The Norway rat, Rattus norvegicus, is known by many names such as the brown rat, common rat, sewer rat, Hanover rat, Norwegian rat, city rat, water rat and wharf rat. Living in close proximity to humans, wild Norway rats are often considered pests (Khlyap et al., 2012). They are well known for invading and damaging property, spoiling food supplies and spreading diseases (Kosoy et al., 2015). Their seemingly unrestricted capacity to reproduce, their ferocious appetite (which can result in cannibalism) and their remarkable ability to survive in adverse and often unsanitary conditions only seem to worsen their reputation among many in the general public. For all of these reasons and more, rats are the targets of intensive pest control strategies.

In spite of their bad reputation in the wild, the laboratory rat is perhaps the archetypal model organism. Widely used in fields such as neuroscience, physiology and toxicology, ‘lab rats’ account for 13.9% of all animals used in research in Europe (European commission, 2012), second only to mice which account for 60.9%. First domesticated from wild Norway rats over 170 years ago (Richter, 1959), today laboratory rats owe their popularity as a model organism largely due to their widespread availability, low breeding costs, short reproductive cycle and ability to thrive in captive environments.

Laboratory rats differ from Norway rats in the wild, just like many other model organisms (Alfred and Baldwin, 2015). In the mid-20^th century, these differences led some researchers to suggest that the laboratory rat had become a degenerated form of its wild cousins and lost its value as a study model (Beach, 1950; Lockard, 1968). While these views are probably unjustified, researchers working with laboratory rats should remain aware of its advanced domestication. While few modern laboratories study wild R. norvegicus colonies, a better appreciation of the rat’s natural history would expand its value as a model organism. Resuming studies of wild rats would give the opportunity to not only ‘refresh’ genetic lines and create new highly specialized strains, but also document the many changes that have taken place in wild populations since most laboratory lines were first obtained.

Rattus norvegicus is one of over 60 species in the mammalian genus Rattus (Musser and Carlton, 2005), which can be divided into seven systematic groups (Box 1). The deepest divergence within the genus occurred 3.5 million years ago and separates a lineage of rats that are endemic to New Guinea from the other groups (Robins et al., 2008). Rats belong to the Muridae family in the Rodentia order. This family also includes mice (genus Mus), and rats and mice are thought to have diverged about 40 million years ago (Adkins et al., 2001).

Despite its name, the Norway rat most likely originated in Asia. It diverged from its sibling species the Himalayan field rat (Rattus nitidus) around 620–644 thousand years ago (Teng et al., 2017), and some of the oldest remains of R. norvegicus have been discovered in the Chinese province of Sichuan-Guizhou (Musser and Carlton, 2005). The Norway rat got its name as it was believed to have immigrated to England from Norway aboard ships in the 18^th century. However, the species originally arrived in European countries from Asia via Russia, superseding the older black rat Rattus rattus. Numerous remains of the species have been discovered at archaeological sites dated to the 14^th century (for instance, in Tarquinia, Italy), suggesting that small populations of these rats had actually inhabited Europe earlier than previously thought (Clark et al., 1989). The Norway rat reached North America between 1750 and 1775 (Nowak, 1999). Some places in northeast and central Asia were not inhabited by the Norway rat until the last decades of the 20^th century (Khlyap and Warshavsky, 2010).

Rats live in almost all terrestrial environments except deserts, tundra and polar ice. They adapt easily to new conditions thanks to their physical resilience, omnivorous diet and flexible behavior. Like the black rat, the Norway rat often lives in the immediate vicinity of humans, including in cities (Aplin et al., 2011), and can pose a serious threat to human health because it may carry various pathogens and parasites (Box 2). Wild Norway rats often inhabit storage facilities, basements, deserted buildings and landfill sites where human-generated waste is deposited (Sacchi et al., 2008). In cities, its habitats are distributed irregularly, and each rat’s home range is relatively restricted compared to rats in less urban settings. City rats prefer areas with rich vegetation, banks of water reservoirs, old buildings and sewer systems (Ayyad et al., 2018; Traweger et al., 2006; van Adrichem et al., 2013). They dig burrows and build extensive systems of tunnels and passages in riverbanks and open spaces, where they live and breed (Barnett, 2005). Like most mammals, rats are characterized by female philopatry and male dispersal (Gardner-Santana et al., 2009). Rats choose their habitats based on the availability of shelter, food and water (Orgain and Schein, 1953).

