Seasonal and Pandemic Influenza Vaccines: Principles and Challenges

Speaker: Kanta Subbarao

Director,
WHO Collaborating Centre for Reference and Research on Influenza
The Peter Doherty Institute for Infection and Immunity
Professor,
Department of Microbiology and Immunology,
The University of Melbourne

Predicting strain interactions and success with genomic data: approaches from modelling and machine learning

SPEAKER: Caroline Colijn

Professor and Canada 150 Research Chair
Department of Mathematics
Simon Fraser University

ABSTRACT: Genomic data gathered over time give the opportunity to examine diversity at high resolution, and to use the results to test predictive models: can we guess in advance which sub-populations of a circulating pathogen will succeed in the near future? We discuss two contrasting approaches, one based on machine learning and the other using a high-dimensional mechanistic model that empirically captures features of the genomic data. We illustrate these approaches using data from human influenza A, Staphylococcus aureus and Streptococcus pneumoniae.

Virus-inclusive single cell RNA sequencing reveals the molecular signature of dengue virus infection in cell lines and human blood

Speaker: Fabio Zanini

Postdoctoral Scholar
Department of Bioengineering
Stanford University
 

Abstract

Dengue virus (DENV) infects millions of people annually and can cause severe manifestations including hemorrhage and shock. However, a thorough understanding of the host response to DENV is lacking, partly because conventional approaches ignore heterogeneity in virus abundance across cells. In this talk, I will  introduce viscRNA-Seq (virus-inclusive single cell RNA-Seq), an approach to probe the host transcriptome together with intracellular viral RNA at the single cell level. I applied viscRNA-Seq to monitor DENV infection in cultured cells and peripheral blood cells from dengue infected human subjects.

Longitudinal sampling of cultures cells enabled the identification of host factors that play pro- or antiviral roles. In blood cells from dengue patients, interferon response genes were upregulated in a cell-specific manner prior to severe symptoms. The majority of DENV-RNA containing cells were naive IgM B cells expressing the CD69 and CXCR4 receptors and antiviral genes, followed by monocytes. Unexpected patterns of genetic diversity were detected in the viral genome and the host antibody repertoire. ViscRNA-Seq enables a multi-faceted molecular elucidation of viral infection in cell lines and human tissues and the discovery of novel virus-host genetic interactions.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Download flyer: [pdf]

Influenza evolution... getting personal

SPEAKER: Adam Lauring

Principal Investigator and Assistant Professor
Lauring Lab,
Department of Microbiology and Immunology,
Department of Ecology and Evolutionary Biology
University of Michigan

ABSTRACT: While influenza virus evolution has been well characterized on the global scale, much less is known about how the virus evolves within infected individuals. My laboratory has been interested in these local scale processes with the goal of understanding the extent to which global processes are recapitulated at the host level and how within host processes contribute to larger evolutionary dynamics. I will present our recent work on influenza virus evolution in cultured cells, in individual hosts, and within households. I’ll briefly review our characterization of the fitness effects of point mutations and our extensive study of mutation rates using a new twelve class Luria Delbruck fluctuation test. I’ll devote the majority of the talk to studies of influenza virus evolution within and between naturally infected human hosts. Here, we have used high depth of coverage sequencing to determine the relative impact of positive selection and genetic drift on mutation frequencies within hosts. Finally, I will cover our recently published study of transmission bottlenecks in a household cohort.   

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

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Viral transmission during outbreaks: genomic analysis of Ebola, Zika, and mumps viruses

SPEAKER: Shirlee Wohl

Recent PhD, Sabeti Lab,
Harvard University,
Broad Institute of MIT and Harvard

ABSTRACT: Genomics has emerged as a powerful tool for combating viral outbreaks. In this talk, I will describe how genomic data was used to understand the evolution and spread of three viruses during recent outbreaks. First, I will present our analysis of Ebola virus sequences from the 2014–2016 outbreak in West Africa, and discuss what these genomes tell us about cross‐border and individual transmission. I will then describe our efforts to characterize movement of Zika virus throughout the Americas in 2016, focusing on challenges related to low viral content in Zika samples. Finally, I will spend most of the talk discussing our recently submitted study of the 2016–2017 mumps virus outbreak in the United States, and will explain how mumps virus sequences from Massachusetts and several other states informed our understanding of disease spread at several geographic scales. In particular, we found evidence for ongoing mumps transmission in the United States, and show that pairing genomic and detailed epidemiological data reveals detailed transmission within a local community.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Download flyer: [pdf]

