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In JoVE (1)
Other Publications (42)
- Journal of Virology
- Health & Place
- Nature
- Science (New York, N.Y.)
- Nature
- Proceedings of the National Academy of Sciences of the United States of America
- Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
- Nature
- International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases
- Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Theoretical Biology
- Journal of the Royal Society, Interface / the Royal Society
- International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases
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- PloS One
- The Lancet Infectious Diseases
- Statistics in Medicine
- PLoS Medicine
- PLoS Medicine
- The New England Journal of Medicine
- PLoS Neglected Tropical Diseases
- Human Genetics
- Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America
- American Journal of Medical Genetics. Part A
- The Journal of Infectious Diseases
- Epidemics
- Journal of Medical Genetics
- Journal of the American Statistical Association
- The American Journal of Tropical Medicine and Hygiene
- PloS One
- The Pediatric Infectious Disease Journal
- Vaccine
- American Journal of Epidemiology
- The American Journal of Tropical Medicine and Hygiene
- Nature Communications
- PLoS Neglected Tropical Diseases
- PLoS Medicine
- PLoS Neglected Tropical Diseases
- Influenza and Other Respiratory Viruses
- Biometrics
- Journal of the Royal Society, Interface / the Royal Society
Articles by Derek Cummings in JoVE
JoVE General
Culture of myeloid dendritic cells from bone marrow precursors
1Medical Sciences Program, McMaster University, 2Centre for Gene Therapeutics, McMaster University, 3Department of Chemical Engineering, University of Waterloo
This video demonstrates the procedure for differentiating myeloid dendritic cells from mouse bone marrow. Isolation of mouse tibia and femur, and processing of bone marrow are demonstrated. Pictures demonstrating cell morphology before and after differentiation, and figures depicting cell phenotype and IL-12 production following maturation using CpG are shown.
Other articles by Derek Cummings on PubMed
Cre Levels Limit Packaging Signal Excision Efficiency in the Cre/loxP Helper-dependent Adenoviral Vector System
Helper-dependent (HD) adenovirus vectors devoid of all viral coding sequences have a large cloning capacity and provide long-term transgene expression in vivo with negligible toxicity, making them attractive vectors for gene therapy. Currently, the most efficient means of producing HD vectors involves coinfecting 293 cells expressing Cre with the HD vector and a helper virus bearing a packaging signal flanked by loxP sites. Cre-mediated packaging signal excision renders the helper virus genome unpackageable but still able to replicate and provide helper functions for HD vector propagation. Typically, helper virus contamination is < or =1% pre- and < or =0.1% postpurification by CsCl banding. While these contamination levels are low, further reduction is desirable. However, this objective has not been realized since the Cre/loxP system was first developed. This lack of progress is due, at least in part, to our lack of understanding of the origins of the contaminating helper virus, thus rendering its reduction or elimination difficult to achieve. This study was designed to investigate the possible sources of contaminating helper virus persisting during HD vector amplification. The results revealed that Cre is limiting in helper virus-infected Cre-expressing 293 cells, thereby permitting helper viruses to escape packaging signal excision and propagate. The results of this study should provide a foundation for developing rational strategies to further reduce or possibly eliminate the contaminating helper virus.
Contacting Your GP when the Surgery is Closed: Issues of Location and Access
This paper examines spatial variation in the delivery of out of hours care through general practice, in two Health Authorities in northwest England. It demonstrates considerable variations in the type of care provided to patients in different parts of the region. These differences are not due primarily to either the geographical or socio-economic characteristics of the areas. Rather, the type of out of hours care delivered depends much more on variations in the structure and organization of service delivery. These factors, in turn, largely reflect the history of service development in each area and the ethos of individual general practitioners instrumental in establishing the service.
