Mass media interventions have been implemented to improve emergency response to stroke given the emergence of effective acute treatments, but their impact is unclear.Systematic review of mass media interventions aimed at improving emergency response to stroke, with narrative synthesis and review of intervention development.Ten studies were included  published between 1992 and 2010. Only three were controlled before and after studies, and only one had reported how the intervention was developed. Campaigns aimed only at the public reported significant increase in awareness of symptoms/signs, but little impact on awareness of need for emergency response. Of the two controlled before and after studies, one reported no impact on those over 65 years, the age group at increased risk of stroke and most likely to witness a stroke, and the other found a significant increase in awareness of two or more warning signs of stroke in the same group post-intervention. One campaign targeted at public and professionals did not reduce time to presentation at hospital to within two hours, but increased and sustained thrombolysis rates. This suggests the campaign had a primary impact on professionals and improved the way that services for stroke were organised.Campaigns aimed at the public may raise awareness of symptoms/signs of stroke, but have limited impact on behaviour. Campaigns aimed at both public and professionals may have more impact on professionals than the public. New campaigns should follow the principles of good design and be robustly evaluated. Given the evidence of effectiveness of thrombolysis for acute stroke and of stroke units, stroke should be treated as a medical emergency in the same way as myocardial infarction -3. HowevA number of different interventions to improve knowledge of stroke symptoms and the appropriate action have been tested, for example, community stroke screening events, patient education programmes and mass media campaigns. A drawback of screening events and patient education programmes is they often target small numbers of people from a specific group such as those who have suffered, or are at risk of, a stroke when it is argued there is a need to target wider demographic groups  and thosMass media interventions have been successful in reducing the use of tobacco , in imprThe evidence base for mass media campaigns more widely is itself limited; a Cochrane systematic review included 15 studies evaluating mass media campaigns designed to increase health service utilisation, all interrupted time series, and of variable methodological quality . The autIn England, as part of the national stroke strategy , the DepIn light of the recent national stroke awareness campaign in the UK and the continued use of mass media campaigns in other countries it is timely to review the effectiveness and development of these interventions. Other reviews in the area of stroke education have focused on stroke prevention  or have The aims of this study are to:• conduct a systematic review to assess the effectiveness of mass media campaigns in changing knowledge (stroke symptoms/signs and need for emergency access), behaviour (access to emergency services) or early treatment with thrombolysis.• examine the methods and theoretical basis for development of the interventions using the MRC Framework guidance.The Cochrane Stroke Group search terms for stroke  were usePrimary studies in English evaluating the effectiveness of mass media interventions were included; where relevant, related papers were obtained to gather information on the methods of intervention development. Studies were selected according to the following criteria: (a) targeted groups: the general public aged 18 or over; (b) outcomes: knowledge of stroke symptoms and, awareness of the need for an emergency response, rates of acute stroke treatments, and time to presentation at hospital; (c) design: randomised controlled trials (RCTs), quasi-experimental studies, controlled (CBA) and uncontrolled before and after (BA) studies and interrupted time series (ITS). Interventions aimed solely at health professionals were excluded, but those that targeted both the general public and health professionals were included.Titles and abstracts were screened to identify studies of likely relevance and full papers obtained. A structured form was used to determine study inclusion. Two reviewers  extracted data from the final papers into structured tables. The results are presented as a narrative synthesis as the interventions varied in their format and presentation, were evaluated using different methods and outcomes, and included a range of study populations.Intervention development for each study was classified using the five key phases suggested in the MRC Framework for evaluating complex interventions  as folloPreclinical phase to identify the evidence to support the type of intervention: this could be from a systematic review or identifying or developing relevant theoryPhase 1 Modelling the processes and outcomes of the interventionPhase 2 Exploratory trial to test out the intervention and outcome measuresPhase 3 Definitive RCTPhase 4 Long term implementationThese phases were entered into a matrix. Each study was examined, using the information from all relevant published articles, to determine how the intervention was developed and evaluated; a summary of the process was recorded into the matrix under the appropriate phase. This enabled the team to examine across studies the extent to which the intervention development and evaluation was in line with the guidance recommended in the MRC Framework.Ten mass media intervention studies met the inclusion criteria and were included in the review Figure . Six tarSix mass media campaigns with patient reported outcomes were reviewed -31. Two In Ontario, Canada, Silver et al.  evaluateFogle et al.  comparedintention to act rather than an actual change in behaviour could be measured.Becker et al.  assessedIn Mainz, Germany Marx et al.  reportedIn Ontario, Canada, Hodgson et al.  assessedFogel et al.  conducteFour papers evaluated studies where the public and health care professionals were both targeted -35. Two In five East Texas counties, Morgenstern et al. ,36 impleThe use of rtPA increased in all patients in the intervention community (p = 0.01) with no change in the control (p = 1.00). There was no change in time to hospital presentation that could be ascribed to the intervention. Time to presentation to hospital decreased in both communities, yet treatment rates increased only in the community receiving the intervention. This would suggest that the main impact may have been on professionals rather than on the public. However, it may be that the community mass media campaign, which was inextricably linked to the professional campaign, also contributed to the professional behaviour change, though this is not possible to disentangle. A later study showed no significant increase in presentation within two hours of onset, but did show increases in rtPA treatment rates that were sustained beyond the intervention, suggesting that the impact was on professional awareness and service organisation rather than public or patient awareness, despite a well developed public campaignIn Durham, North Carolina, USA Alberts et al  evaluateBarsan et al's  study, lIn Houston, Texas, Wojner-Alexandrov et al.  assessedNone of the studies reported that the intervention had an identified theoretical base. For the majority there was no description of intervention development and no mention of any modelling and exploratory or pilot work to test the processes ,32,33,35This review has focused on evaluations of mass media interventions designed to increase public recognition of stroke symptoms, the emergency response to stroke and early intervention. This is particularly pertinent when national mass media campaigns, such as the stroke awareness campaign (FAST) in England , are beiIncluded studies evaluating public only interventions used a range of methods within their mass media campaigns. Out of the six studies only two had a control group ,31; therAs stated earlier, only two studies used a more robust design and included a control arm. Unfortunately, one was underpowered and did not target or measure awareness of the need for an emergency response . The othData on the longer term retention of stroke knowledge of symptoms and signs was poor in most of the studies. Only one study collected outcomes six months after the end of the campaign to assess longer term impact and found that knowledge declined post- intervention . It is iOverall, the impact of these interventions was inconsistent. Nonetheless, all showed some significant increase in awareness of symptoms but little impact on the awareness of the need for, or intention to call, an emergency response, although baseline levels were high. In view of the fact that these campaigns have failed to increase awareness of the need for an emergency response to stroke ,28,29,31The public and professional campaigns largely focused on outcomes of time to hospital and thrombolysis rates -35. MeasGiven the complexity of interventions and the dual nature  of these four studies it is very hard to disentangle any active components that might explain any reported impact. This is a feature noted in the Cochrane systematic review evaluating mass media campaigns designed to increase health service utilisation, incorporating 15 interrupted time series studies ; nonetheDespite the importance of a theoretical base and early stage research in the design of the intervention  only oneA few conducted their community campaigns based on the results of earlier ones ,30 even There are limitations to this review as a result of the range of methods and study designs employed in the included studies. Only three studies used a controlled before and after design ,31,34, lOne published study not included in this review reported the development and piloting of an educational kit  designed to improve knowledge of the symptoms of stroke and the need for emergency action using the FAST acronym . The matIn conclusion, although some studies showed increases in symptom awareness and awareness of need for emergency response, and increased use of emergency transport, none show a full picture of increased awareness, increased use of emergency response, shorter time to arrival and increased use of thrombolysis following a mass media campaign. There is clearly a need for more robust evaluation of such campaigns using studies with at least a controlled before and after design, and including qualitative methods to support understanding of any demonstrated impact and to help unpick the elements of any campaign that might be important. The nationwide campaign in England implemented in February 2009 offered an opportunity to do this, but unfortunately there is no such robust evaluation in progress, despite considerable investment of public resources . When caFinally, the reported studies not only have limited methodological evaluation, but also little evidence of theoretically grounded development and piloting of the interventions. With the exception of the Morgenstern et al. study , there iAuthors JL, MM, HR, MW and RT have no competing interests. GF has consultancy relationships with Boehringer Ingelheim and Lundbeck, grants/grants pending from Servier Pharmaceuticals, Lundbeck and Mitsubishi, payment for development of educational presentations including service on speakers' bureaus from Boehringer Ingelheim and travel/accommodations expenses covered or reimbursed by Boehringer Ingelheim that might have an interest in the submitted work in the previous 3 years.JL conducted the searches and electronic sifting of titles and abstracts. JL and HR independently reviewed the retained papers and extracted data. JL and RT wrote the first draft of the manuscript. All authors commented on the first draft and all revisions.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/784/prepubSearch Terms for Medline.Click here for fileCharacteristics of Included Studies.Click here for fileResults of Evaluations.Click here for file


