Environmental Surveillance System Characteristics and Impacts on Confidence About No Undetected Serotype 1 Wild Poliovirus Circulation

Surveillance for poliovirus during the polio endgame remains uncertain. Building on prior modeling of the potential for undetected poliovirus transmission for conditions like those in Pakistan and Afghanistan, we use a hypothetical model to explore several key characteristics of the poliovirus environmental surveillance (ES) system (e.g., number and quality of sites, catchment sizes, and sampling frequency) and characterize their impacts on the time required to reach high (i.e., 95%) confidence about no circulation (CNC95%) following the last detected case of serotype 1 wild poliovirus. The nature and quality of the existing and future acute flaccid paralysis (AFP) surveillance and ES system significantly impact the estimated CNC95% for places like Pakistan and Afghanistan. The analysis illustrates the tradeoffs between number of sites, sampling frequency, and catchments sizes, and suggests diminishing returns of increasing these three factors beyond a point that depends on site quality and the location of sites. Limitations in data quality and the hypothetical nature of the model reduce the ability to assess the extent to which actual ES systems offer benefits that exceed their costs. Thus, although poliovirus ES may help to reduce the time required to reach high confidence about the absence of undetected circulation, the effect strongly depends on the ability to establish effective ES sites in high‐risk areas. The costs and benefits of ES require further analysis.     

Evaluation of Proactive and Reactive Strategies for Polio Eradication Activities in Pakistan and Afghanistan

Only Pakistan and Afghanistan reported any polio cases caused by serotype 1 wild polioviruses (WPV1s) in 2017. With the dwindling cases in both countries and pressure to finish eradication with the least possible resources, a danger exists of inappropriate prioritization of efforts between the two countries and insufficient investment in the two countries to finish the job. We used an existing differential‐equation‐based poliovirus transmission and oral poliovirus (OPV) evolution model to simulate a proactive strategy to stop transmission, and different hypothetical reactive strategies that adapt the quality of supplemental immunization activities (SIAs) in response to observed polio cases in Pakistan and Afghanistan. To account for the delay in perception and adaptation, we related the coverage of the SIAs in high‐risk, undervaccinated subpopulations to the perceived (i.e., smoothed) polio incidence. Continuation of the current frequency and quality of SIAs remains insufficient to eradicate WPV1 in Pakistan and Afghanistan. Proactive strategies that significantly improve and sustain SIA quality lead to WPV1 eradication and the prevention of circulating vaccine‐derived poliovirus (cVDPV) outbreaks. Reactive vaccination efforts that adapt moderately quickly and independently to changes in polio incidence in each country may succeed in WPV1 interruption after several cycles of outbreaks, or may interrupt WPV1 transmission in one country but subsequently import WPV1 from the other country or enable the emergence of cVDPV outbreaks. Reactive vaccination efforts that adapt independently and either more rapidly or more slowly to changes in polio incidence in each country may similarly fail to interrupt WPV1 transmission and result in oscillations of the incidence. Reactive strategies that divert resources to the country of highest priority may lead to alternating large outbreaks. Achieving WPV1 eradication and subsequent successful OPV cessation in Pakistan and Afghanistan requires proactive and sustained efforts to improve vaccination intensity in under‐vaccinated subpopulations while maintaining high population immunity elsewhere.     

Modeling Poliovirus Transmission in Pakistan and Afghanistan to Inform Vaccination Strategies in Undervaccinated Subpopulations

Due to security, access, and programmatic challenges in areas of Pakistan and Afghanistan, both countries continue to sustain indigenous wild poliovirus (WPV) transmission and threaten the success of global polio eradication and oral poliovirus vaccine (OPV) cessation. We fitted an existing differential‐equation‐based poliovirus transmission and OPV evolution model to Pakistan and Afghanistan using four subpopulations to characterize the well‐vaccinated and undervaccinated subpopulations in each country. We explored retrospective and prospective scenarios for using inactivated poliovirus vaccine (IPV) in routine immunization or supplemental immunization activities (SIAs). The undervaccinated subpopulations sustain the circulation of serotype 1 WPV and serotype 2 circulating vaccine‐derived poliovirus. We find a moderate impact of past IPV use on polio incidence and population immunity to transmission mainly due to (1) the boosting effect of IPV for individuals with preexisting immunity from a live poliovirus infection and (2) the effect of IPV‐only on oropharyngeal transmission for individuals without preexisting immunity from a live poliovirus infection. Future IPV use may similarly yield moderate benefits, particularly if access to undervaccinated subpopulations dramatically improves. However, OPV provides a much greater impact on transmission and the incremental benefit of IPV in addition to OPV remains limited. This study suggests that despite the moderate effect of using IPV in SIAs, using OPV in SIAs remains the most effective means to stop transmission, while limited IPV resources should prioritize IPV use in routine immunization.     