Travelling Waves in the Occurrence of Dengue Haemorrhagic Fever in Thailand
Dengue fever is a mosquito-borne virus that infects 50-100 million people each year. Of these infections, 200,000-500,000 occur as the severe, life-threatening form of the disease, dengue haemorrhagic fever (DHF). Large, unanticipated epidemics of DHF often overwhelm health systems. An understanding of the spatial-temporal pattern of DHF incidence would aid the allocation of resources to combat these epidemics. Here we examine the spatial-temporal dynamics of DHF incidence in a data set describing 850,000 infections occurring in 72 provinces of Thailand during the period 1983 to 1997. We use the method of empirical mode decomposition to show the existence of a spatial-temporal travelling wave in the incidence of DHF. We observe this wave in a three-year periodic component of variance, which is thought to reflect host-pathogen population dynamics. The wave emanates from Bangkok, the largest city in Thailand, moving radially at a speed of 148 km per month. This finding provides an important starting point for detecting and characterizing the key processes that contribute to the spatial-temporal dynamics of DHF in Thailand.
Containing Pandemic Influenza at the Source
Highly pathogenic avian influenza A (subtype H5N1) is threatening to cause a human pandemic of potentially devastating proportions. We used a stochastic influenza simulation model for rural Southeast Asia to investigate the effectiveness of targeted antiviral prophylaxis, quarantine, and pre-vaccination in containing an emerging influenza strain at the source. If the basic reproductive number (R0) was below 1.60, our simulations showed that a prepared response with targeted antivirals would have a high probability of containing the disease. In that case, an antiviral agent stockpile on the order of 100,000 to 1 million courses for treatment and prophylaxis would be sufficient. If pre-vaccination occurred, then targeted antiviral prophylaxis could be effective for containing strains with an R0 as high as 2.1. Combinations of targeted antiviral prophylaxis, pre-vaccination, and quarantine could contain strains with an R(0) as high as 2.4.
Strategies for Containing an Emerging Influenza Pandemic in Southeast Asia
Highly pathogenic H5N1 influenza A viruses are now endemic in avian populations in Southeast Asia, and human cases continue to accumulate. Although currently incapable of sustained human-to-human transmission, H5N1 represents a serious pandemic threat owing to the risk of a mutation or reassortment generating a virus with increased transmissibility. Identifying public health interventions that might be able to halt a pandemic in its earliest stages is therefore a priority. Here we use a simulation model of influenza transmission in Southeast Asia to evaluate the potential effectiveness of targeted mass prophylactic use of antiviral drugs as a containment strategy. Other interventions aimed at reducing population contact rates are also examined as reinforcements to an antiviral-based containment policy. We show that elimination of a nascent pandemic may be feasible using a combination of geographically targeted prophylaxis and social distancing measures, if the basic reproduction number of the new virus is below 1.8. We predict that a stockpile of 3 million courses of antiviral drugs should be sufficient for elimination. Policy effectiveness depends critically on how quickly clinical cases are diagnosed and the speed with which antiviral drugs can be distributed.
Dynamic Effects of Antibody-dependent Enhancement on the Fitness of Viruses
Antibody-dependent enhancement (ADE), a phenomenon in which viral replication is increased rather than decreased by immune sera, has been observed in vitro for a large number of viruses of public health importance, including flaviviruses, coronaviruses, and retroviruses. The most striking in vivo example of ADE in humans is dengue hemorrhagic fever, a disease in which ADE is thought to increase the severity of clinical manifestations of dengue virus infection by increasing virus replication. We examine the epidemiological impact of ADE on the prevalence and persistence of viral serotypes. Using a dynamical system model of n cocirculating dengue serotypes, we find that ADE may provide a competitive advantage to those serotypes that undergo enhancement compared with those that do not, and that this advantage increases with increasing numbers of cocirculating serotypes. Paradoxically, there are limits to the selective advantage provided by increasing levels of ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.
Chaotic Desynchronization of Multistrain Diseases
Multistrain diseases are diseases that consist of several strains, or serotypes. The serotypes may interact by antibody-dependent enhancement (ADE), in which infection with a single serotype is asymptomatic, but infection with a second serotype leads to serious illness accompanied by greater infectivity. It has been observed from serotype data of dengue hemorrhagic fever that outbreaks of the four serotypes occur asynchronously. Both autonomous and seasonally driven outbreaks were studied in a model containing ADE. For sufficiently small ADE, the number of infectives of each serotype synchronizes, with outbreaks occurring in phase. When the ADE increases past a threshold, the system becomes chaotic, and infectives of each serotype desynchronize. However, certain groupings of the primary and secondary infectives remain synchronized even in the chaotic regime.