In the rapidly changing context of research on animal health, INRA launched a collective discussion on the challenges facing the field, its distinguishing features, and synergies with biomedical research. As has been declared forcibly by the heads of WHO, FAO and OIE, the challenges facing animal health, beyond diseases transmissible to humans, are critically important and involve food security, agriculture economics, and the ensemble of economic activities associated with agriculture. There are in addition issues related to public health , the environment, and animal welfare.Animal health research is distinguished by particular methodologies and scientific questions that stem from the specific biological features of domestic species and from animal husbandry practices. It generally does not explore the same scientific questions as research on human biology, even when the same pathogens are being studied, and the discipline is rooted in a very specific agricultural and economic context.Generic and methodological synergies nevertheless exist with biomedical research, particularly with regard to tools and biological models. Certain domestic species furthermore present more functional similarities with humans than laboratory rodents.One Health approach should facilitate closer collaboration between biomedical and animal health research at the level of research teams and programmes.The singularity of animal health research in relation to biomedical research should be taken into account in the organization, evaluation, and funding of the field through a policy that clearly recognizes the specific issues at stake. At the same time, the  Introduction2. Issues and special features of animal health research2.1. Animal health and veterinary public health2.2. Issues at stake in animal health2.3. Importance of diseases, prioritization of issues at stake2.3.1. Special features of diseases according to the types of animals2.3.2. Prioritization of issues at stake2.3.3. Issues at stake in animal health research3. Special features of animal health research3.1. Distinguishing features of the objectives, methods, and biological models3.2. Special features of scientific questioning3.3. Generic and methodological areas of convergence with human health4. Relationships between animal health and human health research4.1. Domestic animal models for human targeted research4.2. Funding and evaluation of research4.3. Parallels between research, surveillance of diseases and the pharmaceutical industry4.3.1. Surveillance and control of diseases4.3.2. Pharmaceutical industry4.4. The "One world, One Health" approach5. ConclusionCompeting interestsAuthors' contributionsAcknowledgementsReferencesUnderstanding of animal health research, and the expectations of donors and research organizations, is changing. A growing number of actors consider such research from the limited perspective of the dangers and risks directly posed to human health by traditional and emerging animal diseases. Some furthermore consider health as an asset shared by all species, animal and human, that would be guaranteed by a single medicine guided by biomedical research. In this evolving context, a collective discussion on the special features of animal health research, the issues at stake and the specific contributions such research can provide to generic health research was deemed necessary. This article summarizes the results of this discussion, addressing the issues at stake at the global level. Presented in three sections, the first describes the challenges facing animal health and research on animal health, the majority of which are not related to zoonotic diseases. The second section describes the distinguishing features of animal health research that are related to scientific constraints, the manner by which the discipline is grounded in an agricultural and economic context, and the perspectives from which scientific questions are posed. The third section addresses the relationships between animal health and biomedical research. The conclusion proposes changes that would permit research to be adapted to the special features of the field while at the same time favouring partnerships with research on human health. This discussion deliberately was limited to livestock; pets and wild animals only are mentioned for purposes of comparison.In animals, health may be defined as the absence of disease or the normal functioning of an organism and normal behaviour based on the observation of a certain number of individuals that determine the standard and thus health . In prodMultifactorial diseases are provoked by a set of risk factors linked in particular to livestock management, with at times the participation of pathogens widespread in livestock. Known as "production diseases", multifactorial diseases are present on a large majority of livestock farms with highly variable frequencies. The major epidemic diseases are highly contagious and impact livestock heavily ; the challenge is to eradicate such diseases from a territory when possible, and their appearence in a totally susceptible population can have extensive health and economic consequences. Other transmissible infectious diseases are less contagious or have slighter impacts, and frequently are present in populations in an endemic manner. Among transmissible diseases are zoonotic diseases, which are those that can be transmitted to humans. Animals also may be healthy carriers of agents that are pathogenic for humans but which do not affect the health of the animal .Animal diseases may be organized schematically into three categories. the sum of all contributions to the physical, mental and social well-being of humans through an understanding and application of veterinary science". In an editorial of the OIE bulletin [key players in the prevention and control of animal diseases and in the improvement of food security, nutrition, food safety, veterinary public health and market access for animals and products". Veterinary public health activities thus include the control of animal diseases that have a direct impact on human health due their zoonotic character, as well as the control of all non-transmissible animal diseases capable of causing important production losses  and disrupting markets .In response to these challenges, and picking up on a framework produced by international bodies , Food and Agriculture Organization of the United Nations (FAO), World organization for Animal Health (OIE)), WHO  currentlbulletin , The VetThere are four types of issues at stake in the field of animal health:Economic issues for a range of diseases that impact the economic viability of livestock farms  and animal production sectors . In industrialized countries, these diseases weigh heavily on the overall economic competiveness of livestock farms, businesses, and animal production sectors. In developing countries, there are the added risks of food scarcity, capital dilution , and the loss of draught and labor power .1/ Public health issues, which concern three domains: zoonoses, infectious or parasitic diseases transmissible from animals to humans, whether contagious , vectorial , or food-borne ; resistance to antibiotics; and traces of medicine in animal products.2/ Environmental issues related to the impact of agriculture; this involves the dumping of xenobiotics into the environment (medicine residues), the spread of resistance to antibiotics, and infectious diseases that can be transmitted between domestic and wild animals (such as bovine tuberculosis detected in wildlife).3/ Animal welfare issues, which are related closely to changes of regulations in this domain. Diseases induce suffering and pain, the absence of which is one of the criteria chosen for recently proposed animal welfare evaluation tools [4/ on tools ."Animal diseases, and a lack of adequate food hygiene resulting in foodborne illnesses, are a problem for everyone because they can threaten human health, disrupt markets and trade, reduce productivity and deepen poverty. Improving the management of livestock with a view to preventing and controlling disease can provide significant economic, social, and human health benefits for the poor and for society at large". Among the report's four key messages, it is noted that, "Livestock diseases pose systemic risks that must be addressed."In a recent report on the state of food and agriculture in the world focusing on livestock, the FAO  summarizcritical strategic challenges, even if they receive less media coverage than public health issues.For all of these diseases, while the issues at stake primarily concern agricultural farms, associated economic sectors also are involved: live animals, products of animal origin, agricultural inputs and services. Consumers and citizens are all concerned, as much by quantitative and qualitative food security as by public health. Livestock and agro-food sectors play a central role in industrialized countries, reaching 53% of the gross domestic product  . This leads to a more reduced presence of infectious and parasitic pathologies in favour of internal medicine, cancerology, and endocrinology, although antibiotic and anti-parasite medicines and vaccines together account for 75% of the consumption of medicine by pets. Lastly, non-captive wildlife constitutes a relatively new subject of animal health research, principally concerning major epidemiological reservoirs of potentially zoonotic agents  and sentinels of contamination and toxicologic pollution of the environment.impact on zootechnical and economic performance. The average mortality rates of animals in Western European livestock systems can be significant for certain age groups, and may reach high levels in herds when pathology is poorly controlled. For example, the mortality of calves before weaning is on average 12%, that of dairy cows 3%, that of piglets before weaning 20% (including stillborns), with another 7% loss between the weaning and slaughter of pigs. The various costs of controlling disease are added to those of mortality. The current economic impact of mastitis in dairy cows in France may be assessed at 350 million €/year, principally due to reductions in productivity and longevity, reduced sale prices of milk and the costs of prevention measures and treatment. In poultry, coccidioses have a major impact; based on a British model [It is difficult to arrange the different challenges presented by animal diseases and their control into an order of priority. There are several ways to assess the importance of animal diseases. The first is to estimate their sh model , their gsh model . The prosh model , even beGlobal Early Warning and Response System for Major Animal Diseases, including Zoonoses) for the surveillance and monitoring of animal diseases nevertheless derive from an approach first initiated by WHO that gave priority to zoonotic diseases. This is why the GLEWS list includes 6 non-zoonotic and 19 zoonotic diseases.OIE's list of notifiable diseases  includesOn the basis of vaccine production, it should be noted that almost all those used in the field of animal health protect against strictly animal pathogens. The rabies vaccine is one of the rare veterinary vaccines meant to protect humans. Certain other veterinary vaccines, such as for leptospira, target a zoonotic agent but are used mainly to protect pets, the exception being the New Zealand cattle vaccination programme that also aims to protect farmers; vaccines against zoonotic agents generally are not meant to protect animals in the name of public health.bibliometric study covering the 2006-2009 period conducted under the European Era-Net EMIDA programme  [Precise light was thrown on the subject by a Animals)  which foAnimals)  accordinAt the European level, it should be noted that an effort to prioritize issues at stake and research involving over 50 infectious and parasitic animal diseases is led by a group of experts under the aegis of Discontools (Disease Control Tools) working with the European ETPGAH platform . The first outputs may be accessed online on the Discontools web site .Given the breadth of the challenges related to animal health, numerous research questions need to be explored that touch upon different domains of biology and social sciences to broaden existing knowledge, with a continuum from basic to applied research. The questions involve knowledge of pathogens, the relationship between a host  and a pathogenic agent, as well as the interaction of pathogens and hosts at the scale of animal populations. The research to be carried out thus aims to propose tools to control the exposure