Characteristics of self-regulation of the epidemic process of infection caused by the Epstein–Barr virus (Herpesviridae: Lymphocryptovirus, HHV-4)

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Introduction

The Epstein-Barr virus (EBV) belongs to the Herpesviridae family, the Gammaherpesvirinae subfamily; its structure and life cycle have been quite extensively studied. Most people acquire an infection caused by EBV (EBV infection) during childhood. The pathogen is generally transmitted via the aerosol route. Primary infection can be asymptomatic or can cause pronounced clinical manifestations typical of infectious mononucleosis [1]. Subsequently, the virus remains for life in the human body, and the infectious process becomes chronic. Latent phases alternate with phases of reactivation [2].

Although the variants of the clinical course of EBV infection are described in detail in modern scientific literature, no effective etiotropic therapy has been developed so far [3–5]. The pathogen’s ability to evade the host immune response poses challenges to the development of vaccines [6]. The lack of efficient treatment strategies and specific prevention methods contributes to the ubiquitous spread of EBV in the human population. Currently, up to 90% of the world’s population is infected with EBV [7].

Most of the scientific studies addressing EBV infection delve into clinical characteristics and immunological aspects of the disease. The studies focusing on epidemiology aspects in Russia tend to be narrowed down to the analysis of incidence of infectious mononucleosis in some regions [8, 9]. In the meantime, the reports of this specific disease do not include any etiological decoding of the diagnosis, thus leading to distortion and incorrect interpretation of the data [10].

Generally, there are no statistical reports on EBV-caused diseases in other countries. Rare articles discussing the epidemiological characteristics of EBV infection are based on anamnestic data or laboratory test results for individual population cohorts. For example, the analysis of the detection frequency of infectious mononucleosis in different age groups in Denmark was based on the survey conducted among blood donors who informed about the presence or absence of the above disease. The obtained results demonstrating higher infection rates among younger children and adolescents cannot be seen as reliable, since the collected information did not include medical documentation with laboratory test data [11].

A more detailed analysis was conducted in the United Kingdom, where researchers studied the incidence of infectious mononucleosis hospital admissions, which tended to increase in 2002–2013. Serological markers for EBV infection were studied using serum samples from 2,366 individuals aged 1 to 25 years, among which chronic latent EBV infection was found in 85.3% of cases. The authors arrived at the conclusion that there was a direct relationship between the frequency of detection of virus infection markers and the age of the study participants [12].

The above situation highlights the importance of the analysis of the main characteristics of the epidemic process of EBV infection, which should be studied through the lens of fundamental theoretical generalizations [13–15]. The pandemic of novel coronavirus infection (COVID-19) has prompted the global community to look at the processes occurring in the interacting parasite and host populations through the prism of the theory of self-regulation of parasitic systems, which was proposed by Russian epidemiologist Vitaly Belyakov in the 1980s. This theory encompasses the mechanisms underlying self-regulation, namely: the heterogeneity of interacting populations through relations between each other; their dynamic variability; the phasal development of the parasite; the regulatory role of social and natural factors in phasal changes of parasitic systems [13].

The validity of Belyakov’s theory has been consistently proven by examples of acute infections, when upon completion of the infectious process, the pathogen leaves the host [14]. The theory of self-regulation of the epidemic process was developed using the example of acute anthroponotic airborne infections, such as acute respiratory infections, streptococcal infections, diphtheria, etc. [16, 17]. The theory of self-regulation of parasitic systems has been used to describe the epidemic process of influenza and other acute respiratory tract infections [18, 19]. Special attention is given to the nature of the interaction between SARS-CoV-2, the causative agent of the novel coronavirus infection, and the human host at the population level [20–23]. At the same time, there are no research publications that would incorporate theoretical epidemiology into the description of interaction processes in the parasite-host system for chronic infections with the aerosol transmission mechanism.

The aim of the study is to assess manifestations of the epidemic process of chronic EBV infection through the lens of the basic tenets of the theory of self-regulation of parasitic systems.

To achieve the aim, we planned to check the presence or absence of phasal transformation, considering the changes in biological properties of the host and pathogen populations during their interaction, and to identify the role of social and natural factors responsible for unevenness and intensity of the development of the epidemic process and its self-regulation.