Strategies for Mitigating an Influenza Pandemic
Development of strategies for mitigating the severity of a new influenza pandemic is now a top global public health priority. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine and non-pharmaceutical (case isolation, household quarantine, school or workplace closure, restrictions on travel) measures. Mathematical models are powerful tools for exploring this complex landscape of intervention strategies and quantifying the potential costs and benefits of different options. Here we use a large-scale epidemic simulation to examine intervention options should initial containment of a novel influenza outbreak fail, using Great Britain and the United States as examples. We find that border restrictions and/or internal travel restrictions are unlikely to delay spread by more than 2-3 weeks unless more than 99% effective. School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates, whereas case isolation or household quarantine could have a significant impact, if feasible. Treatment of clinical cases can reduce transmission, but only if antivirals are given within a day of symptoms starting. Given enough drugs for 50% of the population, household-based prophylaxis coupled with reactive school closure could reduce clinical attack rates by 40-50%. More widespread prophylaxis would be even more logistically challenging but might reduce attack rates by over 75%. Vaccine stockpiled in advance of a pandemic could significantly reduce attack rates even if of low efficacy. Estimates of policy effectiveness will change if the characteristics of a future pandemic strain differ substantially from those seen in past pandemics.
Improved Measles Surveillance in Cameroon Reveals Two Major Dynamic Patterns of Incidence
To characterize the province-specific incidence patterns of measles in Cameroon and determine if an increase in measles incidence during the period January 2000-June 2001 is consistent with coincident epidemics in several regions with different inter-epidemic periods.
Individual-based Computational Modeling of Smallpox Epidemic Control Strategies
In response to concerns about possible bioterrorism, the authors developed an individual-based (or "agent-based") computational model of smallpox epidemic transmission and control. The model explicitly represents an "artificial society" of individual human beings, each implemented as a distinct object, or data structure in a computer program. These agents interact locally with one another in code-represented social units such as homes, workplaces, schools, and hospitals. Over many iterations, these microinteractions generate large-scale macroscopic phenomena of fundamental interest such as the course of an epidemic in space and time. Model variables (incubation periods, clinical disease expression, contagiousness, and physical mobility) were assigned following realistic values agreed on by an advisory group of experts on smallpox. Eight response scenarios were evaluated at two epidemic scales, one being an introduction of ten smallpox cases into a 6,000-person town and the other an introduction of 500 smallpox cases into a 50,000-person town. The modeling exercise showed that contact tracing and vaccination of household, workplace, and school contacts, along with prompt reactive vaccination of hospital workers and isolation of diagnosed cases, could contain smallpox at both epidemic scales examined.
The IFN-independent Response to Virus Particle Entry Provides a First Line of Antiviral Defense That is Independent of TLRs and Retinoic Acid-inducible Gene I
The innate immune system responds to pathogen infection by eliciting a nonspecific immune response following the recognition of various pathogen-associated molecular patterns. TLRs and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 recognize foreign nucleic acid within endosomal and cytoplasmic compartments, respectively, initiating a signaling cascade that involves the induction of type I IFN through the transcription factors IFN regulatory factor (IRF) 3 and NF-kappaB. However, a recent paradigm has emerged in which bacterial DNA and double-stranded B-form DNA trigger type I IFN production through an uncharacterized TLR- and RIG-I-independent pathway. We have previously described a response in primary fibroblasts wherein the entry of diverse RNA- and DNA-enveloped virus particles is sufficient to induce a subset of IFN-stimulated genes and a complete antiviral response in an IRF3-dependent, IFN-independent manner. In this study, we show that the innate immune response to virus particle entry is independent of both TLR and RIG-I pathways, confirming the existence of novel innate immune mechanisms that result in the activation of IRF3. Furthermore, we propose a model of innate antiviral immunity in which exposure to increasing numbers of virus particles elevates the complexity of the cellular response from an intracellular, IFN-independent response to one involving secretion of cytokines and activation of infiltrating immune cells.