Field- and clinically derived estimates of Wolbachia-mediated blocking of dengue virus transmission potential in Aedes aegypti mosquitoes

SPEAKER: Lauren Carrington

Research Fellow
University of Melbourne
Department of Microbiology & Immunology
Peter Doherty Institute for Infection & Immunity

Based at:
Oxford University Clinical Research Unit (OUCRU)
Ho Chi Minh City
Vietnam
 

ABSTRACT: 

The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, I present data demonstrating that wMel-infected Ae. aegypti lower dengue virus (DENV) transmission potential and extend the virus extrinsic incubation period relative to wild-type counterparts, after direct feeding on acutely viremic dengue patients. Furthermore, using patient-derived viremic blood meals and mosquitoes reared directly in the field, the relative protection afforded by Wolbachia against DENV was even greater, compared to lab-rearing conditions. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. These field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-borne arboviruses.

In addition to these data, I discuss our efforts to calibrate our lab-based mosquito in vitro transmission assay with a more realistic, non-human primate infection model. In this collaboration with the US Armed Forces Research Institute for Medical Sciences (AFRIMS; Bangkok, Thailand), we capture data on the viral kinetics and serology in Rhesus macaques after direct bites by DENV-infected mosquitoes. Establishment of such an infection model may provide additional evidence supporting reduced transmission of arboviruses from Wolbachia-infected mosquitoes to humans.

Finally, current arbovirus surveillance methods in Vietnam capture only those cases with clinical manifestations. I introduce a new surveillance study being established in Ho Chi Minh City, where the positive detection of ZIKV infected mosquitoes through active mosquito surveillance will lead to the initiation of human cluster investigations. This surveillance network will provide this urban hub, hyper-endemic for DENV and now ZIKV, a new level of spatial and temporal data relating to virus transmission dynamics, that continues to go unseen by standard clinical surveillance methods.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Pandemic influenza in the age of mammals

Speaker: Martha Nelson, PhD

Staff Scientist
Fogarty International Center, NIH

Abstract: The ecology of influenza A viruses (IAVs) in non-human mammalian hosts underwent dramatic changes at the end of the 20th century and the beginning of the 21st century, introducing important new pandemic threats. As a result, the H1N1 virus that caused the 2009 influenza pandemic came not from birds, but from pigs. Beginning in the 1990s, the genetic diversity of IAVs in US swine increased dramatically and spread across the globe, following the direction of the international trade of live swine. In this talk, I’ll describe how the evolution and spatial spread of diverse IAV lineages in swine facilitated the emergence of the 2009 H1N1 pandemic virus, and how viral genetic diversity continues to expand in swine globally, producing viruses that could cause the next pandemic. In fact, newly emerged viruses circulate in US exhibition swine and have infected > 400 children attending agricultural fairs during summer months. I’ll also discuss new, unpublished findings describing how the genetic diversity of IAV is rapidly expanding in canines in Asia, creating additional pandemic threats. The emergence of new viruses in Asian canines is particularly alarming, as these hosts are raised for consumption and exposed to high viral diversity in live animal markets, and kept as pets with very high human contact in households. Going forward, understanding pandemic risk requires a more complete knowledge of the viral diversity circulating in under-studied mammalian hosts globally, and an understanding of how changes in animal movements and population structures drive the evolution of these new viruses.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Connecting serological data and antigenic maps of dengue viruses to protection and disease severity