of domestic animals to pathogens, reinforce the resistance of hosts to pathogenic agents (notably through vaccination), and to treat sick animals. The containment and control of diseases through control and prevention programmes also requires assessments of economic and social impacts of health management plans.In addition to such targetted research, there is a need for fundamental research geared to producing generic knowledge on animal models. The research undertaken in this field is enriching understanding of biology thanks to comparative biology. The diversity of the model species studied, the availability of experimental mechanisms and of biological material, as well as the mastery of particular infectious models, are all important assets for this research, which produces knowledge on living organisms that does not necessarily have an immediate application, but which may prove to be very useful in the future .Animal health research is distinguished by particular objectives, methods, biological models and scientific questions. However, there nevertheless are areas of generic and methodological convergence with biomedical research.First of all, livestock farming is an economic activity whose end goal is to generate revenue. In this context, animal health is one of several factors that farmers must manage; they do so by minimizing their herds' exposure to health risks and by finding the least expensive way to limit the impact of disease . In a giOver time, questions regarding livestock health have moved beyond a sole objective of achieving economic gains by reducing disease frequency to addressing the sanitary quality of products of animal origin, reducing the use of xenobiotics, and animal welfare in the interest of public health and sustainable development. The multiplicity of the challenges leads to the question of how the best balance may be achieved between these different parameters. To continue working in this direction, animal health stakeholders, whether from the perspective of research or development, need to establish close ties with livestock sciences and agricultural professionals.To take into account these elements, population medicine on farms will be needed, as well as research on diseases that specifically recognizes the close connections between health and animal production science. This implies in-depth collaboration with other animal science disciplines on one hand, and with the various stakeholders in the livestock world on the other. The only pertinent research is that carried out in close contact with the actual practices of farmers and animal sectors. For example, within an integrated agriculture framework, integrated research on livestock health management implies solid understanding of the livestock world, requires close collaboration between animal production, genetics, livestock economics, sociology and animal health disciplines, and relies on a partnership with livestock health stakeholders.A second distinguishing feature of animal health research is the overwhelming predominance of infectious and parasitic diseases, at least for livestock, with a very large diversity of pathologies and a very large repertoire of pathogens involved . Animal A third distinguishing feature of animal health research is related to the special genetic features of livestock animals. The evolution of animal species, which results in the diversity of species, takes much longer time than phases of domestication, which result in the diversity of breeds. The intensive selection practices implemented over the past fifty years has improved production considerably, but the cost has been a sharp drop in genetic diversity among livestock ,20. A diAnimals of economic importance include species that belong to very distinct animal clades such as fish, bees, chicken, pigs, goats, sheep and cattle. These clades diverged from each other hundreds of millions of years ago. Even within mammals, the Laurasiatheria superorder, which includes ruminants and pigs, and the Euarchontoglires superorder, which includes humans and mice, diverged from each other around 100 million years ago, rendering mice and human phylogenetically closer to each other  than they are to ruminants and pigs . These mWhereas the basic structures and the generation mechanisms of the T cell receptors and immunoglobulins are similar from teleost fish to higher mammals, each species presents particularities, such as specific isotypes  and specific mechanisms of antibody diversity generation . Notably, cytokines are specific to some species; for example, those controlling the production of type I IFN in humans and probably pigs does not exist in mice. Across species, mother to offspring transmission of pathogens and of immunity is strongly dependent on developmental characteristics related to oviparity and variations in placentation modalities. Thus whereas baby mice acquire their immunoglobulin pool during pregnancy by translocation through the placenta, ruminants acquire their immunoglobulin pool at birth via the colostrum due to the relative impermeability of their placenta.Most basic and applied research is conducted on laboratory mice, in which some human and domestic animal diseases have been experimentally adapted. In many instances, therapeutic and prophylactic treatments that are effective in laboratory mice do no work when transposed to human and veterinary species. This lack of transposition can be explained by the specific physiological traits mentioned above and by the artificial pathological mouse models used in the laboratories. It is very important for pathogen-host interactions and novel therapeutic and prophylactic treatments to be evaluated on the targeted veterinary species, thereby studying the effect in the actual host and consequently limiting a "mouse" bias as much as possible. Research and experiments on "target" species  therefore often is necessary, and presents an advantage because the research findings may be applied directly to the species without the extra step of validating an extrapolation based on an animal model, in contrast to research undertaken for biomedical applications.Lastly, there are special features related to the types of actions taken for animal disease control and health management. Beyond vaccination and the protection of livestock, animal health rules covering contagious diseases include a range of control methods, including at times the slaughter of animals to eliminate those posing a risk for unaffected animals and humans. These practices lead to specific research questions regarding intervention mechanisms. At the top of this list is the need to update serological tools so that vaccinated animals may be distinguished from infected animals because disease control measures are different for these two categories of animals. Another priority is the set of questions regarding the comparative economic advantage of different control methods and the conditions by which they are appropriated by livestock farmers and public officials.While the livestock world has many other distinguishing characteristics, these do not seem to have a notable impact on the manner by which animal health research is conducted.Bartonella or Borrelia agents of Lyme disease, animal health research would focus on the role of animals as reservoirs of agents potentially pathogenic for humans, and on the elements that allow the development of an infectious agent in its host reservoir versus a human. Biomedical research, on the other hand, would focus on the development of an infectious agent in a human. For prion diseases, an animal health perspective leads to studying the diversity of strains found in the animal and to an attempt to decipher the interactions between the infectious strain and the host species. More broadly, studies of pathogenic agent/host interactions that are pursued from an animal health angle often prove to be fruitful from both a pure and applied perspective. This is due in particular to the genetic knowledge generated on the infected host and the possibility of implementing protocols with an experimental cohort with a defined genetic status. This is, for example, the case with the demonstration in sheep of the modulation of susceptibility to scrapie in connection with the polymorphism of the protein prion coding gene [In addition to the aspects discussed in the preceding sections, one of the main distinguishing features of animal health research are the scientific questions pursued, which are posed from the perspective of animal, and not human, health. Consequently, even in the case of zoonotic agents, the questions asked by animal health teams are not the same as those asked by biomedical teams. In the case of zoonotic vector agents, for example, ing gene .Bartonella strains sampled from humans and different animal species.It thus would appear that, while working on the same agents and with the same tools, the questions pursued in animal health may be different from, and complementary to, those in human biology, and lead to the production of complementary knowledge. It follows that opportunities for collaboration between animal health and biomedical teams should be pursued, each having, through the questions they pursue and their "natural" partnership networks , access to different and complementary types of samples. For example, collaboration could focus on comparing, with an epidemiological objective, In certain fields, research carried out in human biology and animal health use similar tools, and even the same models, to address research questions. When this is the case, notably in the framework of the study of zoonotic pathogens, the only difference lies in the nature of the questions explored.In certain circumstances, the convergence continues up to point where the biomedical and animal health teams share the same questions, and then no evident distinguishing feature remains. The development of projects initially focused on animal health progressively may lead the teams involved to pose questions that are increasingly focussed on models shared with human biology. As an illustration, we may cite fundamental research approaches to the molecular mechanisms of the invasion of cells targeted by the influenza virus, or the biological origin of prions and the determinants of the species barrier modulating their transmission capacity. In such cases, it is easy to imagine that the same research could be conducted in research laboratories unrelated to animal health. However, an animal health perspective offers certain advantages, notably expertise for extensive experimental research in a confinement area, and special links maintained through collaborations with other scientists working notably in the fields of pathogenesis and animal genetics.The discussion presented here was conducted in relation to human biology research work. A parallel approach could be envisioned in relation to work carried out on plant health. Such an analysis may elicit a certain community of tools and methods with animal health, an advantage of comparative biology, but apparently few shared issues at stake for the pathogens of interest.Mice often prove to be an inadequate model in physiopathological, prophylactic, and therapeutic studies for humans. This is due to the reduced size of the species, physiological considerations, and the absence of a natural corresponding pathology. With regard to the latter point, it often is necessary to infect a mouse with the human pathogen agent, and thereby create an artificial model without pertinent symptoms. In certain situations, domestic species prove to be better study models for human-oriented research. Domestic species can be infected by viruses that have co-evolved with their host. These diseases present similarities in molecular and physiopathologic mechanisms to human disorders without being zoonotic. Pigs infected by an influenza virus that has adapted to pigs thus suffer an influenza syndrome resembling that found in humans infected with a human influenza virus. Young calves infected by a respiratory syncytial virus distinct from the human virus develop a broncho-pulmonary pathology close to that of a child. These animal disorders thus allow the development of therapeutic, vaccination, and diagnostic strategies that can be adapted or extrapolated to humans.Furthermore, through evolutionary convergence, certain