Whole genome sequencing for quantifying germline mutation frequency in humans and model species: cautious optimism

Factors affecting the type and frequency of germline mutations in animals are of significant interest from health and toxicology perspectives. However, studies in this field have been limited by the use of markers with low detection power or uncertain relevance to phenotype. Whole genome sequencing (WGS) is now a potential option to directly determine germline mutation type and frequency in family groups at all loci simultaneously. Medical studies have already capitalized on WGS to identify novel mutations in human families for clinical purposes, such as identifying candidate genes contributing to inherited conditions. However, WGS has not yet been used in any studies of vertebrates that aim to quantify changes in germline mutation frequency as a result of environmental factors. WGS is a promising tool for detecting mutation induction, but it is currently limited by several technical challenges. Perhaps the most pressing issue is sequencing error rates that are currently high in comparison to the intergenerational mutation frequency. Different platforms and depths of coverage currently result in a range of 10-10(3) false positives for every true mutation. In addition, the cost of WGS is still relatively high, particularly when comparing mutation frequencies among treatment groups with even moderate sample sizes. Despite these challenges, WGS offers the potential for unprecedented insight into germline mutation processes. Refinement of available tools and emergence of new technologies may be able to provide the improved accuracy and reduced costs necessary to make WGS viable in germline mutation studies in the very near future. To streamline studies, researchers may use multiple family triads per treatment group and sequence a targeted (reduced) portion of each genome with high (20-40 ×) depth of coverage. We are optimistic about the application of WGS for quantifying germline mutations, but caution researchers regarding the resource-intensive nature of the work using existing technology.     

Addressing Parental Vaccine Concerns: Engagement,Balance, and Timing

The recent United States measles epidemic has sparked another contentious national discussion about childhood vaccination. A growing number of parents are expressing concerns about the safety of vaccines, often fueled by misinformation from the internet, books, and other nonmedical sources. Many of these concerned parents are choosing to refuse or delay childhood vaccines, placing their children and surrounding communities at risk for serious diseases that are nearly 100% preventable with vaccination. Between 10% and 15% of parents are asking physicians to space out the timing of vaccines, which often poses an ethical dilemma for physicians. This trend reflects a tension between personal liberty and public health, as parents fight to control the decisions that affect the health of their children and public health officials strive to maintain high immunization rates to prevent outbreaks of vaccine-preventable diseases. Interventions to address this emerging public health issue are needed. We describe a framework by which web-based interventions can be used to help parents make evidence-based decisions about childhood vaccinations.

About the Author

Jason Glanz, PhD, is an epidemiologist and senior research investigator at Kaiser Permanente Colorado, Institute for Health Research. He is also an assistant professor in the Department of Epidemiology, Colorado School of Public Health. Dr. Glanz’s research focuses on vaccine safety and vaccine hesitancy. Dr. Glanz is currently a principal investigator with the Vaccine Safety Datalink, a national Centers for Disease Control and Prevention (CDC)-funded project that examines the safety of vaccines. Dr. Glanz also leads research efforts to develop risk communication strategies to help reduce parental vaccination concerns.     

The use of information technology in improving medical performance. Part I. Information systems for medical transactions

Investment in medical information technologies reached $15 billion in 1996. However, these technologies have not had the wide impact predicted in streamlining bureaucracy, improving communications, and raising the effectiveness of care. In this series, we identify how such technologies are being used to improve quality and performance, the future directions for advancement, and the policy and research developments required to maximize public benefit from these technologies. Each of these articles focuses on a different type of information technology: (1) information systems to manage medical transactions; (2) physician-support technologies to improve medical practice; and (3) patient-focused technologies designed to change how people manage their own care. This first article of a 3-part series examines the successes of and opportunities for using advanced information systems that track and manage medical transactions for large populations to improve performance. Examples of such systems include: HEDIS, which gathers standardized data from health plans on quality of care; the USQA Health Services Research Program, which tracks treatment patterns and outcomes for 14 million insurance members; Ford's program to collect medical data for over 600,000 employees; and Harvard Pilgrim Health Care's system of computerized laboratory, pharmacy, ambulatory, and hospital admission records for its 1.5 million members. Data from these systems have led to modest improvements in knowledge and practice patterns for some diseases. Significant barriers are slowing efforts to add outcomes data to these databases and broaden the databases to cover larger populations. Nonetheless, existing data in currently evolving systems could be used to greater benefit in tracking public health and in identifying more effective treatments and causes of diseases.     