Materials and methods

The study was undertaken as theoretical research and was focused on the epidemic process of EBV infection, which was analyzed though the lens of the basic tenets of Belyakov’s theory of self-regulation of parasitic systems.

The study was performed using data from scientific publications selected from such database sources as Scopus, Web of Science, Cochrane Library, PubMed, CyberLeninka, RSCI, etc. In our search, we also used Researchgate and reference lists of review articles. The keywords were as follows: Epstein-Barr virus, EBV, infectious mononucleosis, self-regulation of the epidemic process, epidemic process of EBV infection. A total of 5,562 publications were selected using the keyword search to be further narrowed down to 183 abstracts. The abstracts were independently assessed for relevance and shortlisted for further search for full-text articles. The final list of full-text articles included 48 publications. The search was not limited to any geographical location. The search timespan was 50 years. The search started on April 7, 2023, and ended on June 21, 2023.

The list of analyzed publications included published articles of the authors of this study, reporting the results of the retrospective epidemiological analysis of the incidence of infectious mononucleosis in Russia in general and in Moscow in particular, as well as the results of the laboratory tests regarding the detection frequency of specific antibodies to EBV proteins: immunoglobulin M antibodies to the capsid antigen (VCA IgM) and immunoglobulin G antibodies to early, capsid, and nuclear antigens (EA IgG, VCA IgG, and EBNA IgG). The above data provided a visual illustration of the tenets of the theory of self-regulation with reference to the studied infection and prompted assumptions regarding phasal variability of the host population during interaction with EBV.

The data were analyzed using formal logic methods. Microsoft Excel software for Windows was used to create graphical representations. All diagrams are borrowed from the previously published articles.

Results

Heterogeneity of EBV and human populations and their interaction

The Epstein-Barr virus, also known as human herpesvirus type 4, exhibits a tropism for different host lymphoid and epithelial cells; it causes a chronic infectious process with alternating phases of latency and reactivation.

The EBV genome encodes more than 85 proteins. The virus population is heterogeneous: There are two types distinguished by the differences in the EBNA2 gene and several variants distinguished by the gene encoding the latent membrane protein (LMP1) [24]. The variability of other genes has been described, including the gene encoding the surface glycoprotein, gp350, which mediates the virus entry into a cell [25]. The scientific literature provides data on the heterogeneity of EBV within one host, which can increase significantly during the reactivation of chronic infection and decrease during the transition to the phase of latency [24]. Since the diversity level is highly associated with the stability of any biological system, the diversity of the EBV population should be analyzed in two aspects concurrently – the heterogeneity of pathogens circulating among the host population and their heterogeneity within one individual, depending on the phase of development of the infectious process. The life-long persistence of EBV in the host cannot be maintained in the latent state. Preservation of biological species requires periodic reproduction of viral progeny [13]. In the meantime, the absence of heterogeneity of the pathogen during reactivation could result in its prompt recognition and elimination by the host immune system. Therefore, EBV heterogeneity is a prerequisite for reactivation and, consequently, for effective circulation in the host population.

Diversity in the host population is governed by functions of the systems responsible for specific and nonspecific susceptibility to EBV. Studies have shown that patients with EBV-caused infectious mononucleosis demonstrated a decrease in the induced IFN-α and IFN-γ production [26, 27]. Primary EBV infection and reactivation of chronic infection are associated with changes in the cellular component of the immune system – elevated levels of cytotoxic CD8⁺ T cells that can recognize and destroy infected host cells, as well as the pronounced deficiency of B cells that are principal EBV targets. Regardless of their age, in patients having clinical manifestations of infectious mononucleosis, the number of B cells with phenotypes «CD19⁺, CD21⁺, CD81⁺», «CD19⁺, CD21⁻, CD81^+’», and «CD19⁺, CD21⁺, CD81⁻» is significantly reduced compared to healthy individuals [28, 29].

The humoral immune response is mediated by specific immunoglobulin antibodies to EBV proteins. The evaluation of the serological status of patients is generally based on qualitative and quantitative detection of VCA IgM, VCA IgG, EA IgG, and EBNA IgG. The detection of VCA IgM and EA IgG antibodies correlates with different phases of primary infection or reactivation of chronic EBV infection, while the presence of VCA IgG and EBNA IgG antibodies is indicative of a chronic latent process [30]. The previous study revealed the existence of a strong inverse correlation between the changes in the VCA IgG and EBNA IgG seroprevalence rates and the intra-annual dynamics of the incidence of infectious mononucleosis. At the same time, the incidence rates did not rise above the upper range of the estimated threshold during months characterized by high detection frequencies for the above markers [31].