domestic species present more functional similarities to humans than mice: for example, sheep for respiratory pathology (immunologic study of asthma treatment), and pigs for skin structure (study of transcutaneous therapy or vaccination), cardio-vascular diseases, and the development of spontaneous melanoma where the progression of tumors resembles that observed in humans.Lastly, domestic animals, due to their large size, allow immune functions to be studied in an original manner that would not be possible with mice. It thus is possible to catheterize lymphatic vessels in pigs, cows, and sheep to study baseline migrant leukocyte populations directly in the lymph during an infection or vaccination, enabling certain immune response features to be monitored in real time.For these different reasons, in-depth knowledge of domestic animal physiopathologies and the existence of high performance animal experimentation platforms are useful for biomedical research. Overall, the diversity of models  studied, the foundation of comparative biology, is important to produce general knowledge that can have diverse applications, notably in human biology.Compared to research on pathogens affecting public health, it is notoriously difficult to find funding for research dedicated to animal health that is focussed on non-zoonotic pathogens or to publish the results in high quality scientific journals. These difficulties seem to be inversely proportional to the genericity of the knowledge produced and to its potential biomedical contribution. For example, in a call for proposals on infectious disease research, an excellent project on a non-zoonotic pathogen will systematically be eclipsed by a project addressing a topic such as hemorrhagic fevers due to the evaluators' perception of the stakes involved. Similarily, numerous human health and scientific journals that have a high impact factor due to the larger size of the scientific community involved in human biology compared to animal health, rarely accept an article on non-zoonotic agents that effectively fall outside their domain.This state of affairs is extremely important to take into consideration given the current imperative to obtain credit to finance research and the use of the "impact factor" criteria in the scientific evaluation of research teams. This point is even more critical as the apparent proximity of animal health and human biology sectors nevertheless does not render their objectives equivalent. An overly hasty approach to the question by evaluators who are ill-informed or insufficiently aware of the issues involved will lead them to apply criteria and indicators to animal health research that are appropriated from human biology and which are completely unsuitable, and indeed unfair, in the field of animal health. Research units that address both zoonotic and non-zoonotic pathogens face a delicate situation. Teams within the same unit are not in the same boat with regard to seeking funding and publication levels.What emerges from this analysis is that, when research of equivalent scientific quality are considered together, work on non-zoonotic diseases are financed less easily, and are published in journals with a lower impact factor, than work on zoonotic animal diseases. In a similar fashion, research on animal diseases are financed and published less easily than human biomedical research. In the absence of specific corrective action, the existence of a "species barrier" in terms of funding and publication is endangering 80% of animal health research. It thus is absolutely necessary to act far upstream of national and international research programmes by ensuring that calls for research proposals specifically mention the issues at stake in animal health on one hand, and that research organizations for their part officially adopt a policy to recognize the stakes and scientific outputs that are specifically linked to animal health.A parallel may be drawn between the domain of research and that of disease surveillance and control. OIE officials call attention to a school of thought circulating at the international level that suggests economies of scale would be possible if veterinary medicine services were regrouped with human health facilities in each country. Along the same lines, public services such as disease surveillance are perceived to be expendable variables that may be played with to cut costs in debt-ridden countries. In the same spirit, this school of thought also advocates that only animal diseases posing risks to humans should be considered important due to their zoonotic character. In such a logic of cost-cutting and the regrouping of animal and human health spheres, financial trade-offs naturally would favour human health priorities at the expense of veterinary services.The OIE's strategy is to take the opposing view which holds that prevention costs less than resolving crises, and that quality prevention is based on national animal health systems that can ensure appropriate surveillance, early detection, transparency, and rapid response to animal disease outbreaks and on a durable network of veterinary services endowed with a specific budget. Thus in 2006, the OIE reiterated its affirmation that veterinary services were a global public good . The disMost pharmaceutical companies have subsidiaries dedicated to animal health, which is related to the fact that economic scales between animal and human health cannot be compared; as an example, sales of a human vaccine may be 20 to 50 times higher than those of a veterinary vaccine. If a choice must be made between two very different vaccine projects, even if each is a priori profitable, the human vaccine automatically will be chosen over the veterinary vaccine. In the same manner, shared services will be put at the disposal of the human vaccine project given the higher economic stakes involved. Lastly, it also is more difficult to find public funding, and thus complementary private funding, for the development of vaccines against non-zoonotic pathogens than for human vaccines. A fusion between human and animal activities would translate into the disappearance of the animal sector, or into animal models being developed only when they have a direct interest for humans. In contrast, what is shared by animal and human vaccines is an ensemble of vaccine production technology, innovations in this field and preceding research on pathogen families, cytology, certain features of immunology, all knowledge that deserves to be shared between human and animal health in the form of cooperation.the only way to prevent all these new hazards (zoonotics) is to adapt the existing systems of health governance at world, regional and national levels in a harmonised and coordinated manner", but "the concept "One World, One Health" should not serve as a pretext for dangerous initiatives like trying to achieve economies of scale based on purely theoretical notions worthy of a sorcerer's apprentice, such as trying to merge the Veterinary Services and the Public Health Services". Taking this perspective, it effectively is out of the question to merge services because each must assume its functions with the resources dedicated to it and the approaches suited to its particular mission; however, it is necessary to develop collaboration, cooperation, and synergies [As mentioned by the Director of the OIE in an editorial , the "Onynergies . For theThe present discussion, the opinion of experts, and a critical reading of the literature has led to the following observations.challenges facing the field of animal health are considerable. They concern food security, economics, agriculture and associated economic activities in both industrialized and developing countries. The challenges facing animal health, beyond those posed by zoonotic diseases, overlap with those of public health and the environment, notably regarding the use of xenobiotics and the development of antibiotic resistance.International bodies  affirm that, over and above the threat of diseases that can be transmitted to humans (zoonotic diseases), the distinguishing features of animal health research are methodological and scientific in nature. They notably pertain to special biological features of domestic species and to the interaction between humans in their practice of livestock husbandry and animals in their biology and evolution. Animal biology generally does not pursue the same scientific questions as human biology, even when the same pathogens are being studied, and the discipline is rooted in a very specific agricultural and economic context. For animal health stakeholders, whether from the perspective of research or development, finding an optimal balance between the economic profitability of a farm, animal welfare, the maintenance of animal health and the quality of products of animal origin involves close collaboration between animal husbandry sciences and the agricultural profession.The Knowledge produced by comparative biology is fed by research conducted on animal species. For example, animal models are a source of generic knowledge due to their special evolutionary features and, in certain cases, their functional similarities with humans. The diversity of the model species studied and the control of particular infectious diseases contribute greatly to the production of knowledge about living organisms.These observations present a strong case in favor of taking into account the uniqueness of animal health research, in terms of its organization, evaluation, and funding, compared to biomedical research. If this is not done, strictly biomedical priorities will lead to the elimination, sooner or later, of quality research on non-zoonotic animal diseases. A special "treatment" of this research thus is necessary with regard to the issues at stake; specially designed calls for proposals should be dedicated to the field, the field's journal corpus should be recognized as being different from that of biomedical research, and the research should be evaluated in the light of this specific corpus.The "One Health" approach is important insofar as it argues that the management of health requires reinforced coordination between human and animal components and, in the same manner, in-depth collaboration between biomedical and animal health research. The organization of such collaboration can only reinforce the capacity of both groups to produce relevant science, and to realize the potential of research efforts and more global approaches integrating human and animal components in federated projects.In terms of research, this collaboration may assume different forms and take place at different levels, ranging from cooperation between teams up to the organization of research and its funding. The questions explored in animal health and human biology regarding the same zoonotic pathogen frequently are complementary. They allow scientific collaborations to be built that can respond to more general questions, and notably to address the complexity of the biological systems of certain diseases. Another form of collaboration is the establishment of calls for joint public health and animal health proposals for research on pathogens whose study and control require combined research approaches. This has been the case for research on transmissible spongiform encephalopathies, with joint animal-human calls for projects and pluridisciplinary projects in the United Kingdom, Netherlands, Germany, France and the European Union. At a more general level, comparative biology represents a precious source of knowledge.The authors declare that they have no competing interests.All authors participated in the collective discussion on the special issues of animal health research, search for bibliography and participated in the writing of the paper in their field of competence; more precisely, VB, JLG, PR, ISC, MVT, SZ and EZ were involved in the field of microbiology, ISC in immunology, CF and CD in epidemiology, BB in genetics, JBC and EZ in animal sciences, SK in economics, DT in sociology. CD, CF and SK were involved in the discussion with scientists from OIE, CD, CF and SZ with Société Merial, ISC, SZ and MVT with Institut Pasteur. TP and CD designed the work and defined the working group. CD chaired the discussions and coordinated the paper. All authors read and approved the final manuscript.