Instabilities in Multiserotype Disease Models with Antibody-dependent Enhancement
This paper investigates the complex dynamics induced by antibody-dependent enhancement (ADE) in multiserotype disease models. ADE is the increase in viral growth rate in the presence of immunity due to a previous infection of a different serotype. The increased viral growth rate is thought to increase the infectivity of the secondary infectious class. In our models, ADE induces the onset of oscillations without external forcing. The oscillations in the infectious classes represent outbreaks of the disease. In this paper, we derive approximations of the ADE parameter needed to induce oscillations and analyze the associated bifurcations that separate the types of oscillations. We then investigate the stability of these dynamics by adding stochastic perturbations to the model. We also present a preliminary analysis of the effect of a single serotype vaccination in the model.
Transmissibility of Swine Flu at Fort Dix, 1976
The 1976 outbreak of A/New Jersey/76 influenza in Fort Dix is a rare example of an influenza virus with documented human to human transmission that failed to spread widely. Despite extensive epidemiological investigation, no attempt has been made to quantify the transmissibility of this virus. The World Health Organization and the United States Government view containment of emerging influenza strains as central to combating pandemic influenza. Computational models predict that it may be possible to contain an emergent pandemic influenza if virus transmissibility is low. The A/New Jersey/76 outbreak at the United States Army Training Center at Fort Dix, New Jersey in January 1976 caused 13 hospitalizations, 1 death and an estimated 230 cases. To characterize viral transmission in this epidemic, we estimated the basic reproductive number and serial interval using deterministic epidemic models and stochastic simulations. We estimated the basic reproductive number for this outbreak to be 1.2 (supported interval 1.1-1.4), the serial interval to be 1.9 days (supported interval 1.6-3.8 days), and that the virus had at least six serial human to human transmissions. This places the transmissibility of A/New Jersey/76 virus at the lower end of circulating flu strains, well below the threshold for control.
Containing a Large Bioterrorist Smallpox Attack: a Computer Simulation Approach
A bioterrorist release of smallpox is a constant threat to the population of the USA and other countries.
Modeling Targeted Layered Containment of an Influenza Pandemic in the United States
Planning a response to an outbreak of a pandemic strain of influenza is a high public health priority. Three research groups using different individual-based, stochastic simulation models have examined the consequences of intervention strategies chosen in consultation with U.S. public health workers. The first goal is to simulate the effectiveness of a set of potentially feasible intervention strategies. Combinations called targeted layered containment (TLC) of influenza antiviral treatment and prophylaxis and nonpharmaceutical interventions of quarantine, isolation, school closure, community social distancing, and workplace social distancing are considered. The second goal is to examine the robustness of the results to model assumptions. The comparisons focus on a pandemic outbreak in a population similar to that of Chicago, with approximately 8.6 million people. The simulations suggest that at the expected transmissibility of a pandemic strain, timely implementation of a combination of targeted household antiviral prophylaxis, and social distancing measures could substantially lower the illness attack rate before a highly efficacious vaccine could become available. Timely initiation of measures and school closure play important roles. Because of the current lack of data on which to base such models, further field research is recommended to learn more about the sources of transmission and the effectiveness of social distancing measures in reducing influenza transmission.
Coupled Contagion Dynamics of Fear and Disease: Mathematical and Computational Explorations
In classical mathematical epidemiology, individuals do not adapt their contact behavior during epidemics. They do not endogenously engage, for example, in social distancing based on fear. Yet, adaptive behavior is well-documented in true epidemics. We explore the effect of including such behavior in models of epidemic dynamics.