Dynamic variability and phases of development of interacting populations

According to Belyakov’s theory of self-regulation, the interaction between the parasite and host populations is rooted in their variability, which governs the uneven development of the epidemic process. The phases that the pathogen population goes through are as follows: reservation, epidemic transformation, epidemic spread, and reservation transformation [13]. The interaction of all elements of the system leads not only to an infectious process, but also to development of population or herd immunity. Thus, the host population also goes through several phases, which do not have specific names and can be defined as phases of a high level of herd immunity, a decreasing level of herd immunity, a low level of herd immunity, and an increasing level of herd immunity. During the interaction, the changes in one population will correspond to the changes in the other. The comparison of changes during the epidemic process of EBV infection is presented in the Table.

 

Table. Interaction-induced phase variability of the EBV and human populations

Таблица. Фазовая изменчивость популяции ВЭБ и человека в результате взаимодействия

EBV population Популяция ВЭБ		Interaction range Область взаимодействия	Human population Популяция человека
phase фаза	description характеристика	manifestations of the epidemic process through the incidence dynamics проявления эпидемического процесса на примере динамики заболеваемости	description характеристика	phase фаза
Reservations Резервации	Low heterogeneity and virulence Гетерогенность и вирулентность низкая	Interepidemic period (low incidence rates) Межэпидемический период (показатели заболеваемости низкие)	Low heterogeneity and susceptibility (the highest level of specific immune protection against EBV in individuals with chronic infection – the latent phase of the disease; the lowest proportion of seronegative individuals in the total population – low risk of infection) Гетерогенность и восприимчивость низкая (максимальный уровень специфической иммунной защиты в отношении ВЭБ у лиц с хронической инфекцией – латентная фаза болезни; минимальная доля серонегативных лиц в общей популяции – низкий риск инфицирования)	High level of herd immunity Высокого уровня популяционного иммунитета
Epidemic transformation Эпидемического преобразования	Increasing heterogeneity and virulence Рост гетерогенности и вирулентности	Increasing incidence Подъем заболеваемости	Increasing heterogeneity and susceptibility (Decreasing level of specific immune protection against EBV in people with chronic infection – reactivation; increase in the proportion of seronegative individuals) Рост гетерогенности и восприимчивости (Снижение уровня специфической иммунной защиты в отношении ВЭБ у лиц с хронической инфекцией – реактивация; рост удельного веса серонегативных лиц)	Decreasing level of herd immunity Снижения уровня популяционного иммунитета
Epidemic spread Эпидемического распространения	Decreasing heterogeneity and high virulence Снижение гетерогенности на фоне высокой вирулентности	Persistent high incidence Стагнация показателей заболеваемости на высоком уровне	Decreasing heterogeneity and high virulence (The lowest level of specific immune protection against EBV in people with chronic infection; the highest proportion of seronegative individuals in the population) Снижение гетерогенности на фоне высокой восприимчивости (Минимальный уровень специфической иммунной защиты в отношении ВЭБ у лиц с хронической инфекцией; максимальная доля серонегативных лиц в популяции)	Low level of herd immunity Низкого уровня популяционного иммунитета
Reservation transformation Резервационного преобразования	Increasing heterogeneity along with decreasing virulence and the number Рост гетерогенности на фоне снижающейся вирулентности и численности	Decline in the incidence Спад заболеваемости	Increasing heterogeneity and decreasing susceptibility (Increasing level of specific immune protection against EBV in people with chronic infection; a decrease in the proportion of seronegative individuals) Рост гетерогенности и снижение восприимчивости (Повышение уровня специфической иммунной защиты в отношении ВЭБ у лиц с хронической инфекцией; снижение удельного веса серонегативных лиц)	Increasing level of herd immunity Нарастания уровня популяционного иммунитета

 

It should be noted that the concept of herd immunity is generally associated with specific immunoprophylaxis strategies. Vaccination is a highly effective measure that can significantly reduce the burden of infectious diseases, morbidity, and mortality [15]. However, there is currently no vaccine against EBV infection, and the level of immune protection required for prevention of the epidemic spread of the pathogen has not been identified [6, 32]. Therefore, this article is focused solely on post-infection immunity, leaving out quantitative assessment of its level, which requires an individual study.

