The bibliometric landscape of infectious disease research in Panama (1990 - 2019): An evaluation of the country’s capability on One Health

Background: This work aims to analyze the landscape of scientic publications on subjects related to One Health and infectious diseases in Panama. Methods: Boolean searches on the Web of Science, SCOPUS and PubMed were undertaken to evaluate the main trends of publications related to One Health and infectious disease research in the country of Panama, between 1990 and 2019. Results: 4,547 publications were identied since 1990, including 3,564 peer-reviewed articles interconnected with One Health related descriptors, and 211 articles focused particularly on infectious diseases. There was a pattern of exponential growth in the number of publications with various contributions from Panamanian institutions. The rates of multidisciplinary, inter-institutional and inter-sectoral research ranged from moderate to low, to very low, respectively. Research efforts have centered largely on protozoan, neglected and arthropod-borne diseases with a strong emphasis on malaria, Chagas and leishmaniasis. Conclusion: Panama has scientic capabilities on One Health to tackle future infectious disease threats, but the ocial collaboration schemes and strategic investment to develop further competencies need to be considered. Through future collaborative efforts, Panama can reduce the risk of pandemics by developing surveillance strategies to improve the prediction of disease spillover, spread and persistence while helping to mitigate the impact on public health and the economy, regionally. future pandemic threats across LAC. We posit that an interdisciplinary approach based on research experience, strong collaboration, stakeholder involvement, and the use of high-tech research instruments while recognizing the constraints of health system in Panama will lead to realistic and sustainable solutions for the ever-growing public health challenges of pandemic threats. These actions will also provide a model for other highly impacted tropical countries globally, including developing nations in LAC.

Conclusion: Panama has scienti c capabilities on One Health to tackle future infectious disease threats, but the o cial collaboration schemes and strategic investment to develop further competencies need to be considered. Through future collaborative efforts, Panama can reduce the risk of pandemics by developing surveillance strategies to improve the prediction of disease spillover, spread and persistence while helping to mitigate the impact on public health and the economy, regionally.

Background
Neglected and emerging infectious diseases are the most alarming public health challenges of the twenty-rst century [1][2][3]. Globally, risky areas for pathogen spillover (e.g., disease hotspots) are projected to occur in tropical and developing regions where human population has grown signi cantly, increasing the interactions between wildlife, domestic animals and people, particularly in the context of habitat disturbance, climate change and socioeconomic inequality [4][5][6][7][8]. Lately, the world has seen a rising number of infectious disease threats with alarming consequences. Ebola, Chikungunya, Zika and, currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exemplify the modern epidemiological era, where increased global travel can suddenly and rapidly turn local pathogen spill-over events into pandemics, resulting almost immediately in hundreds of thousands of infected people and devastated economies worldwide [9,10]. In the case of the coronavirus disease of 2019 (COVID- 19), the new human illness caused by SARS-CoV-2, the overwhelming epidemiological scenario is characterized by collapsed public health systems that could no longer cope with the abrupt escalation of human morbidity and mortality [11,12]. Surprisingly, even though emerging infectious diseases are likely to continue rising in the future [13,14], research about local zoonotic agents (i.e., animal origin) that can become pandemic is rare in most countries, meaning that nobody is preparing to contain or confront future threats [15]. This is a major concern for countries in Latin America and the Caribbean (LAC), with fragile health systems and poor medical infrastructure, which depend on regional research efforts to predict disease transmission and spread within their unique context [16,17].
An effective response to infectious diseases requires high-quality basic and applied research to guide evidencebased interventions and strategic mitigation campaigns [18,19]. The prevention plans targeting infectious diseases also need scientists and institutions to collaborate on the conceptualization of knowledge across multiple disciplines, so that the ecological, epidemiological, and evolutionary complexities of zoonotic -pandemic pathogens are fully taken into consideration [20,21]. The "One Health" model has been advocated to facilitate crossdisciplinary research in response to challenges in human, animal, and environmental health [22]. In 2017, Xie and collaborators sought to study key One Health publications with a system dynamics approach, in order to de ne a conceptual framework for future descriptions of the interdisciplinary engagements involved in this concept [23]. The authors selected 19 articles of 2,368 to reveal a rich theoretical model of interactions among various disciplines and the systematic representation of the numerous components engaged in One Health problem solving. The overall goal of the One Health model is to build institutions that can integrate new scienti c knowledge from multiple disciplines and subjects, and use this knowledge to prevent or react to regional outbreaks and pandemic emergencies [19,24].