Species introductions of anthropogenic origins are a major aspect of rapid ecological change globally. Research on biological invasions has generated a large literature on many different aspects of this phenomenon. Here, we describe and categorize some aspects of this literature, to better understand what has been studied and what we know, mapping well-studied areas and important gaps. To do so, we employ the techniques of systematic reviewing widely adopted in other scientific disciplines, to further the use of approaches in reviewing the literature that are as scientific, repeatable, and transparent as those employed in a primary study. We identified 2398 relevant studies in a field synopsis of the biological invasions literature. A majority of these studies (58%) were concerned with hypotheses for causes of biological invasions, while studies on impacts of invasions were the next most common (32% of the publications). We examined 1537 papers in greater detail in a systematic review. Superior competitive abilities of invaders, environmental disturbance, and invaded community species richness were the most common hypotheses examined. Most studies examined only a single hypothesis. Almost half of the papers were field observational studies. Studies of terrestrial invasions dominate the literature, with most of these concerning plant invasions. The focus of the literature overall is uneven, with important gaps in areas of theoretical and practical importance. The literature on biological invasions is enormous; it has grown rapidly since the mid-twentieth century as scientists, managers, policy makers, and the public have become increasingly aware of the many applied issues of managing invasive species, as well as the fundamental ecological questions raised by biological invasions. This body of scientific information on biological invasions addresses many different questions, and varies greatly in scope and focus. A goal of many of these papers has been to attempt to explain biological invasions by posing hypotheses regarding the invasive species, the invaded communities, and their interactions, and there have been a large number of experimental studies that have tested these hypotheses. Others are about the impacts of invasion, control of invasives, or other topics.  from the literature addressing a fundamental understanding of biological invasions. The systematic review addressed the state of our knowledge about the mechanisms that permit species to invade novel environments. We carried this out by attempting to identify and characterize the literature, including what hypotheses have been tested, and what organisms and systems have been studied. A secondary goal of our work was to create a publicly accessible database of this literature for future research. We did not attempt to quantify or analyze the outcomes and conclusions of these papers here; rather, our goal is to gain a better understanding of what has been studied. Future research – our own and that of others – will be needed to address and quantify the outcomes of the research covered in this literature database.The purpose of categorizing studies was to map the literature. In other words, we address a very basic, almost elementary question: what has been published on this topic? What we know depends on what has been studied. If no scientific information exists on a question (in published or unpublished form), we cannot answer the question scientifically. Mapping where we have good information and where we have gaps is essential for making progress. We point out that categorizing studies does not constitute a vote count. A vote count depends on the statistical significance of the outcomes of significance tests. In a vote count, one amasses a body of literature on a question  and then counts up the number of “ayes” and “nays” based on the significance tests in each paper, then presumably conclude that if the ayes outweigh the nays, the effect is real, and if there are many more ayes than nays, that it is an important effect. There are well-known statistical reasons why vote-counts are not a reliable approach and can produce uninformative, misleading, and biased results , and have clearly stated and specific inclusion/exclusion criteria.Systematic reviews are often, but not necessarily, combined with quantitative synthesis – meta-analysis – of the research results, although either can be carried out without the other. A major goal of systematic reviewing is to bring scientific methodology to the review process. Ideally, by using clearly defined protocols, the review process can be both repeated by others and more efficiently and accurately updated in the future .Since the seminal book by Elton , narratiWe began with the same literature search for both the field synopsis and systematic review. The systematic review was a subset of the literature gathered in the field synopsis, which was examined in greater detail. We initiated a literature search for both the field synopsis and systematic review using the ISI Web of Science database and search engine by employing the following search string to identify relevant papers by topic :Topic =  AND topic =  NOT Topic = (cancer* OR cardio* OR surg* OR carcin* OR engineer* OR operation OR medic* OR crop OR rotation OR ovar* OR polynom* OR purif* OR respirat* OR “invasive technique”).Next, we limited our database to relevant fields of study by using the “refine” function in the Web of Science to exclude non-relevant subjects such as medicine, agriculture, engineering, astronomy, or physics. We only searched for English language publications. We did not attempt to redefine “invasive” or “invaded”, but left those categorizations and definitions to the authors of the published papers . The initial search included records from 1911 to June 6, 2010. The search was updated on September 29, 2011.Ideally, field synopses and systematic reviews should search several databases. Because of the large scope of our review, we were not able to do so. As an alternative, we used the search engine SCOPUS to analyze a more limited sample of papers, to determine the extent to which the results would vary with the search engine and to gauge the inclusiveness of our search results from the Web of Science database. The search and exclusion options are not identical between the two databases, but we used the same search terms. We carried out the SCOPUS search on March 8, 2011. Unlike Web of Science, SCOPUS does not include a categorical exclusion feature . The records resulting from the SCOPUS search were compared with our Web of Science records by comparing the primary author, first characters of the title, source title, volume, issue, and beginning page number of the record (using a program we wrote), and identical records were discarded. We then narrowed the results to a subset of studies, those on field experiments, to compare with the Web of Science results by including only those articles identified in the SCOPUS search that had “field” or “experiment” in the abstract. For these papers, we categorized the focus of the work, the invasion hypotheses examined, invasive species identities, trophic levels, locations (to country and state), ecosystems, and biomes.We next used the title and abstract (when available) of each paper identified above to assess if the study was relevant according to the criteria below. Further selection was carried out by examining the text of the articles. We defined relevant studies as those concerned with fundamental understanding of biological invasions and we excluded research on agricultural systems, studies concerned primarily with chemical or biological control or management, methods for the eradication of invasive species, papers recording the identification and location of invaders, those focused on predicting potentially invasive species, invasive pathogens, and on the economic impacts of invasions.We then categorized the studies by date and research focus. The research foci were papers concerned with invasion hypotheses, fundamental questions in ecology and evolution, studies on impacts of invasions, and combinations of one or more of these categories. For subsets of the papers first identified, we had two readers make eligibility and categorization decisions; these were checked, discussed, and rectified until readers were trained. All decisions were reviewed by EL.The systematic review was a more detailed analysis of a subset of the papers identified in the field synopsis. We excluded papers concerned with invasion impacts. Studies were then categorized as follows: by type of research, invasive species being studied, trophic level of the invader, invaded ecosystem and biome, and hypothesis being evaluated  of the studies we categorized were concerned with explaining causes of biological invasions, while a smaller, but still substantial number of studies (761) were primarily concerned with documenting or testing the impacts of invaders . Those sField observational studies were by far the most common type of research, representing 46% of the studies . Field eWe were able to identify the locations of 703 experimental and observational studies carried out in the field . AlthougAlmost three quarters of empirical studies  were carried out on invaders that are primary producers . Fewer tSimilarly, terrestrial systems were overwhelmingly represented among field studies , with far fewer studies carried out in freshwater or marine systems, estuaries or wetlands . This isWe categorized the 1405 studies concerned broadly with evaluating hypotheses for invasions into 17 of the most common hypotheses explaining invasions, plus a category “other” for less common or less easily categorized hypotheses a. Most oFor those papers concerned with the hypothesis of inherent superiority of the invading species, the most common explanations for the superiority were, in order, competitive superiority, broad environmental tolerance, high reproductive output, rapid growth, dispersal ability, clonal reproduction, and self-compatibility b.The SCOPUS search initially returned 18,226 possibly relevant records. Approximately half of these were identified as duplications of the Web of Science papers found, leaving 9835 SCOPUS records, from which we created a subset of 652 records concerned with field experimental studies. Of these 652 records, 47 were found by examining titles and abstracts to be relevant to our review and not duplicated in the Web of Science search. We estimated how many papers would be added from a full evaluation of SCOPUS records as follows: As 7.2% (47/652 studies) of the papers we initially identified were found to be relevant, we could estimate that 7.2% of the remaining 9183 (9835 – 652) non-duplicate SCOPUS papers, or 661 additional papers, would be found to be relevant if we had the capacity to do a complete evaluation of these publications. As a second estimate, as 6.2% of the Web of Science papers initially identified in the process of carrying out the Field Synopsis were found to be relevant, if we instead use this number (0.062*9183 = 569), we obtain an estimate of a range of 569–661 papers that could potentially be added from a full evaluation of the uniquely identified papers in the SCOPUS database.A comparison of these 47 papers unique to the SCOPUS search with the 312 experimental fieldwork studies that were identified in the Web of Science search indicates a greater representation of non-U.S.