Incubation Periods of Acute Respiratory Viral Infections: a Systematic Review
Knowledge of the incubation period is essential in the investigation and control of infectious disease, but statements of incubation period are often poorly referenced, inconsistent, or based on limited data. In a systematic review of the literature on nine respiratory viral infections of public-health importance, we identified 436 articles with statements of incubation period and 38 with data for pooled analysis. We fitted a log-normal distribution to pooled data and found the median incubation period to be 5.6 days (95% CI 4.8-6.3) for adenovirus, 3.2 days (95% CI 2.8-3.7) for human coronavirus, 4.0 days (95% CI 3.6-4.4) for severe acute respiratory syndrome coronavirus, 1.4 days (95% CI 1.3-1.5) for influenza A, 0.6 days (95% CI 0.5-0.6) for influenza B, 12.5 days (95% CI 11.8-13.3) for measles, 2.6 days (95% CI 2.1-3.1) for parainfluenza, 4.4 days (95% CI 3.9-4.9) for respiratory syncytial virus, and 1.9 days (95% CI 1.4-2.4) for rhinovirus. When using the incubation period, it is important to consider its full distribution: the right tail for quarantine policy, the central regions for likely times and sources of infection, and the full distribution for models used in pandemic planning. Our estimates combine published data to give the detail necessary for these and other applications.
Estimating Incubation Period Distributions with Coarse Data
The incubation period, the time between infection and disease onset, is important in the surveillance and control of infectious diseases but is often coarsely observed. Coarse data arises because the time of infection, the time of disease onset or both are not known precisely. Accurate estimates of an incubation period distribution are useful in real-time outbreak investigations and in modeling public health interventions. We compare two methods of estimating such distributions. The first method represents the data as doubly interval-censored. The second introduces a data reduction technique that makes the computation more tractable. In a simulation study, the methods perform similarly when estimating the median, but the first method yields more reliable estimates of the distributional tails. We conduct a sensitivity analysis of the two methods to violations of model assumption and we apply these methods to historical incubation period data on influenza A and respiratory syncytial virus. The analysis of reduced data is less computationally intensive and performs well for estimating the median under a wide range of conditions. However for estimation of the tails of the distribution, the doubly interval-censored analysis is the recommended procedure.
The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling
An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics.
Multiyear Climate Variability and Dengue--El Niño Southern Oscillation, Weather, and Dengue Incidence in Puerto Rico, Mexico, and Thailand: a Longitudinal Data Analysis
The mosquito-borne dengue viruses are a major public health problem throughout the tropical and subtropical regions of the world. Changes in temperature and precipitation have well-defined roles in the transmission cycle and may thus play a role in changing incidence levels. The El Niño Southern Oscillation (ENSO) is a multiyear climate driver of local temperature and precipitation worldwide. Previous studies have reported varying degrees of association between ENSO and dengue incidence.
Outbreak of 2009 Pandemic Influenza A (H1N1) at a New York City School
In April 2009, an outbreak of novel swine-origin influenza A (2009 H1N1 influenza) occurred at a high school in Queens, New York. We describe the outbreak and characterize the clinical and epidemiologic aspects of this novel virus.
Serotype-specific Differences in the Risk of Dengue Hemorrhagic Fever: an Analysis of Data Collected in Bangkok, Thailand from 1994 to 2006
It is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention in Bangkok, Thailand.
Evidence for Inheritance in Patients with VACTERL Association
VACTERL/VATER association is typically a sporadic disorder. We present data on inheritance in 78 probands with VACTERL association, and show that 9% of probands have a primary relative with at least one component feature of VACTERL association. The prevalence of component features in first-degree relatives is significantly higher than expected in the general population, which has implications for counseling of affected families and for research into possible etiologies.
Identifying the Probable Timing and Setting of Respiratory Virus Infections
Show how detailed incubation period estimates can be used to identify and investigate potential healthcare-associated infections and dangerous diseases.
Analysis of Component Findings in 79 Patients Diagnosed with VACTERL Association
VACTERL association is a relatively common condition, though the causes remain poorly understood. We present data on 79 patients diagnosed with VACTERL association and perform statistical analysis on a selected subset of 60 patients with at least three component features, and who, after review, did not meet criteria for a likely alternate diagnosis. Considered individually, no two component features are significantly associated, but several multivariate statistical techniques suggest novel patterns of the co-occurrence of component features, and latent class cluster analysis demonstrates the presence of five major subgroups of patients. These findings have implications for both our understanding of VACTERL association and for the approach to research involving this condition.
