Scoping Review and Bibliometric Analysis of the Most Influential Publications in Achalasia Research from 1995 to 2020

Objective To identify and evaluate characteristics of the most influential articles in achalasia research during the period 1995-2020. Methods Articles in Scopus, Web of Science Core Collection (WoSCC), and PubMed were scanned from 1995 to 2020 with achalasia as the keyword. We retrieved the articles that met all criteria by descending order after using EndNote to remove the duplicated references. Our bibliometric analysis highlighted publication year, country, journals, and networks of keywords. Results Fifteen percent of the top 100 most-cited articles were published in Annals of Surgery. They were performed in 15 countries, and most (n = 55) were from the USA. The number of citations of the 482 articles ranged from 30 to 953, 38 of which had been published in American Journal of Gastroenterology. Those articles were from 31 countries, and most of the studies (n = 217) had been performed in the USA. Most of articles (n = 335) were clinical research. Treatments were hotspots in the field of achalasia in the past years. The most influential title words were “achalasia,” “esophagomyotomy,” “pneumatic dilation,” and “lower esophageal sphincter.” Conclusion Our study offers a historical perspective on the progress of achalasia research and identified the most significant evolution in this field. Results showed treatment was the most influence aspect in achalasia.


Introduction
There is no standard or established method of quickly and effectively accessing influential publications of medical research [1]. As the number of articles which researchers need to be familiar with increases so does the importance of selective searching and generalization. Even though medical knowledge is continually advancing and new articles are published daily, the impact of articles published in the past is not decreased. Accurately determining the influence of medical papers is vital for guiding decisions in clinical practice and improving physicians' ability to quickly find important articles in a specific scientific research field. Articles of relevance to other studies are often cited in subsequent papers, so the most widely used and useful method for measuring the impact of research activity is identifying the number of citations in the published literature.
Achalasia is a rare esophageal motility disorder. The condition was first described in 1672 by Sir Thomas Willis, and Hurt and Rake coined the term achalasia, which means "failure to relax" in 1929 [2]. The symptoms include dysphagia to solids and liquids, substernal chest pain during meals, heartburn, aspiration pneumonia, regurgitation of food or saliva, and/or weight loss [3]. The diagnosis, prevention, and treatment of achalasia are well investigated, but the pathogenesis has not yet been completely described. Efforts to fully understand this disease are ongoing, and this study is aimed at identifying and evaluating the landmark articles in achalasia research.

Scoping Review.
Scoping review is a form of knowledge synthesis, which combines and integrates a variety of study designs to summarize and synthesize evidence comprehensively. The aim is to provide information for practices, plans, and policies and to provide directions for future research priorities [4]. This study was abided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist [5]. The Arksey and O'Malley approach framework was adopted, which summarized five stages for reporting a scoping review.
2.1.1. Identifying the Research Question. What is known from the existing literature in the field of achalasia research?

Identifying of Databases and Relevant Studies.
We followed the PRISMA-ScR [5]. Articles were retrieved from three databases (including WoSCC, Scopus, and PubMed) with the time span restricting from 1995 to 2020, using the search term "achalasia" on November 15, 2020. EndNote (X9 Edition, New York, USA) was used to remove the duplicated references. We only included articles published in English with 30 or more citations.

Study Selection.
Two reviewers selected the articles with predefined inclusion and exclusion criteria (Table 1) independently (Huifang Xia and Shali Tan). Any discrepancy was resolved by discussion. The filtering methods included the time span (1995 to 2020), and language was limited in English. And the preliminary filtering through title and abstract to exclude the irrelevant articles, the final screening was done by reading the full text.

Bibliometric
Analysis. The selection of study was in accordance with the scoping review. The qualified articles were ranked in a descending order by the citation numbers after removing duplications. Data regarding journals, publication year, country, and author were collected. Impact factor, CiteScore, Eigenfactor score (ES), Essential Science Indicators (ESI), and Article Influence Score (AIS) were analyzed to evaluate journals' impacts. Journals with a higher score of these indicators are generally considered to be more prestigious than those with a lower score [6]. The 100 most cited articles were analyzed by authorship considering the first and the second authors, journal name and year of publication, title, and the number of citations from the specified databases.