-based journals in the SCOPUS papers  that were not identified by Web of Science search. The journals included in SCOPUS appear mostly to be more narrowly restricted by field or geographically . There were also a somewhat larger proportion of marine publications in the SCOPUS results  in comparison with those in the Web of Science search .Biological invasions have received a great deal of scientific attention, with intense controversies, many hypotheses proposed, with important implications for fundamental understanding of the ecology and evolution of natural systems, for management, and for their ecological and economic impacts. This interest has produced a large literature, which, however, covers the field unevenly. The field synopsis and systematic review in this paper offer a broader and more comprehensive overview of the literature on biological invasions than has been available previously, and include approximately an order of magnitude more studies than previous reviews. The present paper is neither a conceptual framework, nor a meta-analysis. It does not quantify effect strength . Some of these are as follows: Scientific papers on biological invasions were very limited until the early 1990s, and expanded greatly in the late 1990s; we now have a systematically obtained quantitative assessment of the trajectory of this literature. A large proportion of the work that has been published is based on field observational studies; many fewer studies involve experimental work of all kinds  or other types of investigations . The pioneering work of Charles Elton remains a guiding presence in the field, strongly influencing the hypotheses tested, although new hypotheses are also addressed. Most studies are concerned with ecological rather than evolutionary questions. Terrestrial plant invasions are highly disproportionately represented in this literature. Information about biological invasions is available over a broad geographic range globally, but is focused on particular areas , and there is a dearth of information (at least in English) about biological invasions in the tropics. Most studies evaluating hypotheses for invasions consider one or at most two hypotheses as possible explanations for invasions.We are not able to address the pressing question of whether the foci of the studies effectively represent the occurrences or importance (in any sense of the term) of biological invasions, but we suspect that they do not. While there has been a great deal of interest in the importance of invasive predators and aquatic invertebrates, for example, this emphasis is not reflected in the proportions of published papers. Even if there is some bias in our ability to identify other literature , it is unlikely that this would change the overarching emphasis on terrestrial plant invasions in the literature. One can hypothesize many reasons for this: our search did not do a good enough job in locating papers from other areas ; terrestrial plants may be easier and less expensive to study; reports on some important organisms or systems may be found disproportionately in the so-called gray literature  rather than in publications included in the Web of Science database; or there are a greater number of plant ecologists relative to ecologists who study other systems . The much greater amount that is known in terrestrial systems in contrast to marine ones also does not reflect the economic importance of marine and other less-studied systems.While ecological explanations for invasion are far more likely to be investigated than evolutionary ones, we have no way of knowing if that reflects the prevalence of ecological rather than evolutionary causes of invasions, or merely of the prevalence of ecological rather than evolutionary scientists carrying out the studies. Designing studies that address ecological mechanisms or processes of invasion may be more tractable than evolutionary ones, given the respective time frames over which they occur. Applied ecological aspects of invasions are of more direct concern to the general public than evolutionary ones, and it seems probable that this could influence invasion biology research.Biological invasions have been studied intensively in some locations and some systems and much less in others, but the degree to which the literature we identified accurately reflects the extent and importance of biological invasions in different systems and locations is completely unknown. Interestingly, our findings are only partially in accord with a recent study by Martin et al.  on whereUndoubtedly, our results also reflect in part the restriction of our review to English language publications. For example, Rodriguez-Castañeda  was ableSystematic reviews in the biomedical sciences  are intended to focus on narrow questions. By carrying out a very broadly defined review, our search identified so many relevant publications that we were not able to include several databases, or to fully categorize all of the papers we found. In addition, while medical databases are cross-referenced and so generally automatically exclude duplicate studies when searching more than one database, this was not the case for the ecological literature, and identifying and excluding duplicates were more challenging. The most serious limitation was that due to the time and effort constraints imposed by the very broad search, we were unable to use other means for identifying missing papers, such as combing the literature cited sections of papers.Web of Science searches are idiosyncratic, and sometimes inexplicably fail to turn up portions of the literature, even when the search terms are included in the key words, etc. We know that we missed numerous papers in the search as it was defined, including some important and highly cited ones (e.g., Parker et al. Although our study suffers from limitations, we believe that the conclusions of our research synthesis and the database produced are excellent starting points for future research. Other studies can build on our findings and make advances by correcting the errors we made in carrying this review out. These limitations also do not diminish the great value of the systematic review approach; all other methods of searching the literature suffer from the same problem, but also from many other limitations such as unintended bias and lack of transparency.Systematic review methodology offers many advantages over previous research synthesis methods for ecology, evolution and conservation biology. The results can be better and more accurately evaluated, investigated, and updated. These are some of the reasons it has become standard in medicine and other disciplines. One of the ways in which bias is reduced in other fields is that systematic reviews may be registered before being conducted, with strict protocols detailed in advance and followed during the review process (e.g., see Higgins and Green


The synaptonemal complex (SC) and the centromeres have long been thought to play their roles at quite different, non-overlapping periods during meiosis. The SC is viewed as a hallmark structure that connects homologous chromosomes and is functionally critical for early prophase (zygotene and pachytene), while centromeres are known to assemble the kinetochore, act as a target for microtubules, and direct chromosome movement during anaphase I and II.Drosophila, and higher plants provide evidence that centromeres play an important role in the initiation of synapsis in these systems PLoS Genetics, two studies of mammalian spermatocytes However, several recent studies have suggested much earlier functions for centromeres (at least in some organisms) and detailed post-pachytene functions of the SC. First, studies in budding yeast, The SC is a proteinaceous railroad-track–like structure that assembles in early meiotic prophase immediately following or concomitant with homolog pairing. This assembly process is often referred to as homolog synapsis. Although the SC is structurally complex, it may be thought of as consisting primarily of three components: lateral elements that run along the entire length of each homolog ; transverse filaments that, like the teeth of a zipper, serve to connect the two lateral elements of the SC ; and a set of proteins located at the center of the SC .DrosophilaThe question thus arises as to the function of these short regions of SC that survive the end of pachytene. Studies in yeast have clearly shown that the maintenance of centromeric pairing by short regions of the SC plays a role in mediating the segregation of both exchange and non-exchange chromosome segregation at meiosis I PLoS Genetics, the Pezza and Hunter groups show that the SC at mammalian centromeres also persists beyond the breakdown of synapsis along the chromosome arms at the end of pachytene in mouse spermatocytes In this issue of Unlike SC breakdown along the chromosome arms following the end of pachytene, the much later dissolution of the SC at the centromeres may be a temporally complex process in which at least one SC component remains at the centromeres. Consistent with previous observations, both Bisig et al. zip3 mutants, synapsis occurs predominantly at the centromeres −/−Rnf212 spermatocytes, however, synapsis does not initiate at centromeres even though SC-associated centromere pairing at diplotene in the mutants was similar to that observed in wild-type. These data show clearly that, unlike the situations in yeast, flies, and higher plants, centromeres in the mouse do not have the capacity to initiate synapsis—indeed, they are extremely delayed in terms of their ability to initiate synapsis.However, centromeres do not appear to function as synaptic initiation sites in mammals. Indeed, both Bisig et al. and Qiao et al. demonstrate that centromeres are the last to pair, doing so only at zygotene–pachytene transition. Qiao et al. also use Rnf212 (Zip3 homolog) knock-out mice to explore whether or not centromeres can be “forced” to become synaptic initiation sites. In yeast Finally, Qiao et al. demonstrate that remnants of SC also persist beyond pachytene at the sites of chiasma formation where they may regulate the necessary local remodeling of the homolog axes. In the absence of SYCP1, chiasma-like structures are still observed at diplotene , but these aberrant structures are more numerous and often exhibit fused axial elements as well as fusions of telomeric axes. The authors interpret these data to mean that prior to chiasma formation, the SYCP3-based axes are stabilized by the presence of the central region of the SC.The take-home messages from these stories are that the SC's functions don't end with the disappearance of the majority of the structure at the end pachytene, nor are they limited to synapsis and recombination. Such findings are a complement to the demonstration that in at least some organisms  the centromeres act as sites of the synaptic initiation. Moreover, SC structure at the centromeres may be somewhat different from that of the so-called normal euchromatic SC, and at least some SC components (such as SYCP3) may have functions that persist even after dissolution of the complete SC. Thus the SC needs to be considered as a rather flexible and adaptable structure that functions far more widely  than previously thought. Given their roles in synaptic initiation in some organisms, the same may be true of centromeres. It's a fascinating partnership.