The Norway rat is often considered the first mammal to have been domesticated for research purposes (Richter, 1959). Although some scientists point to the sporadic use of rats in experiments prior to 1850, the first known documented experiment conducted on these animals was a study of the effects of adrenalectomy published in 1856 in France (Philipeaux, 1856). In 1863, a study on the nutritional quality of proteins was conducted on mixed colored rats (Savory, 1863). The rat was first used in psychological studies by Adolph Mayer, a well-known American psychiatrist (Logan, 1999). After 1893, American neurologist Henry Herbert Donaldson started to use rats in biomedical experiments conducted at Chicago University (Lockard, 1968). When he took a post of the director of the Wistar Institute, he brought with him four pairs of albino rats that he then used in multidisciplinary studies conducted together with a large group of scientists. Donaldson intended to standardize the albino rat to create a universal model suited for biomedical research (Lindsey and Baker, 2005). Researchers at the Wistar Institute developed special breeding and reproduction techniques for rats. They designed special cages and entire buildings adapted specially for rat breeding. In 1912, the Wistar Institute began supplying laboratory rats to other research institutions (Lindsey and Baker, 2005).

The breeding colony established by Donaldson inspired his PhD student John Broadus Watson to conduct further experiments which resulted in ground-breaking discoveries in behavioral studies. In 1914, Watson published the book Behavior: An Introduction to Comparative Psychology, which became a major text in the field of animal psychology. His work was developed by Curt Paul Richter, who published numerous studies on topics such as domestication, stress, the biological clock and adrenalectomy between 1919 and 1977 (Lindsey and Baker, 2005).

Rats are often used in similar studies to mice (Phifer-Rixey and Nachman, 2015), though their larger size means they are more useful in some experiments, such as those involving surgery and imaging (Jonckers et al., 2011). Rat models are also considered more reliable than mouse models in the study of certain addictions (Vengeliene et al., 2014), cancer immunotherapy (Bergman et al., 2000), and diabetes and related conditions (Obrosova et al., 2006). Some research areas in which rats are commonly used models now make more and more use of other animal models instead, such as the zebrafish (Danio rerio; Parichy, 2015; Stewart et al., 2012: Kari et al., 2007).

Numerous strains of laboratory rat have been created to ensure control over the genetic variation in experimental subjects. However, the roots of the phylogenetic tree of the laboratory rat strains have not yet been established. Some researchers suggest several independent domestication pathways (e.g., Festing, 1979), but there is no consistent evidence to support this notion. More recent genetic studies based on the measurements of mutation rates in different parts of the rat genome have clarified the relationships between the different strains and led to a shared phylogenetic tree for most inbred strains (Thomas et al., 2003).

Based on their breeding history, laboratory rats may be broadly divided into outbred stocks and inbred strains (Table 1). The outbred stocks are usually used for general study purposes where homozygosity is not crucial and are well suited for behavioral studies. The inbred strains are used for researching issues related to genetic and phenotypic characteristics (Sharp and Villano, 2012). Rat models are also created in laboratories by means of electrical, pharmacological and surgical techniques that induce changes in the animals (e.g., Calcutt, 2004; Teixeira and Webb, 2007; Relton and Weinreb, 2008; Obenaus and Kendall, 2009).

Rat strains differ significantly in their morphology: their body weight and the size of internal organs may vary greatly, while the body length remains the same (e.g., Reed et al., 2011). For example, albino strains consistently exhibit impaired vision, while other strains appear to have the wild-type or even enhanced visual acuity (Prusky et a., 2002). Metabolism and behavior differ between certain strains as do the way these characteristics change with age (Clemens et al., 2014). Differences may also occur where social behaviors are concerned: for example, when play-fighting, juvenile Wistar rats initiate significantly fewer playful attacks than Fisher 344 rats (Schneider et al., 2014).

As many breeding colonies have been isolated for several decades, the inbred animals have different phenotypes than their counterparts bred elsewhere (e.g., Goepfrich et al., 2013). Environmental conditions and specific breeding settings lead to epigenetic differences, while several decades of breeding may result in a cumulation of mutations, which subsequently hinders the generalization of results even to the animals of the same strain (Box 3).