The rst step for countries to begin preparing for future infectious disease scenarios is to understand how research about One Health related subjects is shaped locally. In particular, it is valuable to know whether historical research efforts have been related to the One Health concept, and what are the infectious diseases that have received more research attention. A bibliometric analysis using indirect descriptors of relevant human, animal, and environmental health subjects is a valuable tool to describe the local landscape of scienti c publications related to One Health [23,25]. Nevertheless, priorities in low and middle-income countries in terms of research are not focused on rare zoonotic pathogens that can establish a de Novo human-to-human transmission cycle, nor is research focused on basic or applied multidisciplinary sciences that can aid to better understand complex zoonotic disease interfaces. Instead, only common health problems causing a signi cant burden to society are studied and tackled by local disease control programs [26].
Panama, a megadiverse tropical country from Central America, has a long history of successful research initiatives that led to the control of infectious diseases, dating back to the construction of the Panama Canal [27,28]. However, the threat from novel pathogens has increased in recent years due to a rise in the worldwide shipping trade [29,30], uncontrolled urban development and social inequality [6][7][8]31], climate change [32][33][34], and anthropogenic habitat disturbance [35][36][37][38][39][40][41][42][43][44]. In particular, this ecological scenario can lead to the emergence of new pathogens from animals into people, which could then rapidly spread across the world to cause regional epidemics throughout LAC [17,45]. Panama only reported its rst o cial case of COVID-19 on March 9 th , 2020, around the same time than the rest of Latin-American countries. As of November 5, 2020, there have been over 136,567 con rmed cases and more than 2,766 deaths in the country [46]. Currently, COVID-19 is adversely impacting the public health systems of LAC and the scienti c community must see this challenge as an opportunity to contribute novel knowledge to its global study, which could better prepare the region to tackle future pandemic threats [47]. Herein, we aim to describe the pattern of scienti c publications on topics related to the One Health model, in an effort to establish Panama's research capability to tackle future pandemic threats. In doing so, we delineate potential goals and bene ts of implementing a regional cooperative research program within Central America as well as more broadly across other territories of LAC. We focus on infectious disease research because, initially, the One Health model was concentrated on this topic. Nonetheless, we are aware that, in time, the term has become much broader, targeting themes such as food safety, chronic diseases and antimicrobial resistant, among many others [48], thus in order to avoid bias in the scope of this study our de nition of One Health does include some of these themes as de ned by Xie et al. [23].

Data source
A bibliometric analysis using Boolean searches on the Web of Science (WoS, Clarivate Analytics, Philadelphia, PA, USA) , SCOPUS (Elsevier, Amsterdam, Netherlands) and PubMed (National Center for Biotechnology Information, NIH, Bethesda, MD, USA) was carried out to evaluate the main trends of publications about One Health and infectious disease research in the country of Panama, between 1990 and 2019. We used two independent search tactics in several languages (e.g., English, Spanish, German, Portuguese, Italian). Firstly, broad-spectrum search engines such as WoS and SCOPUS were used to look for publications related to the One Health model. Secondly, a more public health-oriented search engine like PubMed was used to quest for publications speci cally regarding infectious diseases (Supplementary Figure S1).