Network Analysis of Keyword Cooccurrences.
Network analysis is a method used to reveal the scientific structure, the degree of subject correlation, literature retrieval, and others, starting from the topic correlation reflected in the citations. In our study, we did the network analysis of the keyword correlation in citations in the field of achalasia. The network analysis of keywords can identify a research topic by publications that are closely connected to each other in terms of citation relations [7]. By the way of network analysis, current research hotspots can be detected in the field of achalasia.
VOSviewer (version 1.6.15, Netherlands) was applied to perform network analyses. We selected "all keywords" as the unit of analysis and set minimum number of occurrences of a keyword to 5. VOSviewer is a visual tool that can gener-ate a variety of graphs based on bibliometric relations [8]. We chose it for network analysis because of its strong graphics display ability and suitability for use with large-scale data. In the density visualization, yellow nodes indicate increased weights of the neighboring items and the size of the node increases with the number of items in the neighborhood. The color of the node changes toward blue as the weights of the neighboring items decrease.

Results
3.1. Scoping Review. The original search findings from the WoSCC, Scopus, and PubMed yielded 702, 834, and 131 papers, respectively. After removing the duplications, 982 articles were remained. 355 publications were excluded after screening the title and abstract. 145 studies were excluded after reviewing the full text according to the inclusion or exclusion criterion. And 482 papers meeting all identified requirements were included. Figure 1 shows the research flowchart based on the PRISMA-ScR guidelines.
3.1.1. Charting the Data. Characteristics of eligible articles are presented in Table S1, including the first authors, year of publication, number of citations, type of article, and research direction. The type of the article was classified as follows: (i) clinical research, including prospective study, retrospective study, randomized controlled trials (RCTs), and case report; (ii) review, including systematic review, literature review, and meta-analysis; (iii) guideline and consensus; and (iv) basic science research. Research directions involved several aspects: (i) etiology; (ii) diagnosis; (iii) treatment: including methods and curative effect; (iv) classification; (v) pathogenesis; (vi) other: epidemiology, demographics, pathophysiology, complication, clinical characteristics, and prognosis; and (vii) all: including great than or equal to two points mentioned above.
3.1.2. Analyzing Data, Summarizing, and Reporting the Results. About 69.5 percent of articles were talking about the treatment of achalasia, including the methods and the curative effects; 11.4 percent of study direction were other; etiology and all accounted for approximately 6.6 percent and 6.4 percent, respectively; 3.9 percent of publications were related to diagnosis roughly; about 1.7 percent and 0.5 percent of articles were mentioned to classification and pathogenesis severally. 357 articles were clinical research, 87 articles were review, 34 publications were basic science research, and the rest of articles (n = 4) were guideline and consensus ( Table 2). Figure 2 shows the percentage of articles about treatment in all publications each year. Table 3 lists the ten mostcited articles. The mean number of citations was 563, and the range was from 332 to 953. The top-100 articles were cited 953 to 103 times. As shown in Figure 3, the top-100 articles were published between 1995 and 2018 in 29 different journals and 49% were published after the year 2006. Seventeen journals had published two or more articles. Annals of Surgery had the largest number of articles (15%), followed by the Gastroenterology (13%), Gut (9%), and the American Journal of Gastroenterology (9%). Articles published in Annals of Surgery had received 3001 citations. New England Journal of Medicine was the most cited journal, with a mean of 469 citations per article, it is also the journal with the highest scores of CiteScore, IF, ES and AIS. The Journal of the American Medical Association and Gastrointestinal Endoscopy were the journals with the least citations (Table 4). Of the top-100 cited articles, 3% were publications of basic science research, 75% were clinical research, 23% were review, and 2% were guideline or consensus report. The first author was affiliated with an academic department in most publications [9], and 22 authors had published two or more topcited articles. The most frequently published authors are listed in Table 5, led by Pandolfino, with six articles, followed by Annese, Inoue, Kahrilas, and Zaninotto, with five each. The top-100 articles originated from 15 different countries (Table 6): 55 were from the USA, 11 from Italy, 7 from Germany, 5 from Japan, 4 each from the Netherlands and China, and two each from Switzerland and France.    (Table 8).