Differences between laboratory rats and wild rats had previously prompted several scientists to question the legitimacy of generalizing the results of studies conducted on laboratory rats to the species as a whole, or other organisms (Beach, 1950; Lockard, 1968). Yet comparative studies have shown that domestication rarely modifies an animal’s behavioral repertoire to any significant extent (Price, 1999; Stryjek et al., 2012; Modlinska et al., 2015). Instead, most changes tend to affect the frequencies of certain behaviors, or the thresholds at which a stimulus will trigger a response.

Some features of domestication have also unintentionally increased the utility of rats as a model organism. For instance, the laboratory rats’ reluctance to swim and their determined attempts to get out of water are crucial to the Water Morris Test, a popular protocol in the study of memory and learning (cf. Whishaw and Pasztor, 2000).

Several researchers aware of the problems arising from the domestication of the rat conducted experiments on wild Norway rats and comparative studies of both lines. Samuel Anthony Barnett, the author of the classic text "The Rat: A Study in Behaviour" (first published in 1963), caught wild rats and studied them in his laboratory for decades since 1950s, and in the process developed several techniques for handling them (Barnett, 2009). Beginning in 1970s, Bennett G Galef also extensively studied wild Norway rats with a specific focus on their feeding behaviors (e.g., Galef and Clark, 1971), and Robert J Blanchard spent many years investigating the defensive and aggressive behaviors of these animals (e.g., Blanchard et al., 1986).

Jaap Koolhaas also conducted experiments with wild caught Norway rats in the late 1990s (Koolhaas et al., 1999). He studied stress and aggression, and the wild rats were particularly well suited for those experiments due to their poor adaptation to the laboratory setting and their emotional constitution. His work on wild rats resulted in the creation of a wild line of R. norvegicus – the Wild-type Groningen rats.

In 2006, a new laboratory colony of wild Norway rats was set up in Poland (Stryjek and Pisula, 2008). The new line was named WWCPS, which short for Warsaw Wild Captive Pisula Stryjek (Figure 1). In order to prevent the development of domestication features in the breeding colony and maintain the animals’ ‘wild’ genetic status, the colony was systematically enlarged with captured rats in various locations. Since it was established, comparative studies involving rats from this colony have added to the list of known differences between wild rats and laboratory rat lines (Stryjek et al., 2012; Modlinska et al., 2015; Himmler et al., 2014; Himmler et al., 2013; etc.).

Figure 1

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It is important, however, to note that wild rats are not easily handled or manipulated. The fact that these animals are less suited to a laboratory setting can impact the results obtained from them. Wild rats in a laboratory have a higher level of stress hormones in their blood plasma than domesticated laboratory rats; they also exhibit stronger responses to emotional stressors and novel objects (Naumenko et al., 1989; Plyusnina et al., 2011; Koizumi et al., 2019). These factors must be taken into consideration when interpreting results and may constrain the kind of studies that are feasible using wild rats. Before conducting experiments with wild individuals, researchers may need to develop special procedures that better approximate the natural conditions of these animals (i.e., that have "high ecological validity"). Efforts must be made to reduce the stress involved in the breeding and experimental manipulations, as it may affect rat welfare. Nevertheless, studies on wild animals, that have not been subjected to the domestication process, could help the community to assess the generality or specificity of results obtained with laboratory lines. The fact that wild rats show more variability between individuals with regard to many biological traits may also be useful when studying the impact of various stimuli (e.g., environmental changes) on such complex and variable populations. Such experiments would be difficult to achieve using standardized laboratory strains.

Many of the traits that make Norway rats a pest in the wild are the same traits that have contributed to its success as a model organism. Nevertheless, the domestication of the rat for research purposes has also resulted in significant changes. Rather than viewing the rat as a simple model, a "pest" or a "pet", it is important to recognize it as a complex mammal in its own right, and one that is highly adapted to its environment (Burn, 2008). Research on rats in the laboratory will be benefited by researchers who understand the animals they are working with; this includes having an appreciation of the rat’s natural history.

No data was generated as part of this work.