SPEAKER: Leah Katzelnick

Postdoctoral Fellow
University of California, Berkeley

ABSTRACT

Dengue viruses 1‐4 (DENV1‐4) are mosquito‐borne flaviviruses that cause ~500,000 severe dengue cases annually. This seminar will present research on the relationships between anti‐DENV neutralizing and binding antibodies and protection against and enhancement of dengue disease. We studied the antigenic relationships among diverse DENV strains using neutralizing antibody titers and found that DENV strains loosely clustered by DENV type, but many strains were equidistant to strains of a heterologous DENV type as to some homologous‐type strains. Further, many primary infection antisera exhibited persistent heterotypic neutralizing antibody titers for years after primary infection. Through examining anti‐DENV antibody responses in a longitudinal pediatric dengue cohort in Managua, Nicaragua, we found that higher pre‐existing anti‐DENV neutralizing and binding antibody titers were associated protection against symptomatic dengue but that pre‐existing anti‐DENV binding antibodies within a narrow range were associated with enhancement of severe dengue disease. Collectively, these findings suggest that DENV strains are not antigenically homogeneous within DENV type, and that primary infection antibody responses are varied and at high levels protect against a heterotypic DENV infection but at intermediate levels can enhance dengue disease.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Intra-patient evolutionary dynamics of immunodeficiency viruses across time and space

SPEAKER: Alison Feder

Graduate Student
Department of Biology
Stanford University

ABSTRACT

HIV’s high mutation rates and large population sizes make it incredibly adaptable, especially to the antiretroviral drugs used in its treatment. However, as treatments have improved over the course of the epidemic, there has been a shift from HIV evolving resistance predictably and quickly in each patient to resistance emerging rarely, if at all. By studying the manner in which drug resistance emerges, we can gain broader insights into how HIV evolves within its host. I’ll explore two questions: 1) how has intra-patient drug resistance evolution changed over the course of the epidemic and 2) what role does population spatial structure play in influencing the intra-patient dynamics. In answer to the first question, I will present data from 6717 historical HIV sequences from the Stanford HIV Drug Resistance Database that suggest that as treatments have improved over the decades, there has been a transition from soft sweeps of many drug resistance mutations simultaneously to hard sweeps of single drug resistant types. This supports more broadly a prediction from theory that when adaptation is likely (as when drugs failed frequently), sweeps should be soft. In answer to the second question, I will present data from four Simian-HIV infected macaques sampled in multiple tissues over the course of their infection and treatment. I will use these data to estimate selection, migration and population size and suggest how their interaction may explain equivocal evidence of compartmentalization from the HIV literature.
 

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Download flyer: [link]

The Finest Tuned Clocks: Biological Rhythms & Epidemics

Speaker: Micaela E. Martinez, Ph.D.

Associate Research Scholar
Dept. of Ecology & Evolutionary Biology
Princeton University

Abstract

Life on earth has evolved under day-night and seasonal cycles. These environmental cycles pose organisms with challenges and opportunities. Biological clocks have evolved as a mechanism for organisms to internalize time, giving them them the ability to anticipate, and prepare for, predictable changes in their environment. Circadian clocks, for example, are ubiquitous in eukaryotes, and circannual (i.e., seasonal) clocks are found throughout the animal kingdom. I will present research I have completed, and projects I have underway, to characterize cycles in disease transmission, human physiology, and immunity that have realized effects on human health and disease interventions. I will largely focus on two research areas. First, I will discuss the population-level interface of human phenology and infectious disease ecology, revealing the seasonal clockwork of epidemics using big demographic and epidemiological data, combined with dynamic models and cutting-edge statistical inference methods. Second, I will detail a clinical study I’m conducting through the NIH Director’s High-Risk High-Reward research program, in which I aim to discover the biological rhythms in human physiology and immunology that contribute to cycles of infection, birth, and mortality, as well as the evolution of rhythms in parasites, and thus may be leveraged by evolutionary medicine.  

