Peruvian contributions to scientific publications on experimental research against COVID-19: a systematic review [version 1; peer review: awaiting peer review]

Background: One of the countries most adversely affected by the COVID-19 outbreak was Peru. Worldwide scientific knowledge creation has significantly grown because of this pandemic. This systematic study aims to examine several facets


Introduction
Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in December 2019 in Wuhan, China, and has spread worldwide, becoming a pandemic with catastrophic effects. 1-3 SARS-CoV-2 severely affects humans because it is highly transmissible and rapidly mutates 4 and is reported to have a mortality rate between 0.8-19.6% with regional variation. 4,5 Various health strategies have been applied around the world, such as non-pharmacological interventions (use of masks, social distancing, monitoring of infected persons, etc.) and vaccination to reduce the spread of the virus and contagion. 6 However, since the emergence of SARS-CoV-2, there have been approximately 755 million cases of COVID-19 and 6.8 million deaths up to February 2023 (https:// covid19.who.int/).
The first case of COVID-19 in Peru was reported on March 6, 2020, and community transmission began on March 17, 2020. At the beginning of the pandemic, the Peruvian government determined prevention measures and mandatory social isolation to control the spread of SARS-CoV-2. 7,8 However, it could not avoid being one of the countries most affected in the number of cases, deaths per million, and total excess samples during the COVID-19 pandemic. 9 Faced with the current health crisis due to the COVID-19 pandemic, there has been an increase in scientific production on the subject worldwide in different fields due to the need to effectively control the disease (finding health solutions, treatments, diagnostic methods, understanding the pathophysiology of the virus, research into vaccines, etc.). 12,13 As a result, the Peruvian government issued a supreme decree to encourage clinical trials on the prevention, diagnosis, and treatment of COVID-19. 14,15 Additionally, the National Council for Science, Technology, and Technological Innovation (CONCYTEC), called for funding for research. 16 One Health can be used to treat a public health issue affecting people, animals, and the environment. 14,15 The COVID-19 pandemic has shown the importance of worldwide cooperation in developing and distributing vaccines and treatments and exchanging knowledge and resources. 17 Additionally, scientists from several fields, including epidemiology, virology, animal health, and environmental health, collaborate as part of the One Health concept. 14 Thus, various countries have carried out an internal investigation to respond to their own needs regarding COVID-19 according to their capacities and infrastructure. 15,16,18,19 Therefore, the objective of this research is to evaluate the generation capacity of experimental research carried out in Peru, which will help in making future decisions, both to establish future studies, to elucidate the lack of studies in certain areas, as well as to determine the country's roadmap in a current and future state of emergency.

Study protocol
The present systematic review was carried out as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 20 The protocol for this systematic review was registered on INPLASY (INPLASY202340080) and is available in full at inplasy.com. The systematic review has been elaborated according to PRISMA 2020 checklist (see Reporting guidelines). 20 The search was limited to studies published from December 2019 to June 22, 2022, in the PubMed database (Last  accessed on 22 June 2022), with free electronic access that contains more than 35 million citations and abstracts of biomedical literature that includes various literature resources of the National Library of Medicine (NML) such as MEDLINE, PMC, and other databases. 21 The search for the terms associated in the literature with COVID-19 and Peru was carried out using the MeSH term (Medical Subject Heading), and the results were analyzed in a co-occurrence network map of MeSH terms in the VOSviewer software (version 1.6.18). 22 MeSH terms, which are used to index the citations since this is a vocabulary controlled by the NML, organize their descriptors hierarchically so that more specific articles can be found from a broad search. Specialists from various areas constantly update the MESH term; every year, new concepts are modified and added. 23,24 The search string used in PubMed was: ((COVID-19[MeSH Terms]) OR (SARS-CoV-2 [MeSH Terms])) AND (PERU).

Selection criteria and data extraction
The studies included in the systematic review were selected in three stages. First, duplicate articles, original articles other than the English language, critical and systematic reviews, meta-analyses, and publications other than an original article were excluded: letters to the editor, commentary, editorial and case reports, data studies, news, conference, and directory; all these classifications were considered using the PubMed filters. [25][26][27] Secondly, the titles and abstracts of the studies selected using the search strategy were analyzed. Finally, potentially relevant complete studies were retrieved and removed from the articles with a title or abstract that did not provide appropriate data to be considered within the systematic review. The included studies were those that were published in journals of quartile one or two, had first authors and/or corresponding authors with Peruvian institutional affiliations, and/or had Peruvian funding. The research topics for these studies had to produce new scientific knowledge, development, innovation, and/or adaptation of new or improved low-cost technologies, products, mechanisms, or services. 28,29 Data extraction was performed by K.C.-M. and validated independently by M.A.C.-P., with discrepancies resolved through discussion and by conferring with M.A.C.-F. The following data were extracted: first author, first author's institution of affiliation, first author's country, corresponding author, corresponding author's affiliation, corresponding author's country, journal, year of publication, quartile, impact factor, institution funder, research topic, and type of research. The quartiles and impact factors of the journals were obtained from the Scimago Journal and Country Rank and/or on the main pages of each journal, respectively.