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Acceptance summary:

The "lab rat" is a classical model organism but less is known about its former life in the wild. This wide-ranging review gives an interesting introduction to laboratory rats from an ecological perspective, discussing how they compare with their wild counterparts, and covering the history of the domestication of this model species. The revisions have strengthened the article and it will soon make a welcome addition to our collection on the natural history of model organisms. This work should be of special interest to researchers who study rats in the laboratory.

Decision letter after peer review:

Thank you for submitting your article "The Natural History of Model Organisms: The Norway rat, from an obnoxious pest to a laboratory pet" for consideration by eLife. Your article has been reviewed by two peer reviewers and the evaluation has been overseen by two Features Editors at eLife (Stuart King and Peter Rodgers). The following individual involved in review of your submission has agreed to reveal their identity: Amelie Desvars.

The reviewers have discussed the reviews with one another and the Associate Features Editor has drafted this decision to help you prepare a revised submission.

Summary:

This essay is being considered as part of a series of articles on "The Natural History of Model Organisms":https://elifesciences.org/collections/8de90445/the-natural-history-of-model-organisms. Each article should explain how our knowledge of the natural history of a model organism has informed recent advances in biology, and how understanding its natural history can influence/advance future studies.

The "lab rat" is perhaps the archetypical model organism and would thus make a welcome and interesting addition to this collection of articles. The paper is also timely. Rats remain a key laboratory animal for much research, especially in the behavioral and neural sciences, yet there is a nagging suspicion about the consequences of over a hundred years of domestication.

This wide-ranging review explores the history of laboratory rats, their uses and how they compare with their wild counterparts. The conclusion is that laboratory rats retain sufficient physiological and behavioral characteristics of wild rats to be suitable as animal models for many questions. It also concludes that all strains, or stocks thereof, including wild rats, have to be thoughtfully matched to the research question being asked. This will be a valuable resource in guiding researchers to use rats as animal models more effectively, nevertheless revisions are needed to strengthen the article.

Essential revisions:

1) Structure of the article

Overall, the article is comprehensive and well-researched, with many examples. It would, however, benefit from editing to make the text more succinct. Restructuring would also help its ideas to flow more fluidly and make its central message/conclusion clearer.

Below are some general suggestions as to how this could be achieved.

- Introduction

Taking inspiration from the title, the Introduction could be restructured into three, short paragraphs (max 150 words each). The first paragraph could briefly introduce wild rats as one of the most important vertebrate pest species (with risks to public health, animal health, wildlife, agriculture and infrastructures), and explain how they are widely disliked by the public. The second paragraph could then contrast this by describing laboratory rats as a popular model organism with a long history in research. The third paragraph should highlight the concerns about the "laboratorisation" of rats and briefly describe the objectives or central theme for the rest of the article. The third paragraph is the most critical one in the Introduction. All three paragraphs should offer a high level perspective, with more detail given later in the main text.

- Main text

Most sections would benefit from being more concise. For many sections, the word count could be cut by about a third without reducing the scope. The reviewers felt that some topics were discussed in inappropriate sections (i.e. "diet" is currently combined with "behaviour", and "reproduction" is included under "physical traits".

The section on "Natural history" should focus on the origin, evolution, phylogenetics, biogeography of wild rats. The section on Ecology could be a sub-section of this section, and should discuss the distribution of rats in cities more.

Difference between lab and wild rats are currently described in three consecutive sections: "Laboratorisation of R. norvegicus", "New laboratory rat populations recreated from wild colonies" and "Comparative studies on wild and laboratory rats". These three sections could be revised and restructured to describe i) the changes that occurred when wild rats were domesticated for use in the lab, ii) how this subsequently limited the usefulness of lab rats for some research, and iii) how researchers try to overcome these limitations by creating new lab rat populations from wild colonies (with mentions of the advantages and limitations of these new stocks).

- Conclusion

This also needs to be condensed and should avoid introducing too many new concepts that were not discussed in the article.

- Box 1: Disease and pest control

This also needs to offer a high level perspective and can be cut back to avoid too much detail on specific examples of diseases spread by rats. It would be good to instead briefly cover public opinion of rats (as dirty animals, living in sewage and feeding on garbage), and the impact of rats on crops, infrastructures and endangered wildlife. It would be interesting to mention here how humans have tried for centuries to eliminate, or at least control, rat populations, and that research on rodenticide resistance involves both lab and wild rats.