Inferring the Serotype Associated with Dengue Virus Infections on the Basis of Pre- and Postinfection Neutralizing Antibody Titers
Currently, the only tests capable of determining the serotype associated with dengue virus (DENV) infection require sampling during the period of acute viremia. No test can accurately detect the serotype associated with past DENV infections. The standard assay for determination of serotype-specific antibody against DENV is the plaque reduction neutralization test (PRNT), although performance of this test continues to be evaluated.
H1N1pdm in the Americas
In late April 2009 the emergence of 2009 pandemic influenza A (H1N1pdm) virus was detected in humans. From its detection through July 18th, 2009, confirmed cases of H1N1pdm in the Americas were periodically reported to the Pan American Health Organization (PAHO) by member states. Because the Americas span much of the world's latitudes, this data provides an excellent opportunity to examine variation in H1N1pdm transmission by season. Using reports from PAHO member states from April 26th, 2009 through July 18th, 2009, we characterize the early spread of the H1N1 pandemic in the Americas. For a geographically representative sample of member states we estimate the reproductive number (R) of H1N1pdm over the reporting period. The association between these estimates and latitude, temperature, humidity and population age structure was estimated. Estimates of the peak reproductive number of H1N1pdm ranged from 1.3 (for Panama, Colombia) to 2.1 (for Chile). We found that reproductive number estimates were most associated with latitude in both univariate and multivariate analyses. To the extent that latitude is a proxy for seasonal changes in climate and behavior, this association suggests a strong seasonal component to H1N1pdm transmission. However, the reasons for this seasonality remain unclear.
Mutations in ZIC2 in Human Holoprosencephaly: Description of a Novel ZIC2 Specific Phenotype and Comprehensive Analysis of 157 Individuals
Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE.
Modeling Competing Infectious Pathogens from a Bayesian Perspective: Application to Influenza Studies with Incomplete Laboratory Results
In seasonal influenza epidemics, pathogens such as respiratory syncytial virus (RSV) often co-circulate with influenza and cause influenza-like illness (ILI) in human hosts. However, it is often impractical to test for each potential pathogen or to collect specimens for each observed ILI episode, making inference about influenza transmission difficult. In the setting of infectious diseases, missing outcomes impose a particular challenge because of the dependence among individuals. We propose a Bayesian competing-risk model for multiple co-circulating pathogens for inference on transmissibility and intervention efficacies under the assumption that missingness in the biological confirmation of the pathogen is ignorable. Simulation studies indicate a reasonable performance of the proposed model even if the number of potential pathogens is misspecified. They also show that a moderate amount of missing laboratory test results has only a small impact on inference about key parameters in the setting of close contact groups. Using the proposed model, we found that a non-pharmaceutical intervention is marginally protective against transmission of influenza A in a study conducted in elementary schools.
Economic Value of Dengue Vaccine in Thailand
With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1× per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3× per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving.
Visualizing Clinical Evidence: Citation Networks for the Incubation Periods of Respiratory Viral Infections
Simply by repetition, medical facts can become enshrined as truth even when there is little empirical evidence supporting them. We present an intuitive and clear visual design for tracking the citation history of a particular scientific fact over time. We apply this method to data from a previously published literature review on the incubation period of nine respiratory viral infections. The resulting citation networks reveal that the conventional wisdom about the incubation period for these diseases was based on a small fraction of available data and in one case, on no retrievable empirical evidence. Overall, 50% of all incubation period statements did not provide a source for their estimate and 65% of original sources for incubation period data were not incorporated into subsequent publications. More standardized and widely available methods for visualizing these histories of medical evidence are needed to ensure that conventional wisdom cannot stray too far from empirically supported knowledge.