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Recent advances in methods for detecting adaptation in protein-coding DNA

Seminar Speaker: Nicolas Rodrigue, PhD

Assistant Professor
Department of Biology
Carleton University, Canada

Abstract: Statistical modelling of the long-term evolution of protein-coding DNA is an active area of research in molecular phylogenetics.  Several recent works have adopted a mutation-selection framework, whereby the substitution process is specified from a set of parameters controlling a point-mutation process, and another set of (potentially site-specific) parameters controlling the probability of fixation of mutations.  We have previously discussed using such a model as "a more relevant background against which to distinguish positive selection" (Rodrigue, Philippe & Lartillot, PNAS, 2010), and have recently used simulations to illustrate the potential of the approach (Rodrigue & Lartillot, MBE, 2017).  This lecture will outline the rationale of such a model, present results of its large-scale applications over several thousand protein-coding genes, and discuss on-going expansions to the mutation-selection framework.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [link]

Download flyer: [pdf]

A deep dive into the methods underlying model-based geostatistics and their application

Speaker: Professor Simon Iain Hay

Professor of Global Health
Director of Geospatial Science, Institute for Health Metrics & Evaluation (IHME)
University of Washington

Abstract: IHME's Director of Geospatial Science, Professor Simon Hay, will provide a deep dive into the methods underlying model-based geostatistics (MBG), particularly in relation to how MBG is being used to estimate (and map) under-5 mortality at a resolution of 5x5 km. He will focus on the types of data and methodological advancements and challenges faced by IHME's Geospatial Analysis team as they seek to produce accurate, spatially-granular estimates of under-5 mortality in 46 countries in sub-Saharan Africa, and eventually in Asia and the Americas. The methods described are also being applied more broadly to undernutrition and priority diseases for childhood survival (diarrhea, lower respiratory infection, and malaria). Additionally, Professor Simon Hay will illustrate the applications of geospatial analysis in assessing progress towards Sustainable Development Goals.

Streaming video: the seminar will be broadcast live once the event has started. The video recording and may also be viewed at a later date. [link]

Download flyer: [pdf]

The Analysis and Control of Zika and Dengue Virus Epidemics

The Zika epidemic has been declared by the World Health Organization to be a “public health emergency of international concern,” and dengue continues to be a global public health menace. Both viruses are spread by the same Aedes mosquito vector, which now exposes nearly half of the world population to these viruses. In addition, Zika can be spread sexually from male-to-female and possibly through other types of direct contact. These epidemics can be controlled through improved vector control and new vaccines. This session describes the statistical and mathematical methods being developed and used to evaluate the effectiveness of these interventions. Based on their potential levels of effectiveness, the panelists will discuss how these interventions may be used to control Zika, dengue, and other arboviruses spread by Aedes now and in the future.

Organizer:  Ira M. Longini Jr., University of Florida
Moderator:  Natalie Dean, University of Florida
Discussant:  Ira M. Longini Jr., University of Florida

Speakers:
Nicholas P. Jewell, University of California, Berkeley
Testing the Efficacy of Wolbachia Against Dengue Virus Transmission With Randomized Trials

M. Elizabeth Halloran, University of Washington
The Design and Analysis of Vaccine Trials for Zika and Dengue

Gonzalo Vazquez-Prokopec, Emory University
Vector Control Approaches for Immediate Response to Zika Outbreaks

Dynamics of arthropod-borne virus evolution during transmission

Seminar Speaker: Nathan D. Grubaugh, PhD

Postdoctoral Fellow
Department of Immunology and Microbial Science
The Scripps Research Institute

Abstract:  Arthropod-borne viruses (arboviruses), such as Zika, chikungunya, and West Nile virus (WNV), pose as continuous threats to emerge and cause large epidemics. Often these events are associated with novel virus variants optimized for local transmission, which first arise as minorities within a host. Thus the conditions that regulate the frequency of intrahost variants are important determinants of emergence. For arboviruses, these conditions are complex as they cycle between the different environments of their arthropod vectors and vertebrate hosts. First, I will describe the forces that alter WNV genetic diversity during transmission. Next, we will explore the fitness costs and benefits of replicating different enzootic mosquito vectors and avian hosts. The general theme is that in mosquitoes, the WNV genetic repertoire dramatically changes due to repeated bottles and to escape the innate immune response, RNA interference. The consequence, however, is that the diversity generated in mosquitoes decreases its fitness in birds, and thus most WNV variants are rapidly purged upon transmission. Lastly, I will compare these results to a tick-borne virus (Powassan virus) to demonstrate how vector ecology can be a determinate of evolution. The results presented here highlight the complex evolutionary forces that a novel arbovirus variant must overcome to alter infection phenotypes at the population level.