Modeling Undetected Live Poliovirus Circulation After Apparent Interruption of Transmission: Pakistan and Afghanistan

Since most poliovirus infections occur with no paralytic symptoms, the possibility of silent circulation complicates the confirmation of the end of poliovirus transmission. Based on empirical field experience and theoretical modeling results, the Global Polio Eradication Initiative identified three years without observing paralytic cases from wild polioviruses with good acute flaccid paralysis surveillance as an indication of sufficient confidence that poliovirus circulation stopped. The complexities of real populations and the imperfect nature of real surveillance systems subsequently demonstrated the importance of specific modeling for areas at high risk of undetected circulation, resulting in varying periods of time required to obtain the same level of confidence about no undetected circulation. Using a poliovirus transmission model that accounts for variability in transmissibility and neurovirulence for different poliovirus serotypes and characterizes country‐specific factors (e.g., vaccination and surveillance activities, demographics) related to wild and vaccine‐derived poliovirus transmission in Pakistan and Afghanistan, we consider the probability of undetected poliovirus circulation for those countries once apparent die‐out occurs (i.e., in the absence of any epidemiological signals). We find that gaps in poliovirus surveillance or reaching elimination with borderline sufficient population immunity could significantly increase the time to reach high confidence about interruption of live poliovirus transmission, such that the path taken to achieve and maintain poliovirus elimination matters. Pakistan and Afghanistan will need to sustain high‐quality surveillance for polioviruses after apparent interruption of transmission and recognize that as efforts to identify cases or circulating live polioviruses decrease, the risks of undetected circulation increase and significantly delay the global polio endgame.     

Modeling Population Immunity to Support Efforts to End the Transmission of Live Polioviruses

Eradication of wild poliovirus (WPV) types 1 and 3, prevention and cessation of circulating vaccine‐derived polioviruses, and achievement and maintenance of a world free of paralytic polio cases requires active risk management by focusing on population immunity and coordinated cessation of oral poliovirus vaccine (OPV). We suggest the need for a complementary and different conceptual approach to achieve eradication compared to the current case‐based approach using surveillance for acute flaccid paralysis (AFP) to identify symptomatic poliovirus infections. Specifically, we describe a modeling approach to characterize overall population immunity to poliovirus transmission. The approach deals with the realities that exposure to live polioviruses (e.g., WPV, OPV) and/or vaccination with inactivated poliovirus vaccine provides protection from paralytic polio (i.e., disease), but does not eliminate the potential for reinfection or asymptomatic participation in poliovirus transmission, which may increase with time because of waning immunity. The AFP surveillance system provides evidence of symptomatic poliovirus infections detected, which indicate immunity gaps after outbreaks occur, and this system represents an appropriate focus for controlling disease outbreaks. We describe a conceptual dynamic model to characterize population immunity to poliovirus transmission that helps identify risks created by immunity gaps before outbreaks occur, which provides an opportunity for national and global policymakers to manage the risk of poliovirus and prevent outbreaks before they occur. We suggest that dynamically modeling risk represents an essential tool as the number of cases approaches zero.     

Poliovirus Surveillance by Examining Sewage Water Specimens: Studies on Detection Probability Using Simulation Models

Efficiency of environmental surveillance of poliovirus circulation was studied using simulation models. First, three transmission models were defined for describing different scenarios of poliovirus infections in a large unstructured population. Second, environmental factors, such as the total volume of the sewage network and losses of viruses, were modeled for computing the virus output at the sewage sampling site. Third, the effect of sampling and laboratory procedures was accounted for in the probability of detection, given the amount of polioviruses in a specimen. The simulation model can be used for theoretical assessments of the likely efficiency of environmental surveillance, compared with acute flaccid paralysis (AFP) surveillance. Under reasonable assumptions in a vaccinated population, the AFP surveillance can be outperformed if the poliovirus outbreak is not large. However, this depends on the assumed case-to-infection ratio and on the sampling frequency of the sewage water specimens. Increasing the latter will lead to a higher detection probability, which will further enhance the method based on environmental surveillance.     

