Severity of gastric mucosal atrophy affects the healing speed of post-endoscopic submucosal dissection ulcers

INTRODUCTION

The efficacies of endoscopic submucosal dissection (ESD)and surgical gastrectomy for early-stage gastric cancer are generally similar[1]. ESD, being less invasive, is the first-line treatment for early-stage gastric cancer. ESD allows en bloc resection and is associated with a lower recurrence rate than endoscopic mucosal resection(EMR)[2,3].

Gastrointestinal bleeding from ESD-induced ulceration is a common complication[4-7]. Factors associated with an increased risk of post-ESD gastrointestinal bleeding include the size, location, and histology of the gastric cancer; kinds of gastric acid suppressant;patient use of dialysis; and long procedure time[4-7]. The risk of bleeding is reduced by endoscopic coagulation of exposed vessels at the base of ESD-induced ulcers and potent acid inhibition over the first 24 h posttreatment[4-7]. When ESD is performed for gastric cancer, proton pump inhibitors (PPIs) are used to treat ESD-induced ulcers[7]. However, PPIs may not suppress gastric acid secretion over 24 h, especially at night.Administration is required over several days to maximize gastric acid inhibition. More recently, interindividual genetic variations (e.g., CYP2C19 genotype)[8,9] have been linked to different metabolism rates of PPIs.Vonoprazan, a potassium-competitive acid blocker(P-CAB) with more potent and sustained acid inhibition than PPIs, has been approved in Japan[10-12]. Although vonoprazan inhibits gastric H+/K+-ATPase similarly to PPIs, its mechanism of acid inhibition involves inhibition of H+, K+-ATPase by binding reversibly and competitively with K+[13]. It remains unclear whether vonoprazan is associated with improved ulcer healing speed and prevention of post-ESD bleeding, due to the low statistical power of the most recent studies[5,14].

Previous studies have looked at many factors related to ESD-induced ulcer healing, such as location of the tumor[15], submucosal fibrosis[16], initial ulcer size[17,18], diabetes[18], coagulation abnormality[18],electrocoagulation during ESD[18], and method of gastric acid suppression[19].

进入21世纪以来，全球消费领发生重大变化，越来越多个性化产品的出现，逼迫消费制造类企业也要改变传统的产品设计和制造模式；多样化、小批量、快速交货，将成为企业赢得客户的重要砝码，这也就需要企业财务部门对于成本核算的精度和快捷度做出反应，故而企业的财会部门应结合企业实际情况科学制定成本核算方案。

Concurrent Helicobacter pylori (H. pylori) infection has been found to in fl uence the speed of peptic ulcer healing[20,21]. However, it is unclear whether current H. pylori infection and eradication therapy affect the healing of ESD-induced ulcers[22,23]. In addition, there may be an association with the severity of gastritis/gastric atrophy and post-ESD ulcer healing[23,24].

SWOT分析法又称态势分析法，是对组织内外部因素进行分析，从中寻找二者最佳可行战略组合的一种分析工具。其中战略内部因素有：S表示strength(优势)，W表示weakness(弱势)；外部因素有：O表示opportunity(机会)，T表示threat(威胁)。通过SWOT分析法可帮助江苏省高等院校对所面临的优势、劣势、机会和威胁进行系统地分析，从而帮助高等院校最大限度地利用内部优势和环境中的机会，制定出利于学校抓住环境契机、发挥自身优势、摆脱外部威胁、降低发展风险的科学战略。基于SWOT 分析法的江苏省高等院校发展战略态势有以下4种基本策略组合。

Rapid healing of ESD-induced ulcers is key to the prevention of delayed bleeding. We investigated factors that might be associated with healing of post-ESD ulcers, including H. pylori status, profile of the gastric tumor, kinds of acid inhibitory drugs, and severity of gastritis (e.g., gastric atrophy and intestinal metaplasia).

MATERIALS AND METHODS

Patients

24 Fujiwara S, Morita Y, Toyonaga T, Kawakami F, Itoh T, Yoshida M,Kutsumi H, Azuma T. A randomized controlled trial of rebamipide plus rabeprazole for the healing of artificial ulcers after endoscopic submucosal dissection. J Gastroenterol 2011; 46: 595-602 [PMID:21359522 DOI: 10.1007/s00535-011-0372-3]

ESD was performed if cases met the following criteria of early-stage gastric cancer and gastric adenoma according to the Union for International Cancer Control/American Joint Committee on Cancer stages:(1) Intramucosal intestinal-type neoplasm without ulceration, regardless of tumor size; (2) intramucosal intestinal-type cancer with ulceration, ≤ 3 cm; (3)intestinal-type cancer invading the submucosa ＜ 500 μm from the muscularis mucosa, ≤ 3 cm in size; and(4) intramucosal diffuse-type cancer without ulceration,≤ 2 cm. Exclusion criteria were patients with advancedstage gastric cancer, patients who refuse follow-up endoscopy at both 4 and 8 wk after ESD treatment and patients with lack of informed consent.

