Trend in H2S Biology and Medicine Research—A Bibliometric Analysis

The biological and medical importance of hydrogen sulfide (H2S) has been recognized for decades. The aim of this bibliometric study is to analyze the quantity and quality of publications in H2S biology and medicine (H2SBM) based on the databases of Web of Science and Google Scholar. A total of 5881 publications published between 1990 and 2016 were analyzed. The number of H2SBM papers published before 2004 was below 100 annually, but thereafter this number rapidly increased and peaked in 2015 with more than 7-fold increase. All publications related to H2SBM research achieved a total h-index of 136 and were cited 123,074 times. The most published disciplines in H2S biomedicine research were the cardiovascular system (8.5%), neuroscience (6.5%), and gastroenterology hepatology (4.7%). The country with the greatest number of publications in the H2SBM research field was the USA with 1765 (30.0%) publications, followed by China with 995 (16.9%) publications and Japan with 555 (9.4%) publications. The top 3 most published institutes were National University of Singapore, Peking University in China, and University of Groningen in Netherlands. Nitric Oxide Biology and Chemistry was the most exploited journal for H2SBM publications with 461 articles, followed by FASEB Journal with 200 publications and Antioxidants Redox Signaling with 116 publications. The most highly cited publications and researchers in H2SBM research were also unmasked from this bibliometric analysis. Collectively, H2SBM publications exhibit a continuous trend of increase, reflecting the increased H2SBM research intensity and diversity globally.


Introduction
Hydrogen sulfide (H 2 S) was historically considered to be highly toxic and hazardous to the environment. However, in recent decades, H 2 S has been recognized as a novel gasotransmitter, similar to nitric oxide and carbon monoxide [1][2][3][4][5][6][7][8][9][10]. The concept of gasotransmitter and the classifying criteria were first framed in 2002, and since then, we have witnessed the rapid growth of the research field in H 2 S biology and medicine (H 2 SBM) [2,11]. A large amount of work has been conducted globally leading to many breakthrough discoveries on the paramount roles of H 2 S in biology and medicine. H 2 S acts as a universal molecule in different species, including human, mouse, rat, plant, bacteria, virus, and many others [8]. Four international conferences on the Biology and Medicine of H 2 S have been held in Shanghai (China, 2009), Atlanta, GA (USA, 2012), Kyoto (Japan, 2014), and Naples (Italy, 2016) [12][13][14], and the 5th international conference will be held in Toronto, ON (Canada) in 2018. In addition, specific H 2 S-related topics or sections have been featured in numerous symposia such as European Conference on the Biology of Hydrogen Sulfide, and Experimental Biology Meeting. A unique organization, the European Network on Gasotransmitters, was formed in 2011. We are experiencing one of the most expanding research evolutions in the recent history of biomedical sciences.
Despite the large amount of H 2 SBM-related literature that has been published, a systematic analysis of the scientific literature in H 2 SBM research has not been conducted to date. Given the enormous number of publications, a bibliometric analysis that identifies comprehensively the major research topics and outcomes in H 2 SBM will provide insight and guidance for scientists and all relevant stakeholders of academia, industry, and health management. Bibliometrics is often used to measure and compare the publications within a given topic, field, journal, institute, funding agency or country, which would enable the comprehensive recognition of the most important and relevant scientific values and impact [15,16]. To this end, we undertook the present bibliometric study to explore the characteristics of global research publication output from H 2 SBM research by using publicly available databases including Web of Science and Google Scholar.

Search Tools
The H 2 SBM data published between 1990 and 2016 were collected from the Thomson Scientific Web of Science core collection (http://www.webofknowledge.com/WOS), a multidisciplinary index to the journal literature of science and technology [17]. To gather the citation data for H 2 SBM papers, both Web of Science and Google Scholar databases were used up to 15 October 2017. Web of Science produces interdisciplinary literature databases, including the creditable journals of numerous research disciplines. It should be noted that Web of Science only represents about 15% of the total number of English language journals currently published worldwide [17]. In contrast, Google Scholar includes a wider variety of publications more than Web of Science does [18]. Although both Web of Science and Google Scholar have the powerful feature of tracking citing items, the times cited differ greatly between Web of Science and Google Scholar based on different searching algorithm.