2) Figures and tables

The current manuscript has a photo as one figure and three boxes to discuss specific topics that would otherwise disrupt the flow of the text. The reviewers felt that the authors should consider moving some of the details currently written in the text into new tables or figures. For example, the information about the systematic groups in the genus Rattus (subsection “Natural history”, second paragraph) should be removed from the text, and presented as a table, or perhaps as a figure with a phylogenetic tree. A map could help the author explain how the Norway rat colonized different geographic regions (see the last two paragraphs of the aforementioned subsection), and the information displayed in Box 2, "The most common stocks and strains of the laboratory rat", would be more easily read if it was presented in a table.

3) Species common name

It would also be interesting if the authors could briefly explain why this rat is called the "Norway rat" when its origins are thought to be in Asia. A few sentences in the appropriate section would likely satisfy a reader's curiosity.

On a related point, it would be good if the article could also list the other common names, besides brown rat, for completeness – i.e. sewer rat, water rat, city rat, common rat – but then continue to use one name, i.e. Norway rat, throughout the rest of the article to avoid confusing unfamiliar readers.

4) Wild or lab rats?

In some sections, especially under the heading Characteristics of the species", it is unclear whether the text refers to wild rats, laboratory strains or both. Please go through the text and make this clearer. It may help if that specific section is renamed "Characteristics of wild Norway rats, and any comparison to laboratory rats is made explicit, or saved for a later section.

5) References

Several statements need support references from the literature while some references should be updated.

6) Part of a collection

Lastly, since this article is part of a series that has already covered 12 other model organisms (including two other rodents), it would be good if the authors could do more to highlight similarities/differences between rats and any of the other model organisms in the series. For example, when discussing life history traits that make rats a good choice for a model organism, it'd be interesting to note other models that have similar traits, and cite the relevant articles already in the collection to help readers see the connections [https://elifesciences.org/collections/8de90445/the-natural-history-of-model-organisms].

Essential revisions:

1) Structure of the article

Overall, the article is comprehensive and well-researched, with many examples. It would, however, benefit from editing to make the text more succinct. Restructuring would also help its ideas to flow more fluidly and make its central message/conclusion clearer.

Thank you for this comment. The manuscript has been restructured and edited to make it more concise.

Below are some general suggestions as to how this could be achieved. The Associate Features Editor will contact you separately with more specific edits.

- Introduction

Taking inspiration from the title, the Introduction could be restructured into three, short paragraphs (max 150 words each). The first paragraph could briefly introduce wild rats as one of the most important vertebrate pest species (with risks to public health, animal health, wildlife, agriculture and infrastructures), and explain how they are widely disliked by the public. The second paragraph could then contrast this by describing laboratory rats as a popular model organism with a long history in research. The third paragraph should highlight the concerns about the "laboratorisation" of rats and briefly describe the objectives or central theme for the rest of the article. The third paragraph is the most critical one in the Introduction. All three paragraphs should offer a high level perspective, with more detail given later in the main text.

Following your advice, we have rewritten the Introduction section. As you suggested, we have divided the section into three paragraphs, and in the first part we have presented the rat as a nuisance, in the second part we have considered the rat as a laboratory model, and in the last part we have briefly described the controversy around using the domesticated form of the species.

- Main text

Most sections would benefit from being more concise. For many sections, the word count could be cut by about a third without reducing the scope. The reviewers felt that some topics were discussed in inappropriate sections (i.e. "diet" is currently combined with "behaviour", and "reproduction" is included under "physical traits". As mentioned above, the Associate Features Editor will contact you separately with specific edits to help address these issues.

The manuscript has been restructured and edited to make it more succinct. The word count has been cut substantially. The different sections have been reordered.

The section on "Natural history" should focus on the origin, evolution, phylogenetics, biogeography of wild rats. The section on Ecology could be a sub-section of this section, and should discuss the distribution of rats in cities more.

The Ecology section has been replaced and now follows the Natural History section. Both sections have been revised.

Difference between lab and wild rats are currently described in three consecutive sections: "Laboratorisation of R. norvegicus", "New laboratory rat populations recreated from wild colonies" and "Comparative studies on wild and laboratory rats". These three sections could be revised and restructured to describe i) the changes that occurred when wild rats were domesticated for use in the lab, ii) how this subsequently limited the usefulness of lab rats for some research, and iii) how researchers try to overcome these limitations by creating new lab rat populations from wild colonies (with mentions of the advantages and limitations of these new stocks).