Although severity of anemia and oxygenation were expected to affect the healing speed of ESD-induced ulcer, there were no patients with severe anemia of less than 10 g/mL or hypoxemia.

Study protocol

For this study, we enrolled patients who had undergone ESD for resection of gastric tumor and provided blood samples for an anti-H. pylori IgG serological testing and CYP2C19 genotyping. The endoscopic severity of gastritis was characterized by the Kyoto classification[25].According to the Kyoto classification of gastritis, patients are scored according to atrophy (None: A0, atrophic patterns with a margin between the non-atrophic fundic mucosa and atrophic mucosa located in the lesser curvature of the stomach: A1, and atrophic patterns,whose margin does not cross the lesser curvature:A2), intestinal metaplasia (none: IM0, within antrum:IM1, and up to corpus: IM2), hypertrophy of gastric folds (negative: H0, positive: H1), and diffuse redness(negative: DR0, mild: DR1, severe: DR2)[25].

ESD was performed with a single-channel magnifying endoscope (GIF-H290Z or GIF-H260Z; Olympus, Tokyo,Japan). We used a fixed-length disc-tipped knife (Dual knife®, KD-650L/Q; Olympus, Tokyo, Japan) or an insulated-tip diathermic knife (IT knife 2®, KD-611L,Olympus, Tokyo, Japan) and applied electric current using an electrosurgical generator (VIO300D®; ERBE Elektromedizin GmbH, Tubingen, Germany). Visible vessels were heat-coagulated using hemostatic forceps(FD-412LR®; Olympus, Tokyo, Japan). After ESD, 73.5%of patients were dosed with lansoprazole 30 mg and 26.5% were dosed with vonoprazan 20 mg (Table 1) for 8 wk.

The major and minor axes of ESD-induced ulcers were endoscopically measured the day after ESD by measurement forceps (M2-4K®; Olympus Corporation,Tokyo, Japan), and at 4 and 8 wk post-ESD.

首先，“本”“末”两个字里都藏有一个“木”字，代表着“树木”。两个字除了“木”字，剩下的一笔都是横。可别小瞧它，这不起眼儿的一小横，便起到了关键的“指事”作用：

H. pylori infection

Infection status of H. pylori was evaluated based on findings from two tests: an anti-H. pylori IgG serological test (E plate Eiken H. pylori antibody®; Eiken Chemical Co. Ltd., Tochigi, Japan) and a rapid urease test(Helicocheck®; Otsuka Co., Tokyo, Japan). When either test was positive, the patient was diagnosed as positive for H. pylori infection.

CYP2C19 genotyping

Genomic DNA was extracted from the blood (DNA Extract All Reagents®, Applied Biosystems, Foster City CA, United States). Subsequently, genotyping was performed using a single-nucleotide polymorphism(SNP) genotyping assay (TaqMan®, Applied Biosystems)in a real-time polymerase chain reaction (PCR) system(Step One Plus®, Applied Biosystems). Genotyping for identifying the CYP2C19 wild-type gene and two mutated alleles, CYP2C19 *2 (rs4244285, A/G) and*3 (rs-4986893, G/A) were performed to classify each subject as belonging to one of the following four genotype groups: extensive metabolizers (EMs, * 1/ *1), intermediate metabolizers (IMs; * 1/ * 2 or * 1/ * 3),or poor metabolizers (PMs; * 2/ * 2, * 2/ * 3 or * 3/ * 3).

Statistical analysis

Age, ESD procedure time and ESD-induced ulcer area are expressed as mean ± SD. The healing rates of ulcers were calculated as (1-ulcer area/ulcer area just after ESD) × 100 (%) and are expressed as mean ± SD. Statistical differences in these parameters among CYP2C19 genotypes; between H.pylori infection statuses; among degrees of atrophy,intestinal metaplasia, and diffuse redness according to the Kyoto classification; and among tumor locations were determined using one-way ANOVA with Scheffé multiple comparison and Fisher’s exact tests. All P values are two-sided, and P ＜ 0.05 was considered statistically significant. Calculations were performed using commercial software (SPSS version 20, IBM Inc;Armonk NY, United States).