The Global One Health Paradigm: Challenges and Opportunities for Tackling Infectious Diseases at the Human,Animal, and Environment Interface in Low-Resource Settings

Zoonotic infectious diseases have been an important concern to humankind for more than 10,000 years. Today, approximately 75% of newly emerging infectious diseases (EIDs) are zoonoses that result from various anthropogenic, genetic, ecologic, socioeconomic, and climatic factors. These interrelated driving forces make it difficult to predict and to prevent zoonotic EIDs. Although significant improvements in environmental and medical surveillance, clinical diagnostic methods, and medical practices have been achieved in the recent years, zoonotic EIDs remain a major global concern, and such threats are expanding, especially in less developed regions. The current Ebola epidemic in West Africa is an extreme stark reminder of the role animal reservoirs play in public health and reinforces the urgent need for globally operationalizing a One Health approach. The complex nature of zoonotic diseases and the limited resources in developing countries are a reminder that the need for implementation of Global One Health in low-resource settings is crucial. The Veterinary Public Health and Biotechnology (VPH-Biotec) Global Consortium launched the International Congress on Pathogens at the Human-Animal Interface (ICOPHAI) in order to address important challenges and needs for capacity building. The inaugural ICOPHAI (Addis Ababa, Ethiopia, 2011) and the second congress (Porto de Galinhas, Brazil, 2013) were unique opportunities to share and discuss issues related to zoonotic infectious diseases worldwide. In addition to strong scientific reports in eight thematic areas that necessitate One Health implementation, the congress identified four key capacity-building needs: (1) development of adequate science-based risk management policies, (2) skilled-personnel capacity building, (3) accredited veterinary and public health diagnostic laboratories with a shared database, and (4) improved use of existing natural resources and implementation. The aim of this review is to highlight advances in key zoonotic disease areas and the One Health capacity needs.     

Considerations for community engagement when conducting clinical trials during infectious disease emergencies in West Africa

Community engagement in research, including public health related research, is acknowledged as an ethical imperative. While medical care and public health action take priority over research during infectious disease outbreaks, research is still required in order to learn from epidemic responses. The World Health Organisation developed a guide for community engagement during infectious disease epidemics called the Good Participatory Practice for Trials of Emerging (and Re‐emerging) Pathogens that are Likely to Cause Severe Outbreaks in the Near Future and for which Few or No Medical Counter‐Measures Exist (GPP‐EP). This paper identified priorities for community engagement for research conducted during infectious disease outbreaks drawing on discussions held with a purposive sample of bioethicists, social scientists, researchers, policy makers and laypersons who work with ethics committees in West Africa. These perspectives were considered in the light of the GPP‐EP, which adds further depth and dimension to discussions on community engagement frameworks. It concludes that there is no presumptive justification for the exclusion of communities in the design, implementation and monitoring of clinical trials conducted during an infectious disease outbreak. Engagement that facilitates collaboration rather than partnership between researchers and the community during epidemics is acceptable.     

Solving the Problem of Comparing Whole Bacterial Genomes across Different Sequencing Platforms

Whole genome sequencing (WGS) shows great potential for real-time monitoring and identification of infectious disease outbreaks. However, rapid and reliable comparison of data generated in multiple laboratories and using multiple technologies is essential. So far studies have focused on using one technology because each technology has a systematic bias making integration of data generated from different platforms difficult. We developed two different procedures for identifying variable sites and inferring phylogenies in WGS data across multiple platforms. The methods were evaluated on three bacterial data sets and sequenced on three different platforms (Illumina, 454, Ion Torrent). We show that the methods are able to overcome the systematic biases caused by the sequencers and infer the expected phylogenies. It is concluded that the cause of the success of these new procedures is due to a validation of all informative sites that are included in the analysis. The procedures are available as web tools.     