The table demonstrates that a variety of functional humoral and cellular defense mechanisms have been accumulated during the phase of a high level of herd immunity, preventing the transition of the pathogen from the latent existence to replication (reactivation) during chronic EBV infection. The above phase is characterized by a high prevalence of the pathogen among the population, while the proportion of individuals exposed to risk of primary infection remains at the lowest level. Since most of the individuals have a high level of immune protection, the host population has low heterogeneity and low susceptibility to EBV.

Without intense circulation of the pathogen, the human immune system gradually “forgets” it, and its alertness decreases. The proportion of children born to non-immune mothers increases [32]. As the susceptibility to EBV decreases, some individuals develop conditions for reactivation of chronic EBV infection. The heterogeneity of the host population increases. The sources of infection accumulate, demonstrating the trend typical of the phase of a decreasing level of herd immunity. According to the theory of self-regulation, the respective changes in the pathogen population correspond to the phase of epidemic transformation and are associated with increasing heterogeneity and virulence of the virus [13].

The phase of a low level of herd immunity promotes ideal conditions for activation of the transmission mechanism: There is a sufficient number of sources of infection and susceptible individuals. All of them have the lowest levels of immune protection against EBV, thus contributing to the low heterogeneity and the high susceptibility of the host population. Individuals previously not exposed to EBV get infected and individuals with chronic EBV infection develop superinfection (epidemic spread of the pathogen).

In some individuals, the development of primary EBV infection, superinfection, or reactivation of chronic EBV infection triggers an increase in the level of herd immunity. Although there are multiple sources of infection during this period, the pathogen keeps spreading until the peak of heterogeneity is reached. Then, the proportion of susceptible individuals decreases dramatically, and EBV gradually loses its virulence and moves into a latent state.

The aforesaid is confirmed by the results of the previous retrospective epidemiological analysis [31]. Figure 1 presents a fragment of multi-year dynamics of the infectious mononucleosis incidence in Moscow; the timespan between two troughs (2004 and 2015) was 11 years. The lowest incidence rates (2003–2005 and 2015–2017) correspond to the phases of reservation in the pathogen population and high level of herd immunity in host population. The increase in the incidence in 2006–2008 resulted from the increased heterogeneity of interacting populations (phases of epidemic and infection transformation). The highest rates were reported in 2009–2012 and correspond to the phases of epidemic spread and low level of herd immunity. The decrease in the pathogen virulence and host population susceptibility explains the decrease in the incidence in 2013–2014 (phases of reservation transformation and increasing level of herd immunity).

 

Fig. 1. Multi-year dynamics of the infectious mononucleosis incidence in Moscow in 2003–2017 (per 100,000 population)

 

Similar trends are observed in the intra-annual dynamics of the incidence of infectious mononucleosis, which generally demonstrates a slight seasonal upswing during cold months (Fig. 2). The multi-year average rates overshooting the upper range of the background rates were recorded from September to May. The slight decrease in the incidence in January could be caused both by the disconnection of the host population and by the reduction in the reported number of cases of infectious mononucleosis during New Year holidays [31, 33, 34]. Fig. 2 presents the infectious mononucleosis incidence rates compared to the VCA IgG prevalence among Moscow residents. In June–September, the VCA IgG detection frequency demonstrated the highest levels, thus implying low incidence rates among the population. In October–November, the prevalence rates decreased significantly, while the incidence increased. In April–May, on the contrary, while the number of cases of infectious mononucleosis was decreasing, the frequency of detection of the above marker was gradually increasing. The above data provide a vivid illustration of phase transformations, which occur in the host population during the interaction with EBV.

 

Fig. 2. Intra-annual dynamics of the infectious mononucleosis incidence and VCA IgG prevalence in Moscow: The multi-year average rates in 2010–2022.

 

Regulatory role of conditions (social and natural factors)

Based on the tenets of the theory of self-regulation, all social and natural factors can be divided into three groups depending on the type of their impact on the phase nature of development of the epidemic process [13]:

– factors affecting the vertical (through succession of generations) and the horizontal (migration, emergence of new groups) “mixing” of people;

– factors activating the mechanism of pathogen transmission;

– factors decreasing immunity and resistance.