World Health Organization Regional Assessments of the Risks of Poliovirus Outbreaks

While global polio eradication requires tremendous efforts in countries where wild polioviruses (WPVs) circulate, numerous outbreaks have occurred following WPV importation into previously polio‐free countries. Countries that have interrupted endemic WPV transmission should continue to conduct routine risk assessments and implement mitigation activities to maintain their polio‐free status as long as wild poliovirus circulates anywhere in the world. This article reviews the methods used by World Health Organization (WHO) regional offices to qualitatively assess risk of WPV outbreaks following an importation. We describe the strengths and weaknesses of various risk assessment approaches, and opportunities to harmonize approaches. These qualitative assessments broadly categorize risk as high, medium, or low using available national information related to susceptibility, the ability to rapidly detect WPV, and other population or program factors that influence transmission, which the regions characterize using polio vaccination coverage, surveillance data, and other indicators (e.g., sanitation), respectively. Data quality and adequacy represent a challenge in all regions. WHO regions differ with respect to the methods, processes, cut‐off values, and weighting used, which limits comparisons of risk assessment results among regions. Ongoing evaluation of indicators within regions and further harmonization of methods between regions are needed to effectively plan risk mitigation activities in a setting of finite resources for funding and continued WPV circulation.     

Preeradication Vaccine Policy Options for Poliovirus Infection and Disease Control

With the circulation of wild poliovirus (WPV) types 1 and 3 continuing more than a decade after the original goal of eradicating all three types of WPVs by 2000, policymakers consider many immunization options as they strive to stop transmission in the remaining endemic and outbreak areas and prevent reintroductions of live polioviruses into nonendemic areas. While polio vaccination choices may appear simple, our analysis of current options shows remarkable complexity. We offer important context for current and future polio vaccine decisions and policy analyses by developing decision trees that clearly identify potential options currently used by countries as they evaluate national polio vaccine choices. Based on a comprehensive review of the literature we (1) identify the current vaccination options that national health leaders consider for polio vaccination, (2) characterize current practices and factors that appear to influence national and international choices, and (3) assess the evidence of vaccine effectiveness considering sources of variability between countries and uncertainties associated with limitations of the data. With low numbers of cases occurring globally, the management of polio risks might seem like a relatively low priority, but stopping live poliovirus circulation requires making proactive and intentional choices to manage population immunity in the remaining endemic areas and to prevent reestablishment in nonendemic areas. Our analysis shows remarkable variability in the current national polio vaccine product choices and schedules, with combination vaccine options containing inactivated poliovirus vaccine and different formulations of oral poliovirus vaccine making choices increasingly difficult for national health leaders.     

Expert Review on Poliovirus Immunity and Transmission

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.S. Centers for Disease Control and Prevention hosted a meeting of international experts in April 2010 to review the available literature relevant to poliovirus immunity and transmission. This expert review evaluates 66 OPV challenge studies and other evidence to support the development of quantitative models of poliovirus transmission and potential outbreaks. This review focuses on characterization of immunity as a function of exposure history in terms of susceptibility to excretion, duration of excretion, and concentration of excreted virus. We also discuss the evidence of waning of host immunity to poliovirus transmission, the relationship between the concentration of poliovirus excreted and infectiousness, the importance of different transmission routes, and the differences in transmissibility between OPV and WPV. We discuss the limitations of the available evidence for use in polio risk models, and conclude that despite the relatively large number of studies on immunity, very limited data exist to directly support quantification of model inputs related to transmission. Given the limitations in the evidence, we identify the need for expert input to derive quantitative model inputs from the existing data.     