Reduction in the Incidence of Influenza A but Not Influenza B Associated with Use of Hand Sanitizer and Cough Hygiene in Schools: a Randomized Controlled Trial
Laboratory-based evidence is lacking regarding the efficacy of nonpharmaceutical interventions (NPIs) such as alcohol-based hand sanitizer and respiratory hygiene to reduce the spread of influenza.
Models of the Impact of Dengue Vaccines: a Review of Current Research and Potential Approaches
Vaccination reduces transmission of pathogens directly, by preventing individual infections, and indirectly, by reducing the probability of contact between infected individuals and susceptible ones. The potential combined impact of future dengue vaccines can be estimated using mathematical models of transmission. However, there is considerable uncertainty in the structure of models that accurately represent dengue transmission dynamics. Here, we review models that could be used to assess the impact of future dengue immunization programmes. We also review approaches that have been used to validate and parameterize models. A key parameter of all approaches is the basic reproduction number, R(0), which can be used to determine the critical vaccination fraction to eliminate transmission. We review several methods that have been used to estimate this quantity. Finally, we discuss the characteristics of dengue vaccines that must be estimated to accurately assess their potential impact on dengue virus transmission.
Influenza Transmission in Households During the 1918 Pandemic
Analysis of historical data has strongly shaped our understanding of the epidemiology of pandemic influenza and informs analysis of current and future epidemics. Here, the authors analyzed previously unpublished documents from a large household survey of the "Spanish" H1N1 influenza pandemic, conducted in 1918, for the first time quantifying influenza transmissibility at the person-to-person level during that most lethal of pandemics. The authors estimated a low probability of person-to-person transmission relative to comparable estimates from seasonal influenza and other directly transmitted infections but similar to recent estimates from the 2009 H1N1 pandemic. The authors estimated a very low probability of asymptomatic infection, a previously unknown parameter for this pandemic, consistent with an unusually virulent virus. The authors estimated a high frequency of prior immunity that they attributed to a largely unreported influenza epidemic in the spring of 1918 (or perhaps to cross-reactive immunity). Extrapolating from this finding, the authors hypothesize that prior immunity partially protected some populations from the worst of the fall pandemic and helps explain differences in attack rates between populations. Together, these analyses demonstrate that the 1918 influenza virus, though highly virulent, was only moderately transmissible and thus in a modern context would be considered controllable.
Decay and Persistence of Maternal Dengue Antibodies Among Infants in Bangkok
Abstract. Maternal dengue antibodies are important in determining the optimal age of dengue vaccination, but no study has quantified the heterogeneity of antibody decay and persistence in infants. We used longitudinal regression methods and survival analysis to measure decay and persistence times of serotype-specific neutralizing antibodies in 139 infants in Bangkok. A biphasic decay pattern was found with half-life times of 24-29 days between birth and 3 months and 44-150 days after 3 months. Atypical decay rates were found in 17% of infants for dengue virus-1 and -4. Median persistence times of plaque reduction neutralization tests > 10 ranged from 6 to 9 months. Persistence times for individuals could not be predicted based on antibody values at birth. Vaccination against dengue before 12 months of age would be ineffective if maternal antibodies at plaque reduction neutralization test levels below 80 interfere with vaccine uptake. Projections of average antibody persistence based on values at birth should be avoided in studies on dengue pathogenesis in infants.
Location-specific Patterns of Exposure to Recent Pre-pandemic Strains of Influenza A in Southern China
Variation in influenza incidence between locations is commonly observed on large spatial scales. It is unclear whether such variation occurs on smaller spatial scales and whether it is the result of heterogeneities in population demographics or more subtle differences in population structure and connectivity. Here we show that significant differences in immunity to influenza A viruses among communities in China are not explained by differences in population demographics. We randomly selected households from five randomly selected locations near Guangzhou, China to answer a questionnaire and provide a blood sample for serological testing against five recently circulating influenza viruses. We find a significant reduction in the frequency of detectable neutralization titers with increasing age, levelling off in older age groups. There are significant differences between locations in age, employment status, vaccination history, household size and housing conditions. However, after adjustment, significant variations in the frequency of detectable neutralization titers persists between locations. These results suggest there are characteristics of communities that drive influenza transmission dynamics apart from individual and household level risk factors, and that such factors have effects independent of strain.