For the rst search strategy, we looked exclusively for peer-reviewed scienti c articles from international journals (Supplementary Figure S1). The set of keywords included "Panama" listed in the a liation eld plus roughly 140 indirect descriptors associated with the One Health model, listed in the title or abstract (e.g., "Panama"[A liation]) AND "Infectious Diseases"[Title/Abstract] OR "Veterinary medicine"[Title/Abstract]), which were extracted from Xie et al. [23] (Supplementary Table S1). Next, all references obtained from WoS and SCOPUS were downloaded in BibTex Collection [49]. Here the goal was to identify areas of discrete or complementary research concentration among local institutions. The terms "Inter-institutional", "Multidisciplinary", and "Inter-sectoral" were assigned to publications involving authors from more than one research institution based in Panama; authors from more than one research area; and authors from the Panamanian Ministry of Health (MINSA), respectively (Table 1). A preliminary search depicted a negligible participation from the Panamanian Ministry of Agriculture (MIDA) in scienti c publications regarding One Health descriptors, thus we excluded this governmental organization from the analysis. We omitted publications that were not conducted in Panama or did not have our targeted search strings as references in their a liations, titles, or abstracts. Additional criteria for exclusion were incorrect time frame (e.g., only articles between 1990 and 2019 were considered in the analysis), and review articles (Supplementary Figure S1).
For the second search strategy, we conducted analogous queries in PubMed for all the scienti c documents (e.g., controlled clinical trials, books, datasets, journal articles, letters, and reviews), and re ned the exploration by searching for the neglected and emerging infectious diseases listed in Mackey et al. [2], Maxwell et al. [15] and Klohe et al. [3] (Supplementary Table S2) (e.g., "Panama"[A liation] AND "Dengue virus"[Title/Abstract]). The latter references are key articles regarding pathogens and diseases with spillover potential in LAC and more broadly as well.

Statistical analysis
The variables of analysis encompassed the year of publication, research institution, research subject, type of collaboration (e.g., Inter-institutional, multidisciplinary, and inter-sectoral), type of disease (e.g., agent name and transmission mode) and type of document. We calculated and compared relative frequencies, percentages, sum, and the population median with descriptive and inferential statistics using the software Prism 8 (Graphpad Software, San Diego, CA, USA). Data collection and exploration was performed during the same week (from April the 5 th to April the 12 th , 2020) to avoid bias owing to changes in publication patterns over time.

Results
4,547 publications about One Health related subjects were identi ed using combined Boolean searches in WoS and SCOPUS from the country of Panama since 1990, representing 59.5% (4,547 / 7,632) of the total publication output of the country in these databases during the same time frame. Of these 4,547 publications, 78.3% (3,564 / 4,547) were reliable peer-reviewed articles from international journals after eliminating duplicates (Table 1 (Table 1). We also gathered 256 scienti c documents through re ned searches in PubMed, with 82.0% (211 / 256) focusing speci cally on neglected and/or emerging infectious diseases (Supplementary Figure S1).
We identi ed a statistically signi cant correlation between the number of cumulative peer-reviewed articles associated with the One Health model in Panama and the year of publication (rho = 0.99, two-tailed P < 0.05), depicting a strong monotonic positive relationship between scienti c productivity and time. The results could not be explained by the increase in the number of scientists alone, as the data tted an exponential growth pattern [Y= 2.0e-044*exp(0.052*X); R 2 = 0.98] better than a classic tendency of linear population growth [Y= 11.04 *X -22018; R 2 = 0.80] ( Fig. 1 A). The growth in scienti c productivity about One Health related subjects appears to be in uenced heavily by STRI, taking off around the year 2000 ( Fig. 1 B). A similar but much lesser tendency was also observed among other Panamanian institutions, although the increase in publication records started approximately 10 years later, closer to 2010 ( Fig. 1 B). Excluding STRI from the growth chart, the increase in scienti c productivity about One Health related subjects in Panama seems associated to, and continues to be propelled by, the launch of City of  Fig. 1 C). Overall, we detected low to moderate rates of multidisciplinary (5.9% -60.4 %) and inter-institutional research (14.1% -67.3%), respectively, re ecting a modest but rising effort by local institutions to combine knowledge and competencies. However, the rate of inter-sectoral research was very low (< 0.01% -11.5%) ( Table 1).