The Costs of Future Polio Risk Management Policies

Decisionmakers need information about the anticipated future costs of maintaining polio eradication as a function of the policy options under consideration. Given the large portfolio of options, we reviewed and synthesized the existing cost data relevant to current policies to provide context for future policies. We model the expected future costs of different strategies for continued vaccination, surveillance, and other costs that require significant potential resource commitments. We estimate the costs of different potential policy portfolios for low-, middle-, and high-income countries to demonstrate the variability in these costs. We estimate that a global transition from routine immunization with oral poliovirus vaccine (OPV) to inactivated poliovirus vaccine (IPV) would increase the costs of managing polio globally, although routine IPV use remains less costly than routine OPV use with supplemental immunization activities. The costs of surveillance and a stockpile, while small compared to routine vaccination costs, represent important expenditures to ensure adequate response to potential outbreaks. The uncertainty and sensitivity analyses highlight important uncertainty in the aggregated costs and demonstrates that the discount rate and uncertainty in price and administration cost of IPV drives the expected incremental cost of routine IPV vs. OPV immunization.     

Characterizing Poliovirus Transmission and Evolution: Insights from Modeling Experiences with Wild and Vaccine‐Related Polioviruses

With national and global health policymakers facing numerous complex decisions related to achieving and maintaining polio eradication, we expanded our previously developed dynamic poliovirus transmission model using information from an expert literature review process and including additional immunity states and the evolution of oral poliovirus vaccine (OPV). The model explicitly considers serotype differences and distinguishes fecal‐oral and oropharyngeal transmission. We evaluated the model by simulating diverse historical experiences with polioviruses, including one country that eliminated wild poliovirus using both OPV and inactivated poliovirus vaccine (IPV) (USA), three importation outbreaks of wild poliovirus (Albania, the Netherlands, Tajikistan), one situation in which no circulating vaccine‐derived polioviruses (cVDPVs) emerge despite annual OPV use and cessation (Cuba), three cVDPV outbreaks (Haiti, Madura Island in Indonesia, northern Nigeria), one area of current endemic circulation of all three serotypes (northern Nigeria), and one area with recent endemic circulation and subsequent elimination of multiple serotypes (northern India). We find that when sufficient information about the conditions exists, the model can reproduce the general behavior of poliovirus transmission and outbreaks while maintaining consistency in the generic model inputs. The assumption of spatially homogeneous mixing remains a significant limitation that affects the performance of the differential equation‐based model when significant heterogeneities in immunity and mixing may exist. Further studies on OPV virus evolution and improved understanding of the mechanisms of mixing and transmission may help to better characterize poliovirus transmission in populations. Broad application of the model promises to offer insights in the context of global and national policy and economic models.     

Review and Assessment of Poliovirus Immunity and Transmission: Synthesis of Knowledge Gaps and Identification of Research Needs

With the intensifying global efforts to eradicate wild polioviruses, policymakers face complex decisions related to achieving eradication and managing posteradication risks. These decisions and the expanding use of inactivated poliovirus vaccine (IPV) trigger renewed interest in poliovirus immunity, particularly the role of mucosal immunity in the transmission of polioviruses. Sustained high population immunity to poliovirus transmission represents a key prerequisite to eradication, but poliovirus immunity and transmission remain poorly understood despite decades of studies. In April 2010, the U.S. Centers for Disease Control and Prevention convened an international group of experts on poliovirus immunology and virology to review the literature relevant for modeling poliovirus transmission, develop a consensus about related uncertainties, and identify research needs. This article synthesizes the quantitative assessments and research needs identified during the process. Limitations in the evidence from oral poliovirus vaccine (OPV) challenge studies and other relevant data led to differences in expert assessments, indicating the need for additional data, particularly in several priority areas for research: (1) the ability of IPV‐induced immunity to prevent or reduce excretion and affect transmission, (2) the impact of waning immunity on the probability and extent of poliovirus excretion, (3) the relationship between the concentration of poliovirus excreted and infectiousness to others in different settings, and (4) the relative role of fecal‐oral versus oropharyngeal transmission. This assessment of current knowledge supports the immediate conduct of additional studies to address the gaps.     