By “mixing” we mean interaction between the individuals who have not been previously exposed to EBV (or any of its genetic variants) and infected people. Note that the highest proportion of individuals who are not immune to EBV is observed in the age group of children younger than 2 years old [32]. With increasing age, the seroprevalence rates tend to increase and reach the highest level by the age of 30–40 years, demonstrating a slight decrease by the age of 50–60 years [7]. The above patterns illustrate the role of demographic changes in the structure of the population as one of the factors regulating the intensity of the epidemic process [14].

The frequency and intensity of contacts among individuals depend on their social activity, which is lowest among younger children and older people. Social processes contributing to horizontal mixing include migration of population, including daily commuting by public transport, formation of new organized groups (for example, through conscription), and restarting of the previously established groups, for example, after summer vacations (preschool and school educational organizations) [35, 36]. In the case of EBV, the main prerequisite for horizontal mixing is the existence of territorial patterns of the spread of its genetic variants [24].

In addition to the aforesaid, the role of horizontal mixing in the regulation of the epidemic process can depend on the population density of a certain area. The analysis of data on EBV infection did not demonstrate any significant correlation between the VCA IgM and EA IgG detection frequency and the population density in regions of Russia. At the same time, there is a linear relationship of moderate strength between the multi-year average incidence rates of infectious mononucleosis and the population density. The explanation can be found in the fact that the closeness of contacts among individuals has an impact on the EBV spread among non-immune individuals, while having no significant effect on reactivation of chronic infection, which is triggered by other factors [37]. The analysis of the causes underlying changes in the incidence of infectious mononucleosis in 2020 shows that the restrictive measures aimed at disconnection of the population and reduction of the risk of aerosol transmission of SARS-CoV-2 resulted in reduction of intensity of the epidemic process of EBV infection [38].

An important role in the epidemic spread of the pathogen is played by factors inducing the activation of transmission mechanisms. The aerosol transmission is the main transmission route for EBV; it requires the presence of the pathogen in the upper respiratory tract as well as factors inducing the formation of the aerosol.

It has been found that the EBV DNA detection frequency in the saliva of the examined individuals does not have significant differences during warm and cold seasons of the year, while the incidence of infectious mononucleosis is characterized by an autumn-spring seasonal upswing [33] concurrent with the peaks of other upper respiratory tract infections [34]. It should be noted that infectious mononucleosis develops without pronounced catarrhal symptoms, which, in their turn, contribute to the formation of an infectious aerosol. During seasonal upswings, EBV co-circulates in the host population with other pathogens that cause upper respiratory tract infections. The previous studies have shown that during cold months of the year, EBV was detected in nasopharyngeal and oropharyngeal swabs in 33.7–37.1% of individuals examined during the influenza and ARVI monitoring, and in 16.3–18.6% of individuals, it was detected together with other pathogens. In co-infections, a runny nose and cough result in the formation of an infectious aerosol containing EBV, along with other pathogens [39, 40].

Note that pathogens of other infectious diseases not only have a significant role in activation of the aerosol transmission mechanism, but also trigger the reactivation of chronic EBV infection, since they significantly change immunological reactivity and can enter a competitive relationship with EBV, having tropism for the same cells. Scientific publications describe cases of reactivation of EBV infection in patients with HIV infection [41, 42], hepatitis B [43], tuberculosis [44, 45], and COVID-19 [46].

In addition to pathogenic microorganisms, EBV reactivation can be induced by different types of ionizing radiation, as, for example, demonstrated in astronauts during spaceflights [47]. In the experiment, the cell culture containing the EBV-positive cell line was exposed to 4 different types of radiation: ¹³⁷Cs gamma rays, 150-MeV protons, 600 MeV/n carbon ions, and 600 MeV/n iron ions at doses of 0.1, 0.5, 1.0, and 2.0 Gy. It was found that the EBV lytic gene transcription and, consequently, EBV reactivation occurred for all types and doses of radiation 4 days after the exposure. Gamma rays were most effective in inducing reactivation. The researchers also found that EVB reactivation could occur due to the effect of different types of radiation on latently infected cells in the absence of changes in the host immune system [48].