'Changing climate, changing health, changing stories' profile: using an EcoHealth approach to explore impacts of climate change on inuit health

Global climate change and its impact on public health exemplify the challenge of managing complexity and uncertainty in health research. The Canadian North is currently experiencing dramatic shifts in climate, resulting in environmental changes which impact Inuit livelihoods, cultural practices, and health. For researchers investigating potential climate change impacts on Inuit health, it has become clear that comprehensive and meaningful research outcomes depend on taking a systemic and transdisciplinary approach that engages local citizens in project design, data collection, and analysis. While it is increasingly recognised that using approaches that embrace complexity is a necessity in public health, mobilizing such approaches from theory into practice can be challenging. In 2009, the Rigolet Inuit Community Government in Rigolet, Nunatsiavut, Canada partnered with a transdisciplinary team of researchers, health practitioners, and community storytelling facilitators to create the Changing Climate, Changing Health, Changing Stories project, aimed at developing a multi-media participatory, community-run methodological strategy to gather locally appropriate and meaningful data to explore climate-health relationships. The goal of this profile paper is to describe how an EcoHealth approach guided by principles of transdisciplinarity, community participation, and social equity was used to plan and implement this climate-health research project. An overview of the project, including project development, research methods, project outcomes to date, and challenges encountered, is presented. Though introduced in this one case study, the processes, methods, and lessons learned are broadly applicable to researchers and communities interested in implementing EcoHealth approaches in community-based research.     

Introducing One Health to the Ethical Debate About Zoonotic Diseases in Southeast Asia

Pandemic plans recommend phases of response to an emergent infectious disease (EID) outbreak, and are primarily aimed at preventing and mitigating human‐to‐human transmission. These plans carry presumptive weight and are increasingly being operationalized at the national, regional and international level with the support of the World Health Organization (WHO). The conventional focus of pandemic preparedness for EIDs of zoonotic origin has been on public health and human welfare. However, this focus on human populations has resulted in strategically important disciplinary silos. As the risks of zoonotic diseases have implications that reach across many domains outside traditional public health, including anthropological, environmental, and veterinary fora, a more inclusive ecological perspective is paramount for an effective response to future outbreaks.     

A Focused Ethnographic Study of Sri Lankan Government Field Veterinarians’ Decision Making about Diagnostic Laboratory Submissions and Perceptions of Surveillance

The global public health community is facing the challenge of emerging infectious diseases. Historically, the majority of these diseases have arisen from animal populations at lower latitudes where many nations experience marked resource constraints. In order to minimize the impact of future events, surveillance of animal populations will need to enable prompt event detection and response. Many surveillance systems targeting animals rely on veterinarians to submit cases to a diagnostic laboratory or input clinical case data. Therefore understanding veterinarians’ decision-making process that guides laboratory case submission and their perceptions of infectious disease surveillance is foundational to interpreting disease patterns reported by laboratories and engaging veterinarians in surveillance initiatives. A focused ethnographic study was conducted with twelve field veterinary surgeons that participated in a mobile phone-based surveillance pilot project in Sri Lanka. Each participant agreed to an individual in-depth interview that was recorded and later transcribed to enable thematic analysis of the interview content. Results found that field veterinarians in Sri Lanka infrequently submit cases to laboratories – so infrequently that common case selection principles could not be described. Field veterinarians in Sri Lanka have a diagnostic process that operates independently of laboratories. Participants indicated a willingness to take part in surveillance initiatives, though they highlighted a need for incentives that satisfy a range of motivations that vary among field veterinarians. This study has implications for the future of animal health surveillance, including interpretation of disease patterns reported, system design and implementation, and engagement of data providers.     

Measured voluntary avoidance behaviour during the 2009 A/H1N1 epidemic

Managing infectious disease is among the foremost challenges for public health policy. Interpersonal contacts play a critical role in infectious disease transmission, and recent advances in epidemiological theory suggest a central role for adaptive human behaviour with respect to changing contact patterns. However, theoretical studies cannot answer the following question: are individual responses to disease of sufficient magnitude to shape epidemiological dynamics and infectious disease risk? We provide empirical evidence that Americans voluntarily reduced their time spent in public places during the 2009 A/H1N1 swine flu, and that these behavioural shifts were of a magnitude capable of reducing the total number of cases. We simulate 10 years of epidemics (2003–2012) based on mixing patterns derived from individual time-use data to show that the mixing patterns in 2009 yield the lowest number of total infections relative to if the epidemic had occurred in any of the other nine years. The World Health Organization and other public health bodies have emphasized an important role for ‘distancing’ or non-pharmaceutical interventions. Our empirical results suggest that neglect for voluntary avoidance behaviour in epidemic models may overestimate the public health benefits of public social distancing policies.     