Perspective: Determinants of the Severity of Poliovirus Outbreaks in the Post Eradication Era

The potential consequences of the reintroduction of poliovirus in the post-eradication era range from trivial (no or self-limited transmission and no clinical cases) to very serious (return of continued transmission of polioviruses and abandonment of the poliomyelitis eradication goal). This paper summarises the key determinants of such outcomes and identifies factors relating to infection surveillance, to vaccination policies at the time of OPV cessation and beyond, and to the still-unknown implications of these policies for infection transmission in environments with poor sanitation, as particularly important. Explicit consideration of these issues should encourage studies on the effectiveness of IPV vaccines in reducing poliovirus transmission in tropical environments, and should influence the location and containment requirements of facilities for vaccine production and storage, and for poliovirus-related research, in the era after cessation of OPV.     

Evaluation of Response Scenarios to Potential Polio Outbreaks Using Mathematical Models

Appropriate response to polio outbreaks represents an important prerequisite for achieving and maintaining global polio eradication. We use an existing dynamic disease transmission model to evaluate the impact of different aspects of immunization campaigns in response to polio outbreaks occurring in previously polio-free areas. This analysis yields several important insights about response strategies. We find that delay in response represents a crucial risk factor for occurrence of large outbreaks and we characterize the tradeoffs associated with delaying the initial response to achieve better population coverage. We also demonstrate that controlling most potential outbreaks will likely require at least three immunization rounds, although the impact of the optimal interval between rounds varies. Finally, long after oral poliovirus vaccine cessation the choice of target age groups during a response represents an important consideration.     

Oral Poliovirus Vaccine Evolution and Insights Relevant to Modeling the Risks of Circulating Vaccine‐Derived Polioviruses (cVDPVs)

The live, attenuated oral poliovirus vaccine (OPV) provides a powerful tool for controlling and stopping the transmission of wild polioviruses (WPVs), although the risks of vaccine‐associated paralytic polio (VAPP) and circulating vaccine‐derived poliovirus (cVDPV) outbreaks exist as long as OPV remains in use. Understanding the dynamics of cVDPV emergence and outbreaks as a function of population immunity and other risk factors may help to improve risk management and the development of strategies to respond to possible outbreaks. We performed a comprehensive review of the literature related to the process of OPV evolution and information available from actual experiences with cVDPV outbreaks. Only a relatively small fraction of poliovirus infections cause symptoms, which makes direct observation of the trajectory of OPV evolution within a population impractical and leads to significant uncertainty. Despite a large global surveillance system, the existing genetic sequence data largely provide information about transmitted virulent polioviruses that caused acute flaccid paralysis, and essentially no data track the changes that occur in OPV sequences as the viruses transmit largely asymptomatically through real populations with suboptimal immunity. We updated estimates of cVDPV risks based on actual experiences and identified the many limitations in the existing data on poliovirus transmission and immunity and OPV virus evolution that complicate modeling. Modelers should explore the space of potential model formulations and inputs consistent with the available evidence and future studies should seek to improve our understanding of the OPV virus evolution process to provide better information for policymakers working to manage cVDPV risks.     

Containment of Polioviruses After Eradication and OPV Cessation: Characterizing Risks to Improve Management

The goal of the World Health Organization is to stop routine use of oral poliovirus vaccine shortly after interruption of wild poliovirus transmission. A key component of this goal is to minimize the risk of reintroduction by destruction of polioviruses except in an absolute minimum number of facilities that serve essential functions and implement effective containment. Effective containment begins with a complete facility risk assessment. This article focuses on characterizing the risks of exposure to polioviruses from the essential vaccine production, quality control, and international reference and research facilities that remain. We consider the potential exposure pathways that might lead to a poliovirus reintroduction, including para-occupational exposures and releases to the environment, and review the literature to provide available estimates and a qualitative assessment of containment risks. Minimizing the risk of poliovirus transmission from a poliovirus facility to increasingly susceptible communities is a crucial and ongoing effort requiring understanding and actively managing the potential exposure pathways.     