The assessment of symptoms of chronic obstructive pulmonary disease (COPD) is important for monitoring and managing the disease and for evaluating outcomes of interventions. COPD patients experience symptoms during the day and night, and symptoms experienced at night often disturb sleep. The aim of this paper is to describe methods used to develop a patient-reported outcome (PRO) instrument for evaluating nighttime symptoms of COPD, and to document evidence for the content validity of the instrument.Literature review and clinician interviews were conducted to inform discussion guides to explore patients’ nighttime COPD symptom experience. Data from focus groups with COPD patients was used to develop a conceptual framework and the content of a new PRO instrument. Patient understanding of the new instrument was assessed via cognitive interviews with COPD patients.The literature review confirmed that there is no instrument with evidence of content validity currently available to assess nighttime symptoms of COPD. Additionally, the literature review and clinician interviews suggested the need to understand patients’ experience of specific symptoms in order to evaluate nighttime symptoms of COPD. Analyses of patient focus group data (N = 27) supported saturation of concepts and aided in development of a conceptual framework. Items were generated using patients’ terminology to collect data on concepts in the framework including the occurrence and severity of COPD symptoms, use of rescue medication at night, and nocturnal awakening. Response options were chosen to reflect concepts that were salient to patients. Subsequent cognitive interviewing with ten COPD patients demonstrated that the items, response options, recall period, and instructions were understandable, relevant, and interpreted as intended.A new PRO instrument, the Nighttime Symptoms of COPD Instrument (NiSCI), was developed with documented evidence of content validity. The NiSCI is ready for empirical testing, including item reduction and evaluation of psychometric properties. Chronic obstructive pulmonary disease (COPD) is defined by persistent airflow limitation that is usually progressive and is associated with an enhanced chronic inflammatory response in the airways and the lungs to noxious particles or gases . These cReducing symptom severity is a key target for the clinical management of COPD and recent guidelines encourage the use of validated questionnaires to assess COPD symptoms ,5. Only In recent years, regulatory agencies have increased their scrutiny of patient-reported outcome (PRO) measures. In particular, the United Stated Food and Drug Administration (FDA) released the “Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims,” which emphasizes the need to demonstrate an instrument’s content validity . AchieviThe aim of the present study was to develop a new PRO measure in accordance with the current FDA PRO Guidance , that coThe research team conducted a review of the respiratory literature through EMBASE and MEDLINE databases (2000–2009), abstracts from the American College of Chest Physicians (2003–2008), the American Thoracic Society (2008–2009), and the European Respiratory Society (2005–2008). Information collected included articles and abstracts about: a) clinical trials which measured nighttime COPD symptoms, b) non-clinical trial literature that contained discussion of nighttime symptoms of COPD, and c) literature on other instruments measuring nighttime symptoms of COPD. Interviews with clinicians were also conducted in order to determine the clinical context of evaluating the benefit of treatment on nighttime symptoms of COPD. Information from this phase of the project was used to draft a framework for exploring patient experiences of nighttime COPD symptoms on which the subsequent instrument development work was based.Focus group discussions were conducted to obtain information directly from COPD patients about the most important concepts related to the experience of COPD symptoms at night. A discussion guide was developed for the focus groups based on the conceptual framework resulting from the literature review and clinician interviews. The study protocol developed for concept elicitation (Version 3.0 dated 23rd December 2009) and cognitive interviews (Version 4.0 dated 4th September 2010) was reviewed and approved by a human subjects institutional review board (IRB).Focus group participants were recruited from out-patient clinic sites in four different locations in the United States: Virginia, New York, North Carolina, and Texas. First, site staff were trained on the study protocol. Then, clinical research coordinators at the sites reviewed patient charts to determine potential patient eligibility. The research coordinators were provided with a screening script to introduce patients to the study, and were instructed to strive for representativeness among recruited patients that would be comparable to that of the general COPD patient population in terms of gender, age, ethnic diversity, and COPD severity. After patients reviewed the IRB-approved information about the study and provided written informed consent, research coordinators completed forms to document each patient’s eligibility and to capture information on clinical characteristics.Focus group participants were selected to match the target population of future clinical trials assessing improvement in nighttime symptoms of COPD. Eligibility criteria for the focus groups were determined based on recommendations from clinical expert interviews. Thus, to be included in the study, focus group participants were required to have experienced COPD symptoms at night and/or the early morning for at least three nights/days a week, be 40 years of age or older, be a current or former cigarette smoker with a smoking history of at least ten pack-years, and have a current medical diagnosis of COPD (including chronic bronchitis and/or emphysema).Participants were excluded from the study if they had experienced a COPD exacerbation or unexpected visit to the clinic, ER, or hospital and/or used prescription medication to treat an exacerbation within six weeks prior to eligibility assessment; used narcotics, sleep aids, sedating antihistamines, sedatives, monoamine oxidase inhibitors (MAOIs), or other medications known to affect daytime somnolence or sleep quality ; did not maintain regular day/night waking/sleeping cycles ; chronically used oxygen therapy ≥15 hours/day; had a Body Mass Index (BMI) of 35 or above; or had a diagnosis of asthma, sleep apnea, or experienced nocturnal symptoms of gastroesophageal reflux disease (GERD) that were not controlled by treatment.Focus group discussions were led by trained and experienced moderators who used a semi-structured interview guide designed to facilitate discussion and create consistency across sessions. A trained research assistant was also present during focus groups to take notes and assist with the session. Moderators elicited information from participants regarding their experiences of nighttime symptoms of COPD, using open-ended questions. After each focus group, the research team reviewed the notes taken and the adequacy of the interview guide and revised it to enhance data collection, if needed.At the close of the focus group discussions, each participant completed health status and sociodemographic questionnaires, including the St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C) ,16 and tA phenomenological approach was used to analyze transcripts of the audio-recordings, based on grounded theory, which refers to the inductive process of identifying analytical categories as they emerge from the data ,20. The A coding dictionary was developed by examining transcript data for themes and subthemes. To begin, two researchers independently reviewed and coded one of the four transcripts. The two researchers met to discuss inter-rater agreement and refined the coding approach and dictionary for use in examining the remaining three transcripts. Each of the three remaining transcripts was coded independently by the two researchers, after which, the two researchers reviewed their findings. The researchers discussed disagreements and reconciled any divergent codes to determine the final coding assessment across all four transcripts. An iterative process was used to identify analytical categories, and to analyze the data to uncover key concepts and insights until no new codes or coding groups were required; i.e., until all text from the transcripts had been assigned to one or more codes. Focus group data were analyzed with the assistance of ATLAS.ti (version 5.0) software . Data frConcepts emerging from the focus group discussions were tracked on tables following each discussion, to monitor saturation. Saturation was defined as the point where themes from prior discussions were echoed in later discussions and no new themes were introduced beyond those previously identified. An analysis of the data from the concept elicitation work with patients confirmed saturation of concepts. Subsequently, the initial framework of concepts identified from the literature and clinician interviews was refined into a conceptual framework for a new PRO instrument.Items were developed for Version 1 of the measure to collect information about all concepts in the revised conceptual framework. The authors used an iterative process of drafting, evaluation, and revision to generate the items, response options, instructions, and recall period for the instrument. Item stems and response options were generated to reflect the terminology used by patients. Recall period was selected to best capture the full variability of the concepts.The initial item pool was reviewed by an expert in cultural and linguistic translation. To create Version 1, grammatical edits and minor changes in wording were made to ensure readability and facilitate consistency in words and meaning across translations.Following development of the item pool, the items were formatted as Version 1 of the PRO instrument, administered to patients, and tested in one-on-one cognitive interviews to further confirm the content validity of the instrument. Cognitive interviews were conducted to assess the respondents’ understanding of the questionnaire and its items, in relation to the intended meaning and to evaluate comprehensiveness of the content to evaluate the target concept . RecruitTrained and experienced interviewers administered Version 1 of the Nighttime Symptoms of COPD Instrument (NiSCI) and conducted interviews using a semi-structured interview guide. The administration of Version 1 of the NiSCI for cognitive interviewing was designed to mimic the format that would be used in clinical trials.Patients were included in two rounds of cognitive interviewing. Following interviews with the first set of participants, the results and the interview guide were reviewed. Minor alterations to the instrument were made based on patient feedback and the interview guide was refined for clarity. Revisions were based on participant comments, and consideration was also given to data gathered during concept elicitation focus groups. The remaining participants completed the revised instrument (Version 2) and were interviewed using the updated interview guide.During cognitive interviews, patients’ comprehension of the instrument and the comprehensiveness of the items were assessed, and patients were asked to provide feedback on the instrument’s instructions, as well as the appropriateness of the recall period and response options. To evaluate patient understanding, interviews were conducted with attention to verbal and non-verbal cues from the participants. At the end of the interview, patients completed the SGRQ, HADS, and a sociodemographic questionnaire. Interviews were audio-recorded and transcribed for analysis.Qualitative analysis software (ATLAS.ti version 5.0)  was usedFollowing analysis of the cognitive interviews, edits were made to Version 1 of the instrument. In order to document the development and refinement of each item in the NiSCI, an item-tracking matrix was developed including information about the development of the item, changes made following translatability assessment, changes following the first round of cognitive interviews, and the final version of items (Version 2) following the second round of interviews.A schematic outline of the project methodology describing the steps for concept elicitation, item generation and cognitive testing can be found in Figure Results of the literature review and clinician interviews (with five pulmonologists and a sleep expert) suggested that to understand patients’ experience of nighttime symptoms of COPD, it is important to evaluate their experience of COPD symptoms as well as the consequences of these symptoms on sleep. The results also informed the development of the protocol for these studies; for example, the necessary exclusion of conditions other than COPD that often result in the experience of respiratory symptoms at nighttime . Additionally, the review of literature did not identify a PRO measure with documented evidence