Global Trends of Publication of Randomized Controlled Trials of Helicobacter Pylori Research

Chun-Ming Zhang Shanghai Changzheng Hospital, Second Military Medical University Qi-Tong Chen Shanghai Changzheng Hospital, Second Military Medical University Cheng Wu Chinese PLA General Hospital Yuan-Qing Huang Bazhong Municipal Hospital of Traditional Chinese Medicine Bin Shi Shanghai Changzheng Hospital, Second Military Medical University Jian Shi (  shijian2008@smmu.edu.cn ) Shanghai Changzheng Hospital, Second Military Medical University


Introduction
A new era of research of gastroduodenal diseases has opened since the identi cation of Helicobacter pylori (H. pylori) by Warren and Marshall in 1983. 1,2 The bacterium was previously called Campylobacter genus, and was rstly named as Helicobacter in October 1989. 3 Currently, H. pylori infection remains one of the most common human infections all over the world. 4 Rigorously designed and performed randomized controlled trials (RCTs) provide high-class evidence of the effect of health care interventions. 5 Consequently, RCTs have much more in uence on health care than other study designs. Thus, publications of RCTs could re ect the trend of clinical research. Since the rst RCT on H. pylori was published in 1987, 6,7 over a thousand RCTs have been reported and major advances have been achieved in H. pylori research. In the present bibliometric study, we aimed to use the PubMed to synthetically analyze the global trends of publication of the RCTs of H. pylori research from 1983 to 2020, to help researchers have a historic perspective on the progress of worldwide H. pylori research, and determine the direction of further clinical research.

Literature search
A computerized literature search was performed based on the website, the PubMed (1983-2020).
Although the RCTs published in 2020 have been included in PubMed, most of them have not been classi ed as "randomized controlled trial" with regard to the publication type. Thus, the literature search in 2020 was conducted manually after a simple search in PubMed. The citation search was conducted using the website, the Science Citation Index Expanded. 8 The language was restricted to English. There was no journal restriction.

Statistical Analysis
Descriptive statistical analyses were mainly used. We analyzed the involved papers and calculated the data with the following items: publication year, country of origin, journal, authorship, a liation, terms and top citations.

Results
The literature search involved 25,915 papers and 1,550 RCTs using the website PubMed (1981-2020).
The rst two RCTs were both published in Lancet in 1987, which reported the failure of o oxacin in Campylobacter pylori infection treatment and the relationship of this bacterium and recurrence of duodenal ulcers. 6,7 These 1,550 RCTs were published from 1987 to 2020, with 2 ones in 1987 (the least) and 102 ones in 1999 (the most). (Fig. 1) However, the annual numbers of RCTs gradually reduced from 102 in 1999 to 32 in 2020. Besides, the annual proportions of RCTs to total papers of H. pylori were also showed in Fig. 1, with 2.49% in 1989 (the lowest) and 8.01% in 1999 (the highest). The annual proportions of RCT to total papers also gradually reduced from 8.01% in 1999 to 3.79% in 2020.   The top 20 productive a liations in the world were listed in Table 3. The top three productive a liations were Baylor College of Medicine (34 RCTs), National Yang Ming University (33 RCTs) and Peking University (29 RCTs). Among the top 20 a liations, 10 ones were in China, with 3 in Italy, 3 in UK, 1 in USA, 1 in Germany, 1 in Korea and 1 in Japan. Besides, the global origin map showed that the most productive areas were the West Europe and the East Asia. (Fig. 4) The ten most highly-cited RCTs were listed in Table 4, with 4 ones in published NEJM, 2 ones in Lancet, and the other journals were Ann Intern Med, JAMA, J Natl Cancer Inst and Gastroenterology. The leading paper had 974 citations, and the mean number of citations of the top ten papers was 584.

729
Although H. pylori infection does not bring about illness in most infected persons, it is a critical risk factor for peptic ulcers and is responsible for the majority of gastroduodenal ulcers. In 1994, H. pylori was classi ed as a rst-class carcinogen in humans by the International Agency for Research on Cancer, 10 despite there were con icting results of carcinogenesis of H. pylori at the time. Since then, it has been widely accepted that H. pylori is an important pathogeny of gastric malignancy and gastric mucosaassociated lymphoid tissue lymphoma. 11 Many RCTs have been published from many parts of the world over the past decades assessing different issues about H. pylori eradication therapy. This study provides attractive information about the global trends of the publication of RCTs on H. pylori research in the past decades. The top three journals published about 1/3 of all the RCTs, especially the AP&T, far more than other journals. However, AP&T and AJG published few RCTs after 2005. This might be attributed to the low ebb of RCTs of H. pylori research and that H. pylori was no longer a hot topic in gastrointestinal diseases. Besides, these two journals' impact factors rose rapidly in the past decade, maybe due to their disease speciality tendency to the hot points in gastrointestinal diseases. However, H. pylori research was once a hot medical issue and regularly published in the top general medical journals (Lancet, NEJM and BMJ).
The G7 industrial countries had the highest productivity of H. pylori research in the past decades. 14 However, in the list of H. pylori research RCTs, China (including mainland, Taiwan and Hong Kong) took the rst place. The mainland of China presented a notable upward trend in many specialties based on the large size of the population, rapid economic development and huge investment into medical health in recent years. [15][16][17] In addition, Korea, Turkey and Iran entered the top ten list, and meanwhile France and Canada fell out of the top ten list. Figure 3 showed The ten most highly-cited RCTs were all published in top general or specialized journals, with 4 in NEJM, 2 in Lancet and 1 in JAMA, hinting great academic in uence of these journals. Besides of the RCTs on H. pylori research, the most in uential articles in H. pylori research were nearly all published in the top general or specialized journals. 18 The ten papers focused on the preventive effect of H. pylori treatment on peptic ulcers, bleeding, gastric dysplasia and cancer, which were the most important topics of H. pylori clinical research.

Conclusions
This study of global publication of H. pylori RCTs showed some interesting points concerning research performance from 1983 to 2020. The publication of H. pylori RCTs reached a peak at 1999 and then declined gradually after 2003. The top three journals were AP&T, Helicobacter, and AJG. The most productive countries were China, Italy, Japan, USA and UK. Besides, the most productive areas were the West Europe and the East Asia. This bibliometric analysis can help researchers take an overall view of global H. pylori research, and determine the direction of further clinical research.

Declarations
Ethics approval and consent to participate: Not applicable.
Consent for publication: Informed consent was obtained in writing by all participates.
Competing interests: The authors declare that they have no competing interests.
Availability of data and materials: All data generated or analyzed during this study are included in this published article or are available from the corresponding author on reasonable request.
Funding: This study was funded in part by Shanghai Natural Science Foundation (19ZR1457100). The study design, data collection, analysis and interpretation of data and drafting of manuscript were solely done by the authors without contribution from any of the funding organizations.
Authors' contributions: SJ, SB and ZCM involved in study design, manuscript writing and revising. ZCM, CQT and WC involved literature search, data collection and statistical analysis and manuscript writing.
ZCM and HYQ involved in creating gures and tables. All authors approved the nal version of the article, including the authorship list.