Advancing a Framework to Enable Characterization and Evaluation of Data Streams Useful for Biosurveillance

In recent years, biosurveillance has become the buzzword under which a diverse set of ideas and activities regarding detecting and mitigating biological threats are incorporated depending on context and perspective. Increasingly, biosurveillance practice has become global and interdisciplinary, requiring information and resources across public health, One Health, and biothreat domains. Even within the scope of infectious disease surveillance, multiple systems, data sources, and tools are used with varying and often unknown effectiveness. Evaluating the impact and utility of state-of-the-art biosurveillance is, in part, confounded by the complexity of the systems and the information derived from them. We present a novel approach conceptualizing biosurveillance from the perspective of the fundamental data streams that have been or could be used for biosurveillance and to systematically structure a framework that can be universally applicable for use in evaluating and understanding a wide range of biosurveillance activities. Moreover, the Biosurveillance Data Stream Framework and associated definitions are proposed as a starting point to facilitate the development of a standardized lexicon for biosurveillance and characterization of currently used and newly emerging data streams. Criteria for building the data stream framework were developed from an examination of the literature, analysis of information on operational infectious disease biosurveillance systems, and consultation with experts in the area of biosurveillance. To demonstrate utility, the framework and definitions were used as the basis for a schema of a relational database for biosurveillance resources and in the development and use of a decision support tool for data stream evaluation.     

Molecular diagnostics of medically important bacterial infections

Infectious diseases are common diseases all over the world. A recent World Health Organization report indicated that infectious diseases are now the world's biggest killer of children and young adults. Infectious diseases in non-industrialized countries caused 45% in all and 63% of death in early childhood. In developed countries, the emergence of new, rare or already-forgotten infectious diseases, such as HIV/AIDS, Lyme disease and tuberculosis, has stimulated public interest and inspired commitments to surveillance and control. Recently, it is reported that infectious diseases are responsible for more than 17 million deaths worldwide each year, most of which are associated with bacterial infections. Hence, the control of infectious diseases control is still an important task in the world. The ability to control such bacterial infections is largely dependent on the ability to detect these aetiological agents in the clinical microbiology laboratory. Diagnostic medical bacteriology consists of two main components namely identification and typing. Molecular biology has the potential to revolutionise the way in which diagnostic tests are delivered in order to optimise care of the infected patient, whether they occur in hospital or in the community. Since the discovery of PCR in the late 1980s, there has been an enormous amount of research performed which has enabled the introduction of molecular tests to several areas of routine clinical microbiology. Molecular biology techniques continue to evolve rapidly, so it has been problematic for many laboratories to decide upon which test to introduce before that technology becomes outdated. However the vast majority of diagnostic clinical bacteriology laboratories do not currently employ any form of molecular diagnostics but the use such technology is becoming more widespread in both specialized regional laboratories as well as in national reference laboratories. Presently molecular biology offers a wide repertoire of techniques and permutations of these analytical tools, hence this article wishes to explore the application of these in the diagnostic laboratory setting.     

C.-E.A. Winslow and the later years of public health at Yale, 1940-1945

This paper is one of a series of papers in which I consider contemporary Yale medical education in general and the Yale Department of Epidemiology and Public Health in particular. It tells of the retirement in 1945 of C.-E.A. Winslow, Professor and Chairman of the Yale Department of Public Health since its inception in 1915; of the committees established by the dean of the School of Medicine and the president of the University, charged with determining the future direction of the department; and of the outcome, which, in 1945, proved favorable to Winslow's public health philosophy in contrast to the medical school's clinical needs and desires.     