STRI has signi cantly more peer-reviewed articles about One Health related subjects since 1990, with a total  (Fig. 1 D). Despite the aforementioned differences, the proportion of One Health associated publications relative to the total institutional output was higher in ICGES (58.6% -365/622) and INDICASAT (55.4% -177/319) followed by STRI (46.0% -2,523/5,482) and UP (32.0% -360/1125) ( Table 1). There was a noticeable difference between STRI and the rest of the institutions in terms of areas of concentration ( Fig.   2A). STRI had the lowest rate of multidisciplinary research, and its One Health related publication record focused largely on environmental ecology, evolutionary biology, plant science and biodiversity (Table 1 Infectious disease research in Panama during the last three decades has centered largely on protozoan, neglected and arthropod-borne diseases, with a strong emphasis on malaria, Chagas disease and leishmaniasis, especially during the last 10 years (Fig. 3 A-F). Additional bacterial and viral infections such as tuberculosis, in uenza, Hantavirus and leptospirosis, have received considerably less attention from the scienti c community than the group of arthropod-borne diseases. No articles were discovered from Panama through PubMed searches about Bovine tuberculosis in humans, Shigellosis, Salmonellosis, Escherichia coli infection, Onchocerciasis or the rest of the disease terms listed in the previous studies used for our methodology. The rate of inter-institutional and intersectoral research particularly concerning neglected and emerging infectious diseases in Panama was low, with most work done by a single institution and without the enrolment of MINSA (Fig. 3 D, G).

Discussion
A recommended rst step for countries trying to prepare for future infectious disease scenarios is to understand how the local One Health publication landscape looks like. Here we make progress toward this end, describing the scienti c output about infectious disease research from Panama in the last 30 years. Our evaluation strives to serve as a tool for local health authorities to determine the country's research capability on speci c aspects of zoonotic pathogens within the One Health umbrella [48,50].
Overall, publication output for One Health related research has grown signi cantly in Panama since 1990. Although the country's research agenda has not explicitly focused on One Health, almost 60% of the entire country's research productivity is interconnected with this concept. We revealed a signi cant pattern of temporal growth in publication records associated with the One Health model, with noticeable differences in the number of peer-reviewed articles and the range of scienti c areas tackled by different institutions. Institutional variation in research focus and publication output related to One Health might be due to differences in the task, budget, number of scientists and/or operation time in the country (Supplementary Figure S3). For instance, STRI is the only unit of the Smithsonian located outside the USA, and researchers have conducted pioneering studies on plant and animal ecology in Panama for more than 100 years. STRI has 15 research facilities scattered across the country, 40 staff scientists and more than 1,400 scienti c visitors every year [51], which may explain its larger input to One Health related studies compared to other institutions (Table 2). Similarly, the ICGES, the oldest public health institute in Panama Infectious disease research in Panama has concentrated on arthropod-borne zoonotic infections, with a strong inclination for protozoan pathogens transmitted by mosquitoes (i.e., Anophelinae -Plasmodium), sand ies (i.e., Phlebotominae -Leishmania) and kissing bugs (i.e., Triatominae -Trypanosoma). Malaria, Chagas disease, and leishmaniasis have been equally and greatly investigated in the country, re ecting the persistence of these neglected tropical diseases in poor rural settings and isolated indigenous communities [6, 32-37, 44, 54, 55], but also SENACYT's steady motivation to sponsor research projects about vector-borne infectious diseases [56]. The Ministries of Health and Agriculture from LAC have recognized some of these zoonoses as endemic or emerging priorities, including Chagas disease and leishmaniasis [15]. However, other zoonoses with spillover potential have received relatively less attention by the Panamanian scienti c community thus far [16]. This is the case of in uenza, Hantavirus, tuberculosis and leptospirosis, plus rare animal diseases such as rabies, brucellosis, salmonellosis, and also recent pandemic infections like West Nile, Chikungunya and Zika arboviruses (Fig. 3). In fact, 60% of the infectious diseases classi ed as priorities for LAC, have not been studied in Panama whatsoever [15,16]. Generally, these outcomes mirror the low publication record seeing in this study by MINSA, MIDA and the Agriculture Research Institute (IDIAP), which are the governmental agencies in charge of investigating these topics, or they may just be due to the recent emergence time of some of these pathogens. Our ndings underline the limited inter-sectoral research between academia and MINSA/MIDA in Panama during the last three decades. Future efforts will have to align the needs among local academic and governmental institutions, and between them and those from the Ministries of Health and Agriculture in LAC [15,57,58].