Network Analysis of the Keyword Cooccurrences in the
Eligible Articles. The network analysis used the total word count to identify influential title words. Each word was counted once no matter how many times it appeared in the same article, and 110 words met the threshold (occurred 5 times at least) in the 1084 keywords. The overlay visualization and modularity clustering in Figure 5(a) show the score each node by its color. Links indicate keyword relevance, and the number of keyword occurrences increases the node size. Nodes are proportional in size and importance. The most influential keywords were "achalasia," "esophagomyotomy," "pneumatic dilation," and "lower esophageal sphincter." Different colors represent the time when the keyword appears. The term "esophagomyotomy" appeared in 2000. It is an early treatment for achalasia that is still used, and it occurred frequently. Peroral endoscopic myotomy (POEM) is a treatment that was developed in the early 21st century that has been rapidly adopted following a widely cited article published by Inoue in 2010. In Figure 5(b), yellow nodes indicate increased weights, and increased size indicates larger numbers, of neighboring items. Blue nodes indicate decreased weights and numbers of the neighboring items.

Discussion
The results of the scoping review and network analysis revealed that most of the articles related to achalasia were clinical research and focused on treatments, which suggested that the majority of investigators paid attention to clinical practice and the field of basic research still needed to be further explored. It also showed that treatment was a hot research topic all the time. Pneumatic dilation, peroral endoscopic myotomy, laparoscopic Heller myotomy, and endoscopic injection of botulinum toxin were the research hotspots since 2010.
Bibliometrics has been used to analyze the most frequently cited publications in clinical fields including urology, psychiatrics, ophthalmology, emergency care, orthopedics, and digestive diseases [9][10][11][12][13][14]. We believe this is the first bibliometrics study in achalasia. The top 100 articles were cited from 101 to 953 times, while the 100 most frequently cited articles on digestive diseases were cited between 853 and 4895 times [9]. Achalasia is rare condition, with a morbidity of about 1 : 100,000 cases of digestive disease and less than 5% of those occurring in children, or about 0.11 per 100,000 pediatric patients [15,16]. That shows why there are more citations for digestive diseases as a group than for achalasia.
The classification of esophageal motility abnormalities is quite important for achalasia as it can classify the subtypes of achalasia. Four of the top ten articles focused on classification, three included the Chicago classification, and the fourth, published in 2001, divided achalasia into typical and atypical types [17]. The Chicago classification was introduced by Pandolfino et al. and is one of the most influential diagnostic criteria used in current clinical practice [18]. The Chicago classification divides achalasia into three subtypes determined by the use of high-resolution manometry [19,20], The first version was published in 2009 following a meeting of the International high-resolution manometry (HRM) Working Group in San Diego in 2008. The second was published in 2012 and was the third most frequently cited article in this analysis [19]. The second most frequently cited article describes version 3.0 of the Chicago classification [21]. Each new version has been updated by evidence published after the older version that is relevant to the clinical interpretation of HRM studies.
Domestic and international studies have found that patients with achalasia of different subtypes have different clinical characteristics and esophageal dynamics. Type I achalasia has features of lower esophageal sphincter (LES) relaxation, absence of esophageal pressurization, and aperistalsis. Type II achalasia is the most common type and is characterized by the absence of peristalsis and intermittent periods of compartmentalized esophageal pressurization. Type III achalasia is the least common. Dysphagia is common to all three types, and a Chicago classification study published in 2018 presented evidence that in the evolution of the disease, type III is the earliest stage of achalasia, type II is an intermediate stage, and type I is the final stage [22,23]. Subtype II is reported to have the best prognosis, followed by subtype I and subtype III, which can be difficult to treat [22,[24][25][26]. The Chicago classification plays an  [27]. POEM has a significant improvement of dysphagia, an improved peri-and postoperative experience, and faster postoperative recovery compared with the outcomes with older methods. Because of its advantages, the use of POEM has been adopted worldwide to treat achalasia. The first description of POEM to treat achalasia in the USA was by published by Swanstrom in 