Search Strategies
dairy animal science, material science ceramics, mechanics, material science paper wood, nuclear science technology, soil science, fisheries, engineering manufacturing, agronomy, computer science interdisciplinary applications, material science textiles, paleontology, construction building technology, remote sensing, engineering industrial, materials science biomaterials, and engineering biomedical. The inclusion and exclusion categories used in our study are intended to relatively focus on the publication directly related to H 2 SBM, not those with the focus on environment production of H 2 S, H 2 S-induced pollution, or H 2 S toxicology. In this study, two indicators for citation impacts are used, including the impact factor (IF) of journals in 2016 and the h-index. IF is a useful indicator to assess the citation quantity of journals [19]; and the h-index is used to measure the productivity and impact of published works from different researchers, research field, countries, institutes, or journals [20]. SSPS software 16.0 (Armonk, NY, USA) was used to analyze the groups' correlation coefficient.

Evolution of H 2 SBM Research
After applying the inclusion and exclusion criteria to the publication databases, 5881 publications in H 2 SBM research were registered from Web of Science core collection database. In recent decades, the literature on H 2 SBM has an overall increasing trend in the total number of scientific publications from 1990 to 2016 ( agronomy, computer science interdisciplinary applications, material science textiles, paleontology, construction building technology, remote sensing, engineering industrial, materials science biomaterials, and engineering biomedical. The inclusion and exclusion categories used in our study are intended to relatively focus on the publication directly related to H2SBM, not those with the focus on environment production of H2S, H2S-induced pollution, or H2S toxicology. In this study, two indicators for citation impacts are used, including the impact factor (IF) of journals in 2016 and the hindex. IF is a useful indicator to assess the citation quantity of journals [19]; and the h-index is used to measure the productivity and impact of published works from different researchers, research field, countries, institutes, or journals [20]. SSPS software 16.0 (Armonk, NY, USA) was used to analyze the groups' correlation coefficient.

Evolution of H2SBM Research
After applying the inclusion and exclusion criteria to the publication databases, 5881 publications in H2SBM research were registered from Web of Science core collection database. In recent decades, the literature on H2SBM has an overall increasing trend in the total number of scientific publications from 1990 to 2016 (

The Top 10 Mostly Cited Publications in H2SBM Research
For all publications related to H2SBM research, an h-index of 136 and total citation of 123,074 times were generated (Web of Science core collection). The median number of citations per article is 20.9. The numbers of citations for the top 10 mostly cited articles ranged from 1073 to 456 by Web of Science or 1754 to 697 by Google Scholar (Table 1) [1][2][3][4][5][6][7][8][9][10]. The median number of citations for these top 10 mostly cited publications was 782 from Web of Science and 1168 from Google Scholar. The rank of the top 10 mostly cited publications listed in Table 1

The Top 10 Mostly Cited Publications in H 2 SBM Research
For all publications related to H 2 SBM research, an h-index of 136 and total citation of 123,074 times were generated (Web of Science core collection). The median number of citations per article is 20.9. The numbers of citations for the top 10 mostly cited articles ranged from 1073 to 456 by Web of Science or 1754 to 697 by Google Scholar (Table 1) [1][2][3][4][5][6][7][8][9][10]. The median number of citations for these top 10 mostly cited publications was 782 from Web of Science and 1168 from Google Scholar. The rank of the top 10 mostly cited publications listed in Table 1  There were 4 different countries of origin for the top 10 mostly cited articles. Canada had the largest number of articles, with 4 from the same group led by R Wang (1st, 2nd, 4th, and 8th). Japan produced 3 articles all with H Kimura as corresponding author (3rd, 6th, and 10th). USA contributed 2 articles, one being from C Szabo group (5th) and another from DJ Lefer group (7th). The 9th one was from PK Moore group in England. In these top 10 mostly cited articles, 6 articles (1st, 3rd, 4th, 6th, 7th, and 10th) were original research articles with 810 mean citation each (Web of science), and the other 4 were review or opinion articles with 741 mean citation each (Web of science). For those 6 research articles, 4 (1st, 4th, 6th, and 7th) were from cardiovascular research and 2 (3rd and 10th) were in neuroscience field.

The Most Receptive H 2 SBM Research Publication Avenues
In total, 5881 H 2 SBM articles were published in a range of more than 100 different journals, and about 23.4% of the H 2 SBM related publications were published in the top 10 journals as listed in

The Most Prolific Countries with H 2 SBM Research Publications
The publication indicators for the top 10 most prolific countries regarding H 2 SBM research were presented in Figure 3. The country with the greatest number of scientific publications in H 2 SBM research field was the USA with 1765 (30.0%) publications, followed by China with 995 (16.9%) publications, Japan with 555 publications (9.4%), England with 449 (7.6%) publications, and Germany with 444 (7.5%) publications. The 6th to 10th productive countries were Canada (413, 7.0%), Italy (314, 5.3%), Singapore (237, 4.0%), Netherlands (191, 3.2%), and France (178, 3.0%). The top 10 prolific countries account for 94.2% of the total number of scientific publications. Table 2 showed the top 10 productive institutes ranked by the numbers of publications. National University of Singapore was ranked the first in terms of publication output with 235 publications,