Risk Management in a Polio-Free World

Inherent in the decision to launch the Global Polio Eradication Initiative in 1988 was the expectation for many people that immunization against poliomyelitis would eventually simply stop, as had been the case with smallpox following its eradication in 1977. However, the strategies for managing the risks associated with a "polio-free" world must be continuously refined to reflect new developments, particularly in our understanding of the live polioviruses in the oral poliovirus vaccine (OPV) and in the international approach to managing potential biohazards. The most important of these developments has been the confirmation in 2000 that vaccine-derived polioviruses (VDPVs) can circulate and cause polio outbreaks, making the use of OPV after interruption of wild poliovirus transmission incompatible with a polio-free world. A comprehensive strategy has been developed to minimize the risks associated with eventual OPV cessation, centered on appropriate long-term biocontainment of poliovirus stocks (whether for vaccine production, diagnosis, or research), the controlled reintroduction of any live poliovirus vaccine (i.e., from an OPV stockpile), and appropriate use of the inactivated poliovirus vaccine (IPV). Although some aspects of this risk management strategy are still debated, there is wide agreement that no strategy would entirely eliminate the potential risks to a polio-free world. The current strategy for risk management in a polio-free world will continue to evolve with better characterization of these risks and the development of more effective approaches both to reduce those risks and to limit their consequences should they occur.     

Risks of Paralytic Disease Due to Wild or Vaccine-Derived Poliovirus After Eradication

After the global eradication of wild polioviruses, the risk of paralytic poliomyelitis from polioviruses will still exist and require active management. Possible reintroductions of poliovirus that can spread rapidly in unprotected populations present challenges to policymakers. For example, at least one outbreak will likely occur due to circulation of a neurovirulent vaccine-derived poliovirus after discontinuation of oral poliovirus vaccine and also could possibly result from the escape of poliovirus from a laboratory or vaccine production facility or from an intentional act. In addition, continued vaccination with oral poliovirus vaccines would result in the continued occurrence of vaccine-associated paralytic poliomyelitis. The likelihood and impacts of reintroductions in the form of poliomyelitis outbreaks depend on the policy decisions and on the size and characteristics of the vulnerable population, which change over time. A plan for managing these risks must begin with an attempt to characterize and quantify them as a function of time. This article attempts to comprehensively characterize the risks, synthesize the existing data available for modeling them, and present quantitative risk estimates that can provide a starting point for informing policy decisions.     

Global Surveillance and the Value of Information: The Case of the Global Polio Laboratory Network

Effective control and eradication of diseases requires reliable information from surveillance activities, including laboratories, which typically incur real financial costs. This article presents data from a survey we conducted to estimate the costs of the Global Polio Laboratory Network (GPLN), which currently supports aggressive global surveillance for acute flaccid paralysis (AFP) to detect circulating polioviruses. The Global Polio Eradication Initiative (GPEI) of the World Health Organization (WHO) provides resources for some of the laboratory network costs, but the total cost of the network remains relatively poorly characterized given the limited documentation of national contributions. We surveyed network laboratories to quantify AFP surveillance support costs and provide data for cost estimates of potential posteradication surveillance policies related to the laboratories. We estimate that the GPLN currently requires millions (US dollars 2002) in total support annually, and that half of the support for national and regional reference laboratories comes from external donors through the WHO or bilateral agreements and half from within nations that host those laboratories. The article also presents the framework for considering the value of information from this global surveillance network and suggests that the expected value of surveillance information from the GPLN currently exceeds its costs. We also provided important insights about how the value of information may change after successful eradication of wild polioviruses.     

Dynamic Forecasting Conditional Probability of Bombing Attacks Based on Time‐Series and Intervention Analysis

In recent years, various types of terrorist attacks occurred, causing worldwide catastrophes. According to the Global Terrorism Database (GTD), among all attack tactics, bombing attacks happened most frequently, followed by armed assaults. In this article, a model for analyzing and forecasting the conditional probability of bombing attacks (CPBAs) based on time‐series methods is developed. In addition, intervention analysis is used to analyze the sudden increase in the time‐series process. The results show that the CPBA increased dramatically at the end of 2011. During that time, the CPBA increased by 16.0% in a two‐month period to reach the peak value, but still stays 9.0% greater than the predicted level after the temporary effect gradually decays. By contrast, no significant fluctuation can be found in the conditional probability process of armed assault. It can be inferred that some social unrest, such as America's troop withdrawal from Afghanistan and Iraq, could have led to the increase of the CPBA in Afghanistan, Iraq, and Pakistan. The integrated time‐series and intervention model is used to forecast the monthly CPBA in 2014 and through 2064. The average relative error compared with the real data in 2014 is 3.5%. The model is also applied to the total number of attacks recorded by the GTD between 2004 and 2014.