Data sources and study selection
A thorough analysis of Peru's experimental scientific research on COVID-19 was carried out in the current paper. The study strategy's flowchart was created and displayed ( Figure 1). To do this, a search was conducted in the PubMed database using the search mentioned above string of MeSH terms, and a network map of the co-occurrence of MeSH terms was created ( Figure 2). Through the search, 794 scientific papers between December 2019 and June 22, 2022, were found. A network map was created using 2,390 keywords, of which 212 achieved thresholds, and the minimum number of keyword occurrences was set at five. The most frequently occurring keywords were "COVID-19" (935 occurrences; total link strength: 7,327) and "HUMANS" (788 occurrences). The size of the nodes shows how frequently they occur. The co-occurrence of the nodes is shown by the curves connecting them in the same publication. The frequency of co-occurrences of two keywords increases with decreasing distance between nodes; in this case, the most frequent terms, such as "COVID-19", "HUMANS", "SARS-COV-2", "PANDEMICS", and "PERU", are observed ( Figure 2). Nine studies on experimental scientific research on COVID-19 were selected ( Figure 1). Data such as PMID, research types, the applicability of the study, theme, specific theme, year, and journal were taken out of the chosen studies ( Table 1).

Type of biomedical research and study applicability
Biomedical research generally encompasses basic and clinical research also called applied research, specifically observational diagnostic studies and experimental studies. 30,31 The basic biomedical research category, comprising 55.6% (n = 5) 32-36 of the total studies considered in the review, came in first position as the category with the most original publications. On the other hand, clinical observation diagnoses accounted for 44.4 % (n = 4) 37-40 of the total number of original articles and was the second type of biomedical research with the highest number of unique publications. Of these, 11.1% (n = 1) of the total original articles of the review were classified as "Experimental" clinical research, specifically a preclinical study, and 33.3% (n = 3) of the total original articles of the review were classified as "Diagnostic Observational" clinical research (Table 1).
Two categories of research-basic and applied-were separated based on inquiry. Basic research seeks to understand phenomena by gathering data, whereas applied research's major goal is to provide an accurate, practical application, or to address a particular issue. 28,29 The systematic review results were classified according to their applicability, of which the most prevalent was "Applied" research with 77.8% (n = 7) of the total original articles of the review. On the other hand, the one with the lowest prevalence was "Basic" research with 22.2% (n = 2) of the total original articles of the systematic review (Table 1).
Thematic area and specific thematic The calls for funding, "Special Projects: Response to COVID-19" and "Special Projects: Modality Emerging Needs to COVID-19 2020-02," both sponsored by CONCYTEC in response to the national emergency of COVID-19, were used to trace general and specific categories for the studies of the systematic review. 28,29 The first place was taken by the thematic area of "Treatment and transmission," which accounted for 55.6% (n = 5) of the total original articles. The second place went to the thematic area of "Diagnosis," which accounted for 33.3% (n = 3) of the total studies, while the third and final place went to the thematic area of "Sanitary accessories," which accounted for 11.1% (n = 1) of the total studies. Study of molecules and potential applications for SARS-CoV-2 was the specific theme that predominated,   accounting for 33.3% (n = 3) of all original articles, followed by "Studies of virus transmission mechanisms to reduce its spread," accounting for 22.2% (n = 2) of original articles. Both specific themes fall under the treatment and transmission thematic area. However, "Diagnosis" was the next most prevalent theme, with "Adaptations of diagnostic tests" accounting for 11.1% (n = 1) of the total number of original articles, "Rapid diagnosis methodology" coming in second with 11.1% (n = 1), and "Tests laboratory" coming in third with 11.1% (n = 1) of the total number of original articles (Table 1). Finally, the specific theme with the lowest number of original articles was "Sanitary accessories", having only one specific subject and one original article "Respirators and ventilators" with 11.1% (n = 1) of the total original articles of the review (Table 1).
Journal impact factor and quartile A first quartile (Q1) journal has a high impact factor and number of citations in a specific thematic area, allowing greater visibility of published articles. 41,42 The authors selected Scientific Reports and PLOS One most often (n = 2; 22.2%), whereas only one original paper (11.1%) was published in each of the other five journals. One journal from the United Kingdom, two from the United States, and four from Switzerland made up the total number of journals in the systematic review research. Seven journals came from the first quartile (Q1). The highest impact factors were 20.693, 6.429, and 6.208, representing the Journal of Medical Virology, Frontiers in Immunology, and International Journal of Molecular Sciences in first, second, and third position, respectively. The fourth-and fifth-placed journals were Scientific Reports with an impact factor of 4,996 and Molecules with 4,927. Finally, Frontiers in Cellular and Infection Microbiology and PLOS One impact factors of 4,300 and 3.240, respectively, were sixth and seventh in the ranking as the journals with the highest impact factor ( Table 2).