Prediction of Dengue Incidence Using Search Query Surveillance
The use of internet search data has been demonstrated to be effective at predicting influenza incidence. This approach may be more successful for dengue which has large variation in annual incidence and a more distinctive clinical presentation and mode of transmission.
Measuring the Performance of Vaccination Programs Using Cross-sectional Surveys: a Likelihood Framework and Retrospective Analysis
The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generally inconsistent with the proportion found to be vaccinated in Demographic and Health Surveys (DHS). We describe a method that estimates the fraction of the population accessible to vaccination activities, as well as within-campaign inefficiencies, thus providing a consistent estimate of vaccination coverage.
From Re-emergence to Hyperendemicity: the Natural History of the Dengue Epidemic in Brazil
dengue virus (DENV) was reintroduced into Brazil in 1986 and by 1995 it had spread throughout the country. In 2007 the number of dengue hemorrhagic fever (DHF) cases more than doubled and a shift in the age distribution was reported. While previously the majority of DHF cases occurred among adults, in 2007 53% of cases occurred in children under 15 years old. The reasons for this shift have not been determined.
Sensitivity and Specificity of Rapid Influenza Testing of Children in a Community Setting
Rapid influenza testing (RFT) allows for a rapid point-of-care diagnosis of influenza. The Quidel QuickVue Influenza A+B test (QuickVue) has a reported manufacturer's sensitivity and specificity of 73% and 96%, respectively, with nasal swabs. However, investigators have shown sensitivities ranging from 22% to 77% in community settings.
Estimating Absolute and Relative Case Fatality Ratios from Infectious Disease Surveillance Data
Summary Knowing which populations are most at risk for severe outcomes from an emerging infectious disease is crucial in deciding the optimal allocation of resources during an outbreak response. The case fatality ratio (CFR) is the fraction of cases that die after contracting a disease. The relative CFR is the factor by which the case fatality in one group is greater or less than that in a second group. Incomplete reporting of the number of infected individuals, both recovered and dead, can lead to biased estimates of the CFR. We define conditions under which the CFR and the relative CFR are identifiable. Furthermore, we propose an estimator for the relative CFR that controls for time-varying reporting rates. We generalize our methods to account for elapsed time between infection and death. To demonstrate the new methodology, we use data from the 1918 influenza pandemic to estimate relative CFRs between counties in Maryland. A simulation study evaluates the performance of the methods in outbreak scenarios. An R software package makes the methods and data presented here freely available. Our work highlights the limitations and challenges associated with estimating absolute and relative CFRs in practice. However, in certain situations, the methods presented here can help identify vulnerable subpopulations early in an outbreak of an emerging pathogen such as pandemic influenza.
A Nonlinear Programming Approach for Estimation of Transmission Parameters in Childhood Infectious Disease Using a Continuous Time Model
Mathematical models can enhance our understanding of childhood infectious disease dynamics, but these models depend on appropriate parameter values that are often unknown and must be estimated from disease case data. In this paper, we develop a framework for efficient estimation of childhood infectious disease models with seasonal transmission parameters using continuous differential equations containing model and measurement noise. The problem is formulated using the simultaneous approach where all state variables are discretized, and the discretized differential equations are included as constraints, giving a large-scale algebraic nonlinear programming problem that is solved using a nonlinear primal-dual interior-point solver. The technique is demonstrated using measles case data from three different locations having different school holiday schedules, and our estimates of the seasonality of the transmission parameter show strong correlation to school term holidays. Our approach gives dramatic efficiency gains, showing a 40-400-fold reduction in solution time over other published methods. While our approach has an increased susceptibility to bias over techniques that integrate over the entire unknown state-space, a detailed simulation study shows no evidence of bias. Furthermore, the computational efficiency of our approach allows for investigation of a large model space compared with more computationally intensive approaches.