The sections you mentioned above have been rewritten and restructured accordingly.

- Conclusion

This also needs to be condensed and should avoid introducing too many new concepts that were not discussed in the article.

The conclusion section has been shortened, and it is now only a brief summary.

- Box 1: Disease and pest control

This also needs to offer a high level perspective and can be cut back to avoid too much detail on specific examples of diseases spread by rats. It would be good to instead briefly cover public opinion of rats (as dirty animals, living in sewage and feeding on garbage), and the impact of rats on crops, infrastructures and endangered wildlife. It would be interesting to mention here how humans have tried for centuries to eliminate, or at least control, rat populations, and that research on rodenticide resistance involves both lab and wild rats.

The section has been revised and the first paragraph shorted as per reviewer’s comments. The references have been updated and missing information added.

2) Figures and tables

The current manuscript has a photo as one figure and three boxes to discuss specific topics that would otherwise disrupt the flow of the text. The reviewers felt that the authors should consider moving some of the details currently written in the text into new tables or figures. For example, the information about the systematic groups in the genus Rattus (subsection “Natural history”, second paragraph) should be removed from the text, and presented as a table, or perhaps as a figure with a phylogenetic tree. A map could help the author explain how the Norway rat colonised different geographic regions (see the last two paragraphs of the aforementioned subsection), and the information displayed in Box 2, "The most common stocks and strains of the laboratory rat", would be more easily read if it was presented in a table.

As you suggested, we have transferred the information about the systematic groups in the genus Rattus to a separate box. We have also moved the description of methods for creating rat models in the laboratory to Box 2 (the most common stocks and strains of the laboratory rat). The presentation of stocks and strains in Box 1 has also been rewritten and reformatted into a table.

3) Species common name

It would also be interesting if the authors could briefly explain why this rat is called the "Norway rat" when its origins are thought to be in Asia. A few sentences in the appropriate section would likely satisfy a reader's curiosity.

On a related point, it would be good if the article could also list the other common names, besides brown rat, for completeness – i.e. sewer rat, water rat, city rat, common rat – but then continue to use one name, i.e. Norway rat, throughout the rest of the article to avoid confusing unfamiliar readers.

A brief explanation of the origin of the name "Norway rat" has been added to the Natural History section. The commonly used names have been listed in the Introduction.

4) Wild or lab rats?

In some sections, especially under the heading "Characteristics of the species", it is unclear whether the text refers to wild rats, laboratory strains or both. Please go through the text and make this clearer. It may help if that specific section is renamed "Characteristics of wild Norway rats", and any comparison to laboratory rats is made explicit, or saved for a later section.

We have revised the characteristics of the species to make sure it only described the characteristics of the wild rat. Changes that had occurred during the domestication process have been presented in a separate section "Changes occurring in the process of laboratorisation of Rattus norvegicus".

5) References

Several statements need support references from the literature while some references should be updated.

The references have been revised and updated according to the reviewer’s suggestions.

6) Part of a collection

Lastly, since this article is part of a series that has already covered 12 other model organisms (including two other rodents), it would be good if the authors could do more to highlight similarities/differences between rats and any of the other model organisms in the series. For example, when discussing life history traits that make rats a good choice for a model organism, it'd be interesting to note other models that have similar traits, and cite the relevant articles already in the collection to help readers see the connections [https://elifesciences.org/collections/8de90445/the-natural-history-of-model-organisms].

A brief comparison with other animal models has been presented in a separate section "Comparison with other animal models", and relevant articles from the series have been cited.

Author details

1. Klaudia Modlinska

   Klaudia Modlinska is at the Institute of Psychology, Polish Academy of Sciences, Warsaw, Poland

   Contribution

   Writing - original draft, Writing - review and editing, Conceptualization, Investigation, Methodology

   For correspondence

   kmodlinska@psych.pan.pl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2161-9019

2. Wojciech Pisula

   Wojciech Pisula is at the Institute of Psychology, Polish Academy of Sciences, Warsaw, Poland

   Contribution

   Writing - original draft, Conceptualization, Investigation, Methodology

   Competing interests

   No competing interests declared

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