Streaming video: the seminar will be broadcast live once the event has started. The video recording may also be viewed at a later date. [video link]

Download flyer: [pdf]

NOTE: This seminar is co-sponsored with the University of Washington Department of Biostatistics.

Confidence densities, uninformative priors, and the bootstrap

Seminar Speaker: Bradley Efron, PhD

Professor of Statistics and Biomedical Data Science
Stanford University

Abstract

There have been a series of conferences around the world under the label "BFF", standing for Bayesian, Frequentist, and Fiducial. I will give a version of the keynote talk at the most recent one. A general problem of BFF interest goes as follows: A family of densities with vector parameter "mu" has yielded data "X", from which the statistician wishes to infera real-valued parameter theta = t(mu). For example X might be multi-variate normal, X~N(m,V), and theta the trace of V. A statistical holy grail task is to find a convincing posterior density of theta given X, when there is no prior information on the distribution of mu. A suite of more or less related answers have been proposed: uninformative priors, matching priors, fiducial methods, and confidence densities (the last being derivatives of confidence distributions.) This talk reviews the various theories, connecting them to bootstrap methods for their implementation.

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The interplay of selective bottlenecks and random chance during avian influenza virus evolution in mammals

SPEAKER: Louise Moncla

PhD Candidate, Department of Pathobiological Sciences,
University of Wisconsin School of Veterinary Medicine

ABSTRACT:

 Zoonotic influenza viruses periodically emerge to cause pandemics. Transmission bottlenecks define the starting genetic material available for onward within-host influenza evolution. However, the relative roles of natural selection, genetic drift and founder effects during influenza transmission are not well understood. It was recently shown that avian influenza virus reassortants resembling the 1918 human pandemic virus can become transmissible among ferrets by acquiring mutations in hemagglutinin (HA) and polymerase. We traced the within-host evolutionary pathway by which this avian-like virus evolved mammalian replication and transmission. During initial infection, within-host HA diversity increased dramatically. The first transmission event was a loose genetic bottleneck, during which 2 polymerase mutations became fixed in the population without conferring a detectable replication advantage. After further evolution, the transmission bottleneck imposed a selective sweep on HA. Intriguingly, our data suggest that the stringency and evolutionary forces governing between-host bottlenecks may change throughout host adaptation. These data unify previous findings from diverse experimental designs and systems that have historically seemed in conflict. To explore this hypothesis, we are developing novel uses for long-read technologies that provide linkage information for all sites across a gene segment. We will use these techniques to dissect within-host influenza population dynamics at a finer scale.

Evolutionary genetics of HCV: from population to patient

SPEAKER: Jeffrey B. Joy, PhD

BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada
Department of Medicine, University of British Columbia, Vancouver, BC, Canada

ABSTRACT:
Hepatitis C virus (HCV) represents a health crisis of global proportions with an estimated 185 million infected persons worldwide including approximately 4.6 million infections of predominantly HCV genotype 1a within North America. Despite the advent of curative HCV therapies many challenges remain at all levels of the epidemic hierarchy. One such challenge concerns resolving the controversy surrounding the timing of the initial spread of hepatitis C genotype 1a in North America. In particular, how and when HCV reached extraordinary prevalence in specific demographic groups has remained unclear. Secondly, natural HCV polymorphisms conferring resistance to direct acting antiviral therapy exist however the frequency of these variants at the population level is uncertain. A third problem facing treatment of HCV particularly in high risk populations is that identification and treatment of individuals with mixed HCV infections (infection with 2 or more distinct viral variants) is challenging and the detection of such mixed infections remains complex. Finally, HCV therapy rapidly leads to undetectable viral load, and consequently the loss of any ability to closely monitor what is happening to the virus in vivo until a patient relapses or achieves sustained virological response. In this talk I will apply evolutionary genetic methods to the abundance of available sequence data at the both the population level and longitudinally within individual patients to contribute to resolving these controversies and problems and provide practical insights into HCV epidemic dynamics at multiple scales. 