Metacommunity and phylogenetic structure determine wildlife and zoonotic infectious disease patterns in time and space

The potential for disease transmission at the interface of wildlife, domestic animals and humans has become a major concern for public health and conservation biology. Research in this subject is commonly conducted at local scales while the regional context is neglected. We argue that prevalence of infection at local and regional levels is influenced by three mechanisms occurring at the landscape level in a metacommunity context. First, (1) dispersal, colonization, and extinction of pathogens, reservoir or vector hosts, and nonreservoir hosts, may be due to stochastic and niche‐based processes, thus determining distribution of all species, and then their potential interactions, across local communities (metacommunity structure). Second, (2) anthropogenic processes may drive environmental filtering of hosts, nonhosts, and pathogens. Finally, (3) phylogenetic diversity relative to reservoir or vector host(s), within and between local communities may facilitate pathogen persistence and circulation. Using a metacommunity approach, public heath scientists may better evaluate the factors that predispose certain times and places for the origin and emergence of infectious diseases. The multidisciplinary approach we describe fits within a comprehensive One Health and Ecohealth framework addressing zoonotic infectious disease outbreaks and their relationship to their hosts, other animals, humans, and the environment.     

Climate Change and Heat-Related Excess Mortality in the Eastern USA

Climate change will increase extreme heat-related health risks. To quantify the health impacts of mid-century climate change, we assess heat-related excess mortality across the eastern USA. Health risks are estimated using the US Environmental Protection Agency’s Environmental Benefits Mapping and Analysis Program (BenMAP). Mid-century temperature estimates, downscaled using the Weather Research and Forecasting model, are compared to 2007 temperatures at 36 km and 12 km resolutions. Models indicate the average apparent and actual summer temperatures rise by 4.5° and 3.3° C, respectively. Warmer average apparent temperatures could cause 11,562 additional annual deaths (95% confidence interval, CI: 2641–20,095) due to cardiovascular stress in the population aged 65 years and above, while higher minimum temperatures could cause 8767 (95% CI: 5030–12,475) additional deaths each year. Modeled future climate data available at both coarse (36 km) and fine (12 km) resolutions predict significant human health impacts from warmer climates. The findings suggest that currently available information on future climates is sufficient to guide regional planning for the protection of public health. Higher resolution climate and demographic data are still needed to inform more targeted interventions.     

Adjusting the focus: A public health ethics approach to data research

This paper contends that a research ethics approach to the regulation of health data research is unhelpful in the era of population‐level research and big data because it results in a primary focus on consent (meta‐, broad, dynamic and/or specific consent). Two recent guidelines – the 2016 WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks and the revised CIOMS International ethical guidelines for health‐related research involving humans – both focus on the growing reliance on health data for research. But as research ethics documents, they remain (to varying degrees) focused on consent and individual control of data use. Many current and future uses of health data make individual consent impractical, if not impossible. Many of the risks of secondary data use apply to communities and stakeholders rather than individual data subjects. Shifting from a research ethics perspective to a public health lens brings a different set of issues into view: how are the benefits and burdens of data use distributed, how can data research empower communities, who has legitimate decision‐making capacity? I propose that a public health ethics framework – based on public benefit, proportionality, equity, trust and accountability – provides more appropriate tools for assessing the ethical uses of health data. The main advantage of a public health approach for data research is that it is more likely to foster debate about power, justice and equity and to highlight the complexity of deciding when data use is in the public interest.     

Lymphatic Filariasis (Elephantiasis) Elimination: A public health success and development opportunity

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis, launched following World Health Assembly Resolution 50.29 (WHA 50.29), has been facilitated in its progress by new research findings, drug donations, the availability of diagnostic tools, disability management strategies to help those already suffering and the development of partnerships. The strategy recommended by the World Health Organization of annual treatment with a two-drug combination has proved safe. DISCUSSION: Using different approaches in several countries the elimination of lymphatic filariasis (LF) has been demonstrated to be feasible during earlier decades. These successes have been largely overlooked. However, the programme progress since 2000 has been remarkable - upscaling rapidly from 2 million treatments in 2000 to approximately 60 million in 2002. Around 34 countries had active programmes at the end of 2002. It is anticipated that there will be further expansion - but this will be dependent on additional resources becoming available. The programme also provides significant opportunities for other disease control programmes to deliver public health benefits on a large scale. Few public health programmes have upscaled so rapidly and so cost-effectively (<$0.03/treatment in some Asian settings) - one country treating 9-10 million people in a day (Sri Lanka). The LF programme is arguably the most effective pro-poor public health programme currently operating which is based on country commitment and partnerships supported by a global programme and alliance. Tables are provided to summarize programme characteristics, the benefits of LF elimination, opportunities for integration with other programmes and relevance to the Millennium Development Goals. SUMMARY: Lymphatic filariasis elimination is an "easy-to-do" inexpensive health intervention that provides considerable "beyond filariasis" benefits, exemplifies partnership and is easily evaluated. The success in global health action documented in this paper requires and deserves further support to bring to fruition elimination of lymphatic filariasis as a public health problem and health benefits to poor people. A future free of lymphatic filariasis will reduce poverty and bring better health to poor people, prevent disability, strengthen health systems and build partnerships.     