Targets and bene ts from implementing a One Health research program in Panama and LAC A cooperative research approach for bioscience and health has been advocated for Panama before, echoing the need for a connection of research priorities among the social, environmental, agricultural and health sectors [59]. To be successful though, this proposal needs to involve a synergistic collaboration among SENACYT, MINSA, MIDA and researchers from various Panamanian institutions with strongly complementary research traditions and strengths [26,59]. However, the rates of multidisciplinary, inter-institutional and inter-sectoral research in Panama are moderate to low, and very low, respectively, which means that the links among academic institutions and between them and stakeholders, are still limited making the implementation of the One Health model challenging. To overcome these problems, the government of Panama needs to create funding instruments that favor interinstitutional and inter-sectoral collaborations, particularly between those institutions that have published little about One Health related subjects (i.e., UTP, IDIAP, private universities, MINSA and MIDA), over single institutional research plans, which do not include the participation of MINSA or MIDA. In addition to local funding instruments, international collaborations, including partnerships among the Ministries of Health and Agriculture along with prominent academic institutions from LAC, need to be considered and sponsored to increase local competitiveness while building the necessary technological capacity to compete for extra funding overseas ( Table 2) The government of Panama needs to allocate extra funding to improve the research infrastructure nationwide, create additional scholarship programs to continue training undergraduate and graduate students, and to build competitive leadership by increasing manpower and job opportunities in interdisciplinary areas across the country ( Table 2). Non-Governmental Organizations (NGOs), both local and international, also need to be part of the One Health agenda, as they may provide in-kind support to strengthen research opportunities during training, response, and post-pandemic activities. Moreover, Panama needs to invest resources to create the rst One health research Centre in Central America in order to coordinate the best available resources to solve complex infectious disease events through building new competencies in bioinformatics, genomics, and vaccine development, while promoting inter-sectoral studies and joint governmental efforts across LAC (Table 2). Since Panama is historically important in terms of disease research with the institutional infrastructure in place, and a Center of commerce and trade, the country is perfectly located to continue carrying out research about infectious diseases. Given Panama's position as a global logistical hub, and major airline center between North and South America, the research and intellectual knowledge generated by a collaborative One Health research program will position the country to respond quickly to newly emerging pathogens of pandemic potential. This has the advantage of stopping or at least slowing the spread of an epidemic regionally and provides a sophisticated research infrastructure for monitoring new pandemic foci ( Table 2). While research institutions in Panama differ in various degrees of expertise and scienti c interest, each of them brings a unique visualization of the disease spillover process, which can effectively supplement joint research efforts about pandemic zoonotic pathogens (Fig. 2). Panama has one of the most species-rich and bestcharacterized faunas of the world, and researchers from STRI, ICGES, INDICASAT and UP bring expertise in tropical ecology, public health, disease epidemiology, and the population and evolutionary dynamics of pathogens, vectors and hosts relationships, which could be easily integrated into a solid research plan under the One Health framework.
The high level of research complementarity among Panamanian institutions can be used to enable an information system for the prediction and mitigation of future zoonotic spillover events, including enhanced voucher collections of wildlife, domestic animal and human tissues plus associated pathogens and vectors [70].
Panama's One Health research program will need to cover research efforts oriented towards eld monitoring and ecological understanding of highly pathogenic disease agents, and the animal hosts that act as reservoirs or vectors in both natural and anthropogenic environments [20,21]. Nevertheless, the focus should also be extended to experimental research, basic epidemiology, mathematical modeling, molecular ecology, clinical trials and social sciences [63] (Table 2). Furthermore, One health's research efforts in Panama need to tackle not only diseases that are transmitted by arthropods, but also sexual, respiratory, and fecal-oral parasitic infections plus chronic and noninfectious health-related issues such as cardiovascular disease, diabetes, cancer, hypertension, obesity, and neurodegenerative illnesses, which have not been studied comprehensively in the country thus far [56]. The country needs to establish an innovative and broad research, education, and training Curricula on One Health by incorporating areas other than infectious diseases, including more recent development within this framework such as food safety, biodiversity, chronic diseases, animal companionship, and antimicrobial resistant, among many others (Table 2). Finally, the private sector, pharmaceutical and biotechnological companies, need to play a role in developing partnerships with academic and governmental agencies to increase research activities towards appropriate medical technologies and therapeutic products, ensuring their availability to, and affordability for the populations in need.