Among other factors that have a direct impact on the parasite-host system we can single out the climatic impact. It has been found that in Russia, areas with high seroprevalence rates for IgG EBNA antibodies among adults are located in unfavorable climatic zones. For example, the Republic of Kalmykia, Astrakhan and Orenburg Regions (the zones of steppes, semi-deserts, and deserts) have a continental climate with sharp daily and seasonal variations in temperature. The Murmansk Region and the Republic of Sakha (Yakutia), which are located in the tundra zone, are characterized by the combination of low temperatures and high humidity [37].

Thus, various natural and social factors are the main drivers regulating the epidemic process, having an impact on its intensity and dynamics, and, consequently, on the heterogeneity of parasite and host populations. V. Belyakov believed that the ability to control these factors should form the core of preventive and epidemic control measures [13]. At the same time, the best results are achieved by measures aimed at enhancement of the host immune protection [14].

Currently, there are no approved vaccines for preventing EBV infection. Vaccine candidates are being developed in different countries; however, none of them have brought the desired result [6]. Therefore, the measures aimed at enhancement of immune protection should include preventive vaccination against other pathogens that play a critical role in the reactivation of chronic EBV infection as well as nonspecific immunoprophylaxis. Reduction of the impact of other factors contributing to reactivation is of high importance, including prevention and timely treatment of concomitant somatic diseases, minimization of adverse household, job-related and other impacts, promotion of healthy lifestyle.

To prevent the activation of the transmission mechanism, the measures should include such key components as disinfection and sterilization (disinfection of indoor air, household items, utensils, surfaces; disinfection, pre-cleaning, and sterilization of medical equipment and instruments; disinfection of epidemiologically dangerous medical waste), as well as personal respiratory protective equipment to be used in crowded places, especially during seasonal peaks in the incidence of upper respiratory tract infections.

The factors contributing to mixing of people are less responsive to man-made impacts. At the same time, the ban on travel across countries and regions, which was imposed during the COVID-19 pandemic, played a crucial role in the implementation of public health measures against the novel infection and can be used in emergency situations caused by other diseases.

Conclusion

The analysis has shown that the chronic course of EBV infection promotes a close long-term interaction between the pathogen and the host. The genetic variability of the pathogen and the functions of specific and nonspecific human immune defense systems play a key role in the interaction between two heterogeneous populations and underlie their phasal self-transformation. A variety of social and natural factors (adverse chemical, physical, biological, climatic impacts, etc.) trigger the reactivation of chronic EBV infection, thus providing the continuous existence of additional (along with patients with primary infection) sources of infection in the host population.

The analysis of the manifestations of chronic EBV infection in the context of the theory of self-regulation of parasitic systems promotes understanding of the factors underlying the unevenness of its epidemic process. The obtained data can be adjusted for other infections having similar transmission mechanisms and virus life cycles (including other herpes infections) to map out strategies for control over the epidemic process of chronic infections spread by aerosol transmission of the pathogen.

About the authors

Tatyana V. Solomay

Central Research Institute of Epidemiology of Rospotrebnadzor; I.I. Mechnikov Scientific Research Institute of Vaccines and Serums, Ministry of Education and Science of Russia

Author for correspondence.
Email: solomay@rambler.ru
ORCID iD: 0000-0002-7040-7653
SPIN-code: 7688-1280

PhD (Medicine), Senior Researcher at the Laboratory of Epidemiological Analysis and Monitoring of Infectious Diseases

Russian Federation, 111123, Moscow; 105064, Moscow

Tatiana A. Semenenko

National Research Center of Epidemiology and Microbiology named after Honorary Academician N.F. Gamalei of the Ministry of Health of Russia; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

Email: semenenko@gamaleya.org
ORCID iD: 0000-0002-6686-9011
SPIN-code: 8375-2270

доктор медицинских наук, профессор, профессор кафедры инфектологии и вирусологии Института профессионального образования; руководитель отдела эпидемиологии

Russian Federation, 123098, Moscow; 119048, Moscow

Vasiliy G. Akimkin

Central Research Institute of Epidemiology of Rospotrebnadzor

Email: vgakimkin@yandex.ru
ORCID iD: 0000-0003-4228-9044
SPIN-code: 4038-7455

D.Sci. (Med.), Professor, Academician of the RAS, Director

Russian Federation, 111123, Moscow

References

Supplementary files