Five Classic Articles in Public Health

In this brief review, Dr. Jonathan Borak comments on five seminal papers that helped shape the fields of epidemiology and public health. These papers include Hill’s criteria for inferring causality; the first proof of the multistage theory of cancer; the first evidence that subclinical lead exposures can cause neurobehavioral impairment in children; a simple yet robust study that had a major influence on setting current air pollution policies; and a landmark review of the general public’s perception of risk in relation to actual public health hazard.Dr. Jonathan Borak is a Clinical Professor of Epidemiology and Public Health at the Yale School of Public Health, Clinical Professor of Internal Medicine at the Yale School of Medicine, and Director of the Yale Interdisciplinary Risk Assessment Forum. In this article, Dr. Borak provides his perspective on five publications that significantly influenced the study and practice of epidemiology and public health. This article is the first in a series that will identify and provide commentary on the top five seminal papers published in a field related to biology and medicine.A former student, a member of the Yale Journal of Biology and Medicine’s Editorial Board, reminded me of a comment I made in class. I had described a particular assigned reading as “one of those classic articles” that should be read by everyone studying public health. Okay, he challenged me, what other “classic articles” were on my list? And so began the following: my short list of five articles that represent “must reading” for all students in public health.First, note that I do not speak for public health in general, a field of great breadth of interest and activity, but only the narrower slice, including toxicology, risk assessment, and related interests. Also, I was principally concerned to identify articles that provide models of critical thinking, addressed issues of substantial public health importance, and served as stepping stones for subsequent research and the formulation of public health policy. I also wanted to include articles that were observational and opportunistic, i.e., based on real world observations and available data, not complex laboratory models.My five choices below include: 1) a landmark presentation of criteria for inferring causality from observational data (Hill 1965); 2) a thought experiment based on the re-analysis of publicly available cancer mortality data, which shaped the fields of cancer biology and risk assessment (Armitrage & Doll, 1954); 3) an early study of the effects of lead exposure in school children (Needleman, 1979); 4) a study of the impact of air pollution on children’s health, which was enabled by a fortuitous labor dispute that shuttered a polluting steel mill (Ransom & Pope, 1992); and, 5) a critical literature review of cognitive psychology research that shaped our understanding about how public health risks are perceived (Slovic, 1987).     

Engaging New Migrants in Infectious Disease Screening: A Qualitative Semi-Structured Interview Study of UK Migrant Community Health-Care Leads

Migration to Europe - and in particular the UK - has risen dramatically in the past decades, with implications for public health services. Migrants have increased vulnerability to infectious diseases (70% of TB cases and 60% HIV cases are in migrants) and face multiple barriers to healthcare. There is currently considerable debate as to the optimum approach to infectious disease screening in this often hard-to-reach group, and an urgent need for innovative approaches. Little research has focused on the specific experience of new migrants, nor sought their views on ways forward. We undertook a qualitative semi-structured interview study of migrant community health-care leads representing dominant new migrant groups in London, UK, to explore their views around barriers to screening, acceptability of screening, and innovative approaches to screening for four key diseases (HIV, TB, hepatitis B, and hepatitis C). Participants unanimously agreed that current screening models are not perceived to be widely accessible to new migrant communities. Dominant barriers that discourage uptake of screening include disease-related stigma present in their own communities and services being perceived as non-migrant friendly. New migrants are likely to be disproportionately affected by these barriers, with implications for health status. Screening is certainly acceptable to new migrants, however, services need to be developed to become more community-based, proactive, and to work more closely with community organisations; findings that mirror the views of migrants and health-care providers in Europe and internationally. Awareness raising about the benefits of screening within new migrant communities is critical. One innovative approach proposed by participants is a community-based package of health screening combining all key diseases into one general health check-up, to lessen the associated stigma. Further research is needed to develop evidence-based community-focused screening models - drawing on models of best practice from other countries receiving high numbers of migrants.