RESULTS

ESD and ESD-induced ulcers

The mean procedure time was 76.4 ± 56.7 min and the mean resected ESD-induced ulcer area was 671.9± 720.9 mm2 at Day 1. Procedure time for lesions in the lower third of the stomach (47.5 ± 3.2 min) was significantly shorter than those for the middle and upper thirds [vs middle (85.7 ± 6.6 min), P = 0.001, vs upper(131.3 ± 17.9 min), P ＜ 0.001, respectively]. The initial ulcer area in the lower third (456.4 ± 265.2 mm2) was significantly smaller than that of the middle third (822.0± 922.2 mm2, P = 0.008).

After ESD, mean ESD-induced ulcer areas at 4 and 8 wk were 71.3 ± 135.6 mm2 and 2.8 ± 15.6 mm2,respectively, and mean healing rates were 90.4% ±0.8% at 4 wk and 99.8% ± 0.1% at 8 wk (Figures 1A and 2A). At 8 wk, mean healing rate in the H. pyloripositive group (99.7% ± 0.1%) was significantly lower than that in the negative group (99.9% ± 0.0%, P =0.035). There were no significant differences between mean healing rates for lansoprazole and vonoprazan treatment at 4 and 8 wk (Figures 1B and C, 2B and C).

Healing rate was associated with the severity of gastric atrophy at 4 wk (A0: 97.9% ± 0.6%, A1: 93.4%± 4.1%, and A2: 89.7% ± 1.0%, respectively).

In patients with severe gastric atrophy, the healingrate was significantly lower than that in patients with mild or no atrophy (A0 + A1) (P ＜ 0.001 and P = 0.010)(Figures 1D and 2E). In addition, at 4 wk, the mean healing rate in the lower third (92.8% ± 1.2%) was significantly delayed compared to the upper two-thirds(83.7% ± 5.3%, P = 0.013) (Figure 1E and 2F). After 8 wk, ESD-induced ulcers were scarred in 85.7% (12/14)in the upper third, 89.2% (58/65) of the middle third,and 83.3% (40/48) of the lower third (P = 0.657) of the stomach. There was no significant association of healing rates at 4 wk with CYP2C19 genotypes (Figure 2D).

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Factors affecting ESD-induced ulcer healing

We investigated the healing rate of ESD-induced ulcers by setting up over 90% of ESD-induced ulcer area at 4 wk and 100% at 8 wk. ESD-induced ulcers with ≥90% healing at 4 wk were associated with absence of atrophy (P = 0.010), depth of gastric tumor (P =0.004), and procedure time P = 0.026) (Table 2). The mean procedure time in the ≥ 90% healing group was significantly shorter than that in the ＜ 90% healing group (65.6 ± 41.1 min vs 89.7 ± 64.0 min, P = 0.026).The prevalence of patients with open-type atrophic gastritis in the ≥ 90% healing group was 78.0%(64/82), which was significantly lower than that in the＜ 90% healing group (96.0%, 43/45, P = 0.01).

Strength Evaluation of Access Tower & Hull Support Structure of Engineering Ships……………ZHANG Shitian(1·11)

In achievement of scar formation at 8 wk, the rates were associated with gender (P = 0.021) and age (P =0.047), but not gastritis or tumor-related factors (Table 2).

In the univariate analysis to identify possible factors related to achievement of 90% healing at 4 wk, healing was associated with gastric atrophy (OR = 6.047,95%CI: 1.334-27.403, P = 0.019), procedure time(OR = 1.009, 95%CI: 1.002-1.017, P = 0.018) and initial ESD-induced ulcer size (OR = 0.001, 95%CI:1.000-1.001, P = 0.032) (Table 3). At 8 wk, gender and initial ESD-induced ulcer size significantly correlated with the achievement of scarring at 8 wk (P = 0.021 and P = 0.013, respectively) (Table 3).

In the multivariate analysis including gender, H.pylori infection, endoscopic severity of atrophy, tumor location, mean procedure time, and mean initial ESD-induced ulcer size, the factor associated with 90%healing at 4 wk was gastric atrophy (OR = 5.678,95%CI: 1.190-27.085, P = 0.029) (Table 4). The factors associated with scarring at 8 wk were gender(female, OR = 4.438, 95%CI: 1.253-15.724, P = 0.021)and initial ESD-induced ulcer size (1.001, 1.000-1