of content validity that could be used to collect data on nighttime symptoms of COPD. This suggested the need to develop a new tool.Table Twenty-seven patients with COPD participated in four focus groups. Of these, twenty-four reported experiencing COPD symptoms at night. During each focus group, participants discussed their experience in terms of the occurrence, severity, and impact of nighttime symptoms of COPD. Nighttime symptoms reported by the participants were shortness of breath (n = 17), cough (n = 15), mucus/phlegm (n = 14), and wheezing (n = 11). Additionally, three participants mentioned experiencing chest tightness, and two mentioned chest congestion. In the discussion, participants discussed the interrelationship among the different COPD symptoms. From their perspective, coughing, wheezing, congestion and mucus/phlegm production were related to each other. For example, patients described congestion being linked to both coughing and phlegm. No new COPD symptoms emerged in the fourth and final focus group, suggesting saturation of concepts Table .Participants also discussed the impacts of nighttime symptoms Table . In threThe conceptual framework for the instrument was developed to depict the relationship of the various nighttime symptoms of COPD experienced by patients and the impact of these symptoms. Concepts that were clinically relevant and reported by patients, either through spontaneous report or following probing, were included in the conceptual framework. The clinical relevance of concepts was confirmed by referring to findings from the earlier clinician interviews and literature review, before finalizing the preliminary conceptual framework.The conceptual framework served as a basis for generating items for the new instrument. As a result, a 16-item instrument, the Nighttime Symptoms of COPD Instrument (NiSCI), was drafted in the form of a daily diary and included questions about the occurrence and severity of COPD symptoms, use of rescue medication at night, and nocturnal awakenings.During the focus groups, participants discussed their experiences with specific symptoms at night. Thus, items were generated to collect information about each of these cardinal symptoms. Additionally, participants discussed their symptoms in terms of severity rather than frequency, therefore, response options were designed to cover the full range of symptom severity rather than assess symptom frequency. Items were not generated for other concepts reported by participants , as they were mentioned in only one of the four focus groups and by fewer than two participants for each concept. Additionally, none of these concepts were mentioned as being “COPD specific symptoms” in clinical guidance documents or during clinician interviews, and therefore, were not considered cardinal symptoms of COPD for evaluation of patients’ experiences of COPD symptoms at night.As participants noted that they were woken up when symptoms worsened and sometimes had to use rescue medication, two items were generated: one to capture the occurrence of nocturnal awakening due to COPD symptoms and a second to assess the number of times rescue medication was used. Table To ensure data quality, the diary was designed to be incorporated on an electronic device .To mimic the layout of the electronic device that will be used in clinical trials, each question or set of questions intended to appear on a single screen was presented to the patient on a single sheet of paper. Planned skip patterns for the instrument were also simulated by the interviewer, with follow-up items being presented based on the participants’ previous response. To ensure patients’ feedback on all of the questions in the instrument, if an item was skipped while the participant was completing the diary as a result of the skip patterns, it was later shown to the participant during the think-aloud portion of the interview. This process ensured that all patients were able to review and comment on all items, regardless of how they completed the instrument. Four patients were interviewed for the first stage of testing, and revisions made based on feedback from patients during this stage were tested with six additional patients.Participants demonstrated an understanding of all instructions and items as intended, and expressed that no aspect of their experience of COPD symptoms at night were missing. Participants reported that they were able to recall their experiences of the previous night as they responded to each item, selecting the response that best represented their experiences. Cognitive interviews supported evidence of patient understanding of the response options.In the first stage of testing, feedback from two participants suggested that further clarification regarding the recall period should be added to the instructions and definitions be explained to patients during patient training. However, timeframe to which the instructions referred (the previous night) was generally understood. Based on this feedback, additional clarifications were added to the instructions and it was noted that the timeframe should be stressed during site and patient training.There was one minor revision made to an item’s response choices following the second stage of interviews to create Version 2 of the instrument: question marks after the symptoms listed in an item were removed for improved clarity on the screen of an electronic device.This manuscript outlines the development of the NiSCI, an instrument to measure nighttime symptoms of COPD, and documents evidence of its content validity. This instrument is intended for future use in clinical trials to collect data to support label claims related to improvements in nighttime symptoms of COPD.Consistent with the methods ,14 requiItem development was guided by the conceptual framework and particular attention was paid to the incorporation of the terminology used by patients. Finally, cognitive interviews with patients following completion of the measure provided evidence that participants interpreted the items, instructions, and response options as intended, and that the items comprehensively evaluated patient experiences of nighttime symptoms of COPD.This qualitative research showed that patients with COPD experience specific symptoms at night, and that the severity of these symptoms is variable across nights. The symptoms that patients described at night were consistent with the cardinal symptoms outlined in the COPD treatment guidelines   and othePatients noted throughout the discussions that their COPD symptoms often caused them to wake up during the night. They were able to report nocturnal awakening resulting from the experience of COPD symptoms as distinct from awakening for other reasons . Research studies in COPD have linked sleep disturbances to negative outcomes, underscoring the importance of both measuring and reducing sleep disturbance . HoweverFocus group participants also discussed the need to use rescue medication when their nighttime symptoms increased in severity. This is consistent with the clinician interviews conducted for this study as well as COPD trials to date, as rescue medication use has often been used as an endpoint in clinical trials of products evaluated for the management of respiratory diseases ,11.The methods used for concept elicitation and cognitive interviewing closely followed the requirements for generating evidence of content validity for PRO tools, to be used to collect data to support label claims .Though the sample sizes for the focus groups and interviews were small, the results showed evidence of saturation of concepts. A limitation of the concept elicitation work was that despite attempts to recruit a diverse group of patients, the final sample was not as diverse as intended, particularly in terms of race and ethnicity. More racial diversity was present in the sample of participants in the cognitive interviews. Subsequent testing of the instrument will also seek to include a diverse sample that represents the COPD population in the United States.Previous studies have demonstrated the importance of nighttime symptoms of COPD on various aspects of patients’ lives -4; howevBMI: Body mass index; COPD: Chronic obstructive pulmonary disease; FDA: Food and Drug Administration; GERD: Gastroesophageal reflux disease; HADS: Hospital Anxiety and Depression Scale; IRB: Institutional review board; ISPOR: International Society of Pharmacoeconomic and Outcomes Research; MAOI: Monoamine oxidase inhibitor; NiSCI: Nighttime Symptoms of COPD Instrument; PDA: Personal digital assistant; PRO: Patient-reported outcome; SD: Standard deviation; SGRQ-C: St. George’s Respiratory Questionnaire for COPD.This study was conducted by United BioSource Corporation (UBC) on behalf of Forest Research Institute, Inc. (FRI), a wholly owned subsidiary of Forest Laboratories, Inc., who funded this work. Asha Hareendran, Andrew C. Palsgrove and Michael L. Schaefer as employees of UBC served as paid consultants to FRI during the conduct of this study and the development of this manuscript. Asha Hareendra is currently employed by UBC. Andrew C. Palsgrove is currently employed by Covance Market Access Services while Michael L. Schaefer is currently employed by Humana, Inc. Covance Market Access Services and Humana, Inc. were not associated with this study. Michelle Mocarski and Robyn Carson are employees of FRI. Juliana Setyawan worked for FRI while performing this analysis but is currently employed by Shire Pharmaceuticals. Shire Pharmaceuticals was not associated with this study. Barry Make received funds from UBC for consultation during development of the instrument.AH led the design of the study and oversaw all aspects of the study including conduct of focus groups and patient interviews, data analysis, development of the draft instrument, and drafting of the manuscript. AP participated in the design of the study, conducted focus groups and patient interviews, analyzed the data, helped in the development of the draft instrument, and led the drafting of the manuscript. MM participated in the design of the study, interpretation of the data, development of the draft instrument, and drafting of the manuscript. MS participated in the design of the study, interpretation of the data, development of the draft instrument, and drafting of the manuscript. JS conceived of the study, participated in its design and coordination, development of the draft instrument, and drafting of the manuscript. RC participated in the design of the study, interpretation of the data, development of the draft instrument, and drafting of the manuscript. BM provided clinical expertise to the team and participated in the design of the study, provided feedback during instrument development, and participated in drafting of the manuscript. All authors read and approved the final manuscript.Andrew C. Palsgrove worked for United BioSource Corporation during the implementation and reporting of this study but is currently employed by Covance Market Access Services. Covance Market Access Services was not associated with this study.Michael L. Schaefer worked for United BioSource Corporation during the implementation and reporting of this study but is currently employed by Humana, Inc. Humana, Inc. was not associated with this study.Juliana Setyawan worked for Forest Research Institute while performing this analysis but is currently employed by Shire Development LLC. Shire Development LLC was not associated with this study.


The study investigated the effect of the transport industry on the transmission and spread of HIV/AIDS. Transport workers are highly mobile and spend long intervals away from the comforts of their homes. They are often involved in risky sexual behaviours that make them vulnerable to HIV infection, and so constitute carriers in the spread of the pandemic.The study entailed interviewing more than 1,000 long haul drivers and workers with the objective of inducing frank talk to assess their sexual habits enroute their long hauls. The limitation of this study was their insistence on anonymity to avoid adverse effects on their social status and marriage stability.More than 80% of interviewees had more than 20 female friends stationed at the villages on highways across the country. 60% of the promiscuous group knew about condoms but never used them. To them, what was the use doing it if you could not have the real thing. Sadly, some of the interviewees stated they had no other pleasurable indulgences in life other than sex, and if they were to die doing the only thing they enjoyed then who is complaining.The NURTW was advised:Create rest stations along the nation’s highways, with lodging, canteen, games, TV/Video sets, and other recreational facilities for drivers and motor boys.Provide GSM phone facilities for workers on long distance engagements to allow them keep in touch with their families.Organize seminars to educate workers on the implications, prevalence and management of HIV/AIDS.Provide medical test and care facilities at those rest stations for the quiet testing of workers for HIV/AIDS and dispensing of necessary drugs to sufferers.