Limitations
To the best of our knowledge, there has been no bibliometric study about One Health research-associated literature in Panama, despite the prominent history of neglected and emerging infectious disease research in the country. Our work has certain limitations that we discuss as follows. The proportion of publications related to One Health may have been overestimated by including indirect descriptors from Xie et al. [23] in the search window, instead of using "One Health" directly as a key word. Furthermore, the proportion of publications about One Health could have been underestimated by focusing exclusively on research concerning the eld of infectious diseases and overlooking various other components currently studied by this approach (e.g., chronic diseases, animal companionship, and antimicrobial resistance). While these are valid possibilities, we acknowledge that zoonotic infectious diseases were central to the One Health movement initially and continue to be a core element of it to date. Also, to avoid bias in our search strategy by picking One Health related terms subjectively, we used information and terminology from 19 scienti c publications, which were recently identi ed through a system dynamics approach, to delineate the central dogma of the One Health concept [23].
In addition, we could have missed articles from scienti c journals that were not indexed in the WoS, SCOPUS or PubMed during the study period, but these are the largest abstract and citation databases of peer-reviewed literature, including medical, technical and social sciences. These search engines have been used before to assess the publication trend of important infectious diseases, including those studied under the One Health framework [18,19,24,25,71]. Finally, we only included the last 30 years of research in the analysis because this is the time period when major science development events occurred in Panama, including the transfer of the Gorgas Memorial Laboratory, a United States institution working on tropical diseases since 1921, to MINSA in 1990, and the subsequent launch of the City of Knowledge, SENACYT and INDICASAT [26,59]. Our work is the rst to evaluate Panama's research capacity on One Health and infectious disease research, and it is intended as a preliminary hypothesis for future studies.

Conclusion
Findings recognize the publication trend associated with the One Health concept in Panama and provide a better understanding as to how collaborative research from local institutions could better prepare health authorities to tackle future infectious disease threats. Research about the control of infectious diseases has a long history in Panama, and the launch of the One Health research program, related to the current situation of COVID-19 in LAC, can build on this proud tradition. Emerging infectious diseases are likely to continue rising in the future due to continuous and COVID-related social and economic pressures on natural resources and deforestation. The global health impact of COVID-19 and the renewed local interest on major construction projects (e.g., mining, highways, timber extraction) in protected areas due to the related economic pressures, highlights the relevance of One Health research in Panama to reduce the risk of pandemics by developing surveillance strategies to improve the prediction of disease spillover, spread and persistence while helping to mitigate the impact on public health and the economy.
The local scienti c community must collaborate to learn more about zoonotic spread between animals, humans and the environment, so that the outcome of high-quality basic and applied research can be used to guide the implementation of effective mitigation strategies. This scienti c knowledge can be used as the starting point to design a proactive strategy to survey, contain and mitigate future pandemic threats across LAC. We posit that an interdisciplinary approach based on research experience, strong collaboration, stakeholder involvement, and the use of high-tech research instruments while recognizing the constraints of health system in Panama will lead to realistic and sustainable solutions for the ever-growing public health challenges of pandemic threats. These actions will also provide a model for other highly impacted tropical countries globally, including developing nations in LAC.

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Competing interests
The authors declare that they have no competing interests.  Real time observations are also essential for priming and evaluating the end products of prediction models. *** The diversity of tropical infectious diseases in LAC is high, and some tropical infections mimic COVID-19 symptoms at the onset of illness. Hence, a network of regional specialized laboratories for accurate diagnoses using validated protocols will allow countries to distinguish among closely related diseases, yet with different pandemic potential.