The Support of H 2 SBM Research by Different Funding Agencies
Funding acknowledgements from publications showed that National Natural Science Foundation of China supported the most H 2 SBM research with 437 (7.4%) publications, followed by the National Institute of Health of USA with 253 (4.3%) and National Heart Lung and Blood Institute of USA (76, 1.3%) (Figure 4). The fourth to tenth funding agencies in supporting H 2

The Support of H2SBM Research by Different Funding Agencies
Funding acknowledgements from publications showed that National Natural Science Foundation of China supported the most H2SBM research with 437 (7.4%) publications, followed by the National Institute of Health of USA with 253 (4.3%) and National Heart Lung and Blood Institute of USA (76, 1.3%) (Figure 4).

Researcher Citation Impact
The top 10 most prolific researchers in H2SBM publications are listed in Table 3. Among these 10 researchers, R. Wang from Canada had the highest citation being 8545 from 130 publications. The 2nd and 3rd most cited authors were PK Moore (7765) and H Kimura (6873) both with 115 publications. M Whiteman from England was the most prolific scientist with 136 publication cited by 3554 times. For these top 10 most productive scientists, PK Moore had the highest h-index of 47 and R Wang was the second with an h-index of 45, separating from the others with a gap. These eminent researchers were definitely considered to be the forerunners in H2SBM research.

Researcher Citation Impact
The top 10 most prolific researchers in H 2 SBM publications are listed in Table 3. Among these 10 researchers, R. Wang from Canada had the highest citation being 8545 from 130 publications. The 2nd and 3rd most cited authors were PK Moore (7765) and H Kimura (6873) both with 115 publications. M Whiteman from England was the most prolific scientist with 136 publication cited by 3554 times. For these top 10 most productive scientists, PK Moore had the highest h-index of 47 and R Wang was the second with an h-index of 45, separating from the others with a gap. These eminent researchers were definitely considered to be the forerunners in H 2 SBM research.

Other Publication Performance Indicators
In general, the top 3 most extensively studied disciplines in H 2 SBM research were biochemistry molecular biology (34.3%), cell biology (17.7%), and pharmacology pharmacy (12.7%) ( Figure 5A). Especially for H 2 S-related medicine research, cardiovascular system (8.5%), neuroscience (6.5%), and gastroenterology hepatology (4.7%) took the top 3 positions ( Figure 5B). Furthermore, it was shown that 10.0% of the publications are review paper, while research articles contribute to 62.7% of the total publications ( Table 4). The rest types of H 2 SBM publication were meeting abstract (23.0%), proceeding paper (3.0%), and others (1.1%). The average citations (42.5) for review papers were 64.1% more than that of research papers (25.9). In contrast, the h-index for research papers (120) was about 44.6% more than that of review papers (83). In these 5881 publications, only 6.2% of them were published in open-access journals ( Table 5

Other Publication Performance Indicators
In general, the top 3 most extensively studied disciplines in H2SBM research were biochemistry molecular biology (34.3%), cell biology (17.7%), and pharmacology pharmacy (12.7%) ( Figure 5A). Especially for H2S-related medicine research, cardiovascular system (8.5%), neuroscience (6.5%), and gastroenterology hepatology (4.7%) took the top 3 positions ( Figure 5B). Furthermore, it was shown that 10.0% of the publications are review paper, while research articles contribute to 62.7% of the total publications ( Table 4). The rest types of H2SBM publication were meeting abstract (23.0%), proceeding paper (3.0%), and others (1.1%). The average citations (42.5) for review papers were 64.1% more than that of research papers (25.9). In contrast, the h-index for research papers (120) was about 44.6% more than that of review papers (83). In these 5881 publications, only 6.2% of them were published in open-access journals ( Table 5

