular ultrasound imaging as a safe and preclinically wellevaluated method. besides the diagnostic use of molecular ultrasound contrast agents, which have been already evaluated in clinical trials, the potential of this method also for theranostic purposes will be highlighted. the assessment of the amount of arterial calcification with computed tomography is a standard method in the risk stratification of coronary heart disease. coronary calcium detection by ct has been shown to identify atherosclerotic plaque and to quantitatively assess coronary calcium. many studies have demonstrated the association between the degree of coronary calcium, the burden of atherosclerosis, and the risk for cardiovascular events associated with coronary calcium. the cac scoring can provide individual risk assessment and reclassify the low and particularly intermediate framingham risk cohort into lower-and higher-risk strata. the absence of cac is associated with a very low risk of future cardiovascular events, with modest incremental value of other diagnostic tests in this very low-risk group. the role of cac in the workup of symptomatic patients is under discussion and there is evidence that the absence of cac has a high negative predictive value for ruling out acute coronary syndrome. although cac measurement is highly standardised, some technical aspects have to be considered and all possibilities of dose reductions utilised. this presentation will show the technical and epidemiological fundamentals of cac scoring and discuss the clinical applications of the method. coronary cta has gained an important role in the evaluation of patients with chest pain, suspected of coronary artery disease (cad). in comparison to invasive coronary angiography, coronary cta with 64-multidetector ct has an excellent sensitivity for coronary stenosis. specificity for stenosis is less excellent, but has improved with newer ct generations. the strongest impact of coronary cta has been on the exclusion of stenosis in symptomatic patients at low-intermediate pre-test probability. in contrast to invasive angiography, coronary cta yields more information than just the severity of stenosis. coronary cta also allows determination of plaque types (calcified, non-calcified, partly calcified) and quantification of the atherosclerotic plaque burden. also, new developments point to the possibility to assess the haemodynamic significance of stenosis based on ct density measurements in the coronary arteries, or evaluation of myocardial perfusion. thus, coronary cta yields quantitative imaging biomarkers that could be used for risk stratification in the future. recent studies have shown that whether or not a patient has stenosis and plaque, as well as the type and burden of plaque, affects the risk of myocardial infarction and mortality. therefore, the impact of coronary cta imaging biomarkers reaches beyond the mere assessment of stenosis for symptomatic treatment and could potentially alter medical management of patients for improvement of long-term prognosis. a-608 17:00 c. added value of carotid and peripheral artery imaging for risk assessment l. natale; rome/ it (lnatale@rm.unicatt.it) technical protocols optimisation of mra and cta of carotid and peripheral arteries is crucial for image quality and to complete the analysis of both lumen and vessel wall. furthermore, mra protocol needs to be integrated with dedicated pulse sequences in order to obtain vessel wall imaging that is already included in cta datasets. new ct and mr scanners allow this optimisation in terms of radiation exposure, contrast media dose reduction and spatial resolution. all these parameters will be discussed for both techniques. according to international guidelines, non-invasive imaging indications will be discussed, with particular attention to high risk population (e.g.: diabetic patients). some possible imaging biomarkers of plaque composition will be discussed. learning objectives: 1. to become familiar with optimal technical considerations for performing cta and mra of the carotid and peripheral arteries. 2. to understand clinical indications for carotid and peripheral cta and mra. 3. to discuss the role of cta and mra parameters including plaque imaging as biomarkers of cardiovascular disease.