Uncovering the properties and limitations of models of sequence evolution

Speaker: Stephanie Spielman, PhD

Institute for Genomics and Evolutionary Medicine
Temple University

ABSTRACT

Natural selection leaves signatures of its activity in DNA. As sequencing increasingly assumes a central role in modern biological research, we have an unprecedented opportunity to elucidate the myriad ways in which evolution shapes the diversity of life's genomes. Most commonly, we study these "fingerprints" of natural selection using statistical models of sequence evolution. In the context of of protein-coding sequence evolution, two popular complementary models have emerged: dN/dS-based models, which measure the relative rate of nonsynonymous to synonymous substitutions, and mutation—selection models, which measure site-specific amino acid propensities (or "fitness") using population genetics principles. Importantly, these models have been constructed and studied independently from one another. As a consequence, it has been entirely unknown whether different models reveal similar or incompatible information about the strength and direction of natural selection, in turn hindering our ability to draw robust conclusions about evolutionary pressures. In this talk, I will discuss how we can bridge this gap by deriving a precise relationship between dN/dS-based and mutation—selection models. I use this relationship to identity previously unappreciated limitations and behaviors of these models. For example, this work reveals that dN/dS inferences in the popular software PAML (codeml) are strongly biased, and further that standard metrics of model selection (AIC and BIC) may be positively misleading. I offer specific recommendations for how to most reliably apply models of protein-coding sequence evolution and interpret their results.

Download flyer: [pdf]
Streaming video: [link]
   (Note: live video link will only be available once seminar has begun. A recording will be posted that may be viewed at a later date.)

Population Genomics of Bacterial Pathogens

Speaker: Kathryn Holt, PhD

NHMRC Career Development Fellow and Associate Professor
Centre for Systems Genomics, University of Melbourne

Abstract:

 Over the last decade, high throughput genome sequencing has revolutionised our ability to investigate and understand bacterial pathogen populations. I have been involved in establishing and applying population genomic frameworks and associated tools to the study of several important pathogens, including typhoid, dysentery and the emerging hospital superbugs Klebsiella pneumoniae and Acinetobacter baumannii . The insights and implications offered by population genomics vary substantially between organisms, but understanding the evolution and spread of antimicrobial resistance is a common and important goal. Here I will highlight some recent insights into the evolution and spread of two highly drug-resistant bacterial pathogens that have very different population structures – SalmonellaTyphi (typhoid) and Klebsiella pneumoniae.

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Exploring the dynamics of influenza virus evolution, selection, and host adaptive immunity

Speaker: Pinky Langat, PhD candidate

Sanger Institute, University of Cambridge, UK

Abstract

 Advances in high-throughput sequencing and phylogenetic approaches have improved our ability to investigate genetic and antigenic variation of influenza viruses and adaptability of host immunity. I will describe studies characterising the genotypic diversity of swine influenza A viruses circulating in Europe, and the global antigenic diversity of swine influenza A viruses using advances in antigenic cartographic models. In addition, to better understand the molecular evolution and epidemiology of influenza B virus on a global scale, we analysed the most comprehensive dataset of whole influenza B virus genomes to date, identifying distinct patterns of antigenic evolution and genome-wide diversity between the two lineages and in different parts of the world. Finally, as part of on-going work to explore how antigenically-variable pathogens shape B cell selection, we isolated naïve and germinal center (GC) B cells from mice challenged with distinct influenza B viruses. By sequencing and analysing B cell receptor repertoires of the GC response to influenza exposure, we can investigate characteristics of B cell selection and affinity maturation to different strains, furthering our potential to study immune adaptability in more detail.

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