Funding and grants
Only one (11.1%) of the included articles was jointly funded by Peru and the United States. The organizations that funded the most original articles were the National Health Institute (INS), CONCYTEC, and Universidad Católica de Santa Maria representing 22.2% (n = 2) of total included articles. The country that financed the largest number of original studies was Peru, with 88.9% (n = 8) of the total articles. Co-financing for one study (11.1%) in the systematic review came from INS and CONCYTEC, "Universidad Católica de Santa Mara" and "US Grants" jointly funded one study (11.1%) and CONCYTEC and Universidad San Juan Bautista jointly funded one study (11.1%). Only two universities in Peru-Universidad Católica de Santa Mara and Universidad San Juan Bautista-funded articles included in the systematic review ( Table 3).  Heredia and FARVET SAC, on the other hand, both published articles on the "Treatment and transmission" theme. Finally, Pontificia Universidad Católica del Peru published an article with the theme "Sanitary accessories". Based on the affiliation of the first author, Lima, Peru, produced the most original articles, accounting for 55.6% (n = 5) of the total; Arequipa, Peru, produced 33.3% (n = 3) of the total; and the city of Cusco, Peru produced the least original articles. The city of Chincha accounted for 11.1% (n = 1) of all originals ( Table 5).    Universidad Cayetano Heredia, and FARVET SAC, each had two corresponding authors (22%; n = 2). Finally, Harvard Medical School, Massachusetts General Hospital, and Pontificia Universidad Católica del Peru are the organizations that produced the fewest included articles in the systematic review, accounting for a combined 11.11% (n = 1) of all the systematic review's articles (Table 5).

Discussion
Scientific research plays a significant role in preventing and controlling pathogens, such as SARS-CoV-2, which can cause pandemics, so it must be strengthened and increased to have a better response against future pathogens. 43,44 There was a sharp rise in the number of scientific papers on the COVID-19 pandemic because of the numerous investigations that researchers carried out around the world. 16,45 For this reason, this systematic review summarizes the experimental scientific research carried out in Peru against COVID-19 to identify and analyze trends and gaps in the experimental scientific field to guide the priorities and actions of researchers in future studies.
Peru was one of the countries most affected by COVID-19, 46,47 not only because of the vast death toll 48,49 but also because of the country's economy. 50 Nonetheless, until 2021, Peru had allocated around 2.9 million US dollars to 50 projects to conduct scientific research related to COVID-19. 51 However, as reported in this systematic review, the production of original experimental articles was deficient, since only nine studies were found to have originated in Peru, of which six were executed with government funds. This number, as mentioned, is extremely modest considering that there was an average of 137 study articles published every day in the months immediately after the virus emerged. This demonstrates how productive research groups throughout the world were. 48,52 Insufficient laboratory infrastructure and funding, a lack of professional security for scientists, a lack of policies to direct scientific projects, and political corruption contribute to low scientific productivity in developing nations like Peru. 49,50,53 Applied research made up 78% of the studies examined. In contrast to basic research, which aims to understand how nature functions without any other practical incentive, applied research focuses on using current knowledge to address a specific need. 54 Since applied research stresses the quick resolution of specific population problems, it is recommended that developing nations focus their investment efforts there. 37 Peru will continue to follow this pattern as long as the country lacks the resources to conduct basic and novel research. A developing nation is thought to benefit from focusing its investment efforts on applied research since it stresses the quick resolution of issues that impact the populace. 53 RENACYT is the National Scientific, Technological, and Technological Innovation Registry of natural persons, Peruvian or foreign, who carry out science, technology, and innovation activities in Peru. According to the regulations established in 2021, Peru had 4,702 active researchers in February 2023 (https://servicio-renacyt.concytec.gob.pe/). Accordingly, there were 147 researchers for every million people, of whom 31% were researchers in the health sciences. This ratio is lower than that of other South American nations like Chile, Colombia, and Mexico, where there are 400 researchers for every million people. 34 Peru's weak scientific output is directly tied to the country's low researcher population.
Recent decades have seen a rise in the importance of scientific collaboration, which is more effective than individual work and increases the possibility of publishing in high-impact journals through collaborative research. 50,55 Considering the affiliation of the first author and that of the corresponding author of the included studies that form part of this review, only one presented an international collaboration between the University of Peru and a US institution. 35 Given that international collaborations have a stronger beneficial impact than national, local or intra-university ones, Peru should boost its cooperation to increase research productivity. 56

Conclusions
Peru is one of the countries that has funded the growth of experimental research related to COVID-19. Still, as this study indicates, there has been low publication output compared to scientific production worldwide, despite having a financial incentive, and there was very little international collaboration in these papers. Despite the low scientific productivity in Peru, the researchers who wrote the publications reported their findings in high-impact journals. As a result, Peru should support appropriate policies to increase the number of researchers and financial support to allow research to be published for the benefit of its citizens and to better prepare for pandemics like COVID-19 in the future.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.