2012, who reported continuing remission of dysphagia over 11 months of follow-up in a series of 18 patients [28]. POEM may be more effective than     BioMed Research International other treatment modalities for patients with type III achalasia because it achieves a more durable myotomy than laparoscopic Heller myotomy (LHM) [29,30]. Pneumatic dilation (PD) is an outpatient endoscopic procedure for treating achalasia and acts by disrupting the circular muscle fibers of the LES to eliminate functional obstruction at the level of the gastroesophageal junction. Sev-enteen of the top 100 articles (ranks 6,7,22,26,34,35,46,50,54, 57, 62, 64, 80, 81, 82, 88, and 91) described the use of PD to treat achalasia. The measurement of intracavitary pressure measurement to evaluate the effectiveness of PD treatment was first described in 1971, and other frequently cited articles described the use of esophageal sphincter pressure to guide the next steps of treatment as well as the use of timed barium oesophagrams [31][32][33]. Some studies that compared PD and surgical esophagomyotomy concluded that surgical esophagomyotomy was better than PD [34][35][36][37], and others concluded that PD was better suited as the initial treatment of achalasia [38][39][40], and a study by West recommended surgical myotomy as over PD in the elderly [37]. Several articles published after 2006 reported comparable success rates for PD and LHM [33,41,42]. Postprocedure monitoring of the occurrence of adverse events such as fever, shortness of breath, chest pain, and subcutaneous emphysema for several hours after PD has been recommended. The most serious complication of PD is esophageal perforation, with a reported incidence of 0% to 8%, of cases [43]. If a perforation   Endoscopic injection of botulinum toxin (EBTI) is used to treat the pathophysiology of achalasia rather than by mechanically or surgically disrupting the sphincter muscle  8 BioMed Research International [28]. EBTI blocks the release of presynaptic acetylcholine at the neuromuscular junction of the LES to relax the muscle and relieve symptoms. Its advantages include simplicity, little trauma, few adverse reactions, and the tolerance of most patients. Its shortcomings are poor longterm efficacy, with sustained results for only several months [44]. Secondly, some patients with loss of the nor-mal anatomic planes develop fibrosis at the level of the gastroesophageal junction, which is associated with increased incidence of mucosal perforation, difficulty in performing a subsequent myotomy, and a worse prognosis [32,45]. Because of the shortcoming and low effectiveness of EBTI, only eight of the top 100 papers described the use of that therapy. The use of LHM in achalasia was first reported by Shimi et al. in 1991 [46], and its use has expanded since then. It is more effective than other surgical treatments and has the longest remission time. The procedure can be performed in patients with no serious systemic disease, who have failed conservative treatment, experienced recurrences after repeated dilation, and have failed other treatments. Most experts recommend LHM as the first-line treatment for achalasia of the cardia. The fifth most cited article (428 citations) was published in 2011 by Boeckxstaens et al., and it compared the outcomes of LHM in 106 patients and PD in 95 patients [33].
The majority of the top 100 and the 482 articles reported the results of studies performed in the USA, and that is in line with similar studies of articles in the fields of digestive disease and emergency medicine [9,13]. The preponderance of articles from the USA and other developed countries reflects the ample financial resources available to support research by the scientific community. It has also been reported that investigators in the USA tend to cite publications by other American authors [47,48].
There are some study limitations. Although we searched data from the WoSCC, Scopus, and PubMed databases, we only included articles published in English, which may have lost sight of influential articles published in other languages and included in other databases. These limitations maybe have influenced the creation of this list of landmark articles. In addition, since the scope of our study was extremely wide, it was not able to perform a quantitative systematic review as Guzman-Ortiz et al. conducted [49], but we did a scoping review. In sum, achalasia research is extensive and it is constantly advancing. This review of papers of great significance and influence in the field of achalasia highlights some key topics and some major developments that have occurred over the last 25 years.

Conclusion
Our study offers a historical perspective on the progress of achalasia research and identified the articles that contributed the most to the prophylaxis and treatment of achalasia. The most cited articles, authors, journals, and title words are listed.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.