Discussion
Using bibliometrics to analyze H 2 SBM literatures allows us to uncover trends in the historical development and help us develop an understanding of the prevalent areas of interest in this field. To the best of knowledge, this study is the first of its kind to assess the productivity in the field of H 2 SBM during the period between 1990 and 2016 at global level.
Analysis of major research focuses indicated that cardiovascular function is the most common topic in H 2 S medicine research. Four of the top 10 mostly cited H 2 SBM papers explored the regulatory roles of H 2 S in vascular system. For example, some of these studies established the role of H 2 S as an endogenous K ATP channel opener in vascular cells and the cardio-protective effects of H 2 S under both health and disease conditions [1,2,4,8]. Other hot topics included neuroscience and gastroenterology hepatology, etc. The research area of S-sulfhydration modification of protein and its impact on cellular functions is growing at the fastest pace (138 papers) since the first research paper on S-sulfhydration was published in 2009 [20], which provides the clue for the molecule-to-molecule interaction mechanism for the cellular functions of H 2 S. It should be noted that H 2 SBM research is also facing challenges in selective areas. Clinical trials comprised less than 3% of all publications, and phase I-III clinical trials were relatively scarce. The unstable chemical features and tissue-specific effects of H 2 S lead to the difficulty of developing druggable H 2 S-releasing compounds. There are strong demands for future application of H 2 S-based therapy.
In term of the number of published papers in H 2 SBM research, USA took the first place. The increasingly leading position of USA was also supported by the fact that two of the ten most productive institutions in H 2 SBM research were located in USA, including University of California System and University of Texas Medical Branch Galveston. China's total expenditure on Research and Development has been significantly increased over the last 10 years, and National Natural Science Foundation of China was the most acknowledged funding agency in H 2 SBM publications. As a consequence, the total number of H 2 SBM papers from China was the second most among all countries, and two universities from China (Peking University and Fudan University) took the second and fourth position in the top 10 most prolific institutes. Singapore is the eighth most productive country in H 2 SBM research, while National University of Singapore is the number 1 most prolific institute in H 2 SBM research, attributable to the institution's effort to assemble a H 2 S-focused pharmacology research unit and hiring a great number of H 2 SBM researchers in this university more than a decade ago. The ranks for the most prolific institutes or countries did not consider the trans-national or trans-institutional relocation of the leading H 2 SBM research team(s).
The number of citations an article received is a good indicator for its impact and contribution to research community. Based on the Web of Science, the total citations (7821) of the top 10 most cited papers count for 6.3% of all citations generated by 5881 H 2 SBM literatures, which reflects the importance of these papers. Nine from the 10 most highly cited articles were published in relatively higher-impact factor journals (IF > 5) except one from Biochemical and Biophysical Research Communications (IF = 2.47). The h-index, the number of published papers (N) that have been cited N or more times, is often used to assess the career-long citation impact of researchers [21,22]. One important finding was that PK Moore and R Wang had the highest h-index being 47 and 45 following a wide gap with other researchers in H 2 SBM research, reflecting their career-long important contribution and impact to the field.
It is noted that the ratio of review papers to research articles was about 1:6.2. This trend needs to be carefully assessed. In general, review papers generate higher citations than original research articles (Table 4). This fact partially stimulates the interests of certain journals and researchers to produce review papers more than focusing on original research articles. We have seen too many review articles repeating the same topics by the same or different authors without new data or new ideas. We have seen review articles that review other review articles. This is the time to call the attention for H 2 SBM researchers and also all other biomedical researchers to produce more original research articles and lesser redundant reviews.
Although open access journals provide easy access to the published papers, no evidence suggests that open access articles receive significantly more citations than non-open access articles [23]. This is the same situation as H 2  In the bibliometric analysis completed, 98.6% of the 5881 publications found were published in English. This is not surprising since the majority of journals registered in Web of Science publish in English. In the top 10 countries that published the largest number of H 2 SBM, 4 countries are English-speaking, including USA, England, Canada, and Singapore, and total 48.7% publications were from these 4 countries. Of the 10 institutions that had the largest number of H 2 SBM publications, 6 were based in English-speaking countries.
The readers are reminded of the limitations of this study. Only publications indexed by Web of Science were analyzed. It is known that only a small part of existing journals were indexed in Web of Science. Certainly, some H 2 SBM publications are missed or not included in this analysis. This study did not look at the most cited institutes due to technique difficulty and time limitation. It is worth noting that University of Saskatchewan from Canada contributed 32 publications in H 2 SBM research, while its average citation per item (152.28) was more than 3 times of those from the top 10 most prolific institutes (Table 2), clearly pointing to a pioneer position of University of Saskatchewan in H 2 SBM research. Another limitation is that, besides the categories of article and review, other document categories (e.g., meeting abstracts, editorial materials, letters, and notes, etc.) were also included in this study, which usually did not give sufficient study details.
In conclusion, bibliometric analyses were performed to evaluate publication outcome related to H 2 SBM research at global level. An overall increase in H 2 SBM publications in the recent decades reflects the rapid advancement of this field. In the years to come there will be a continued increase in the productions of H 2 SBM research, probably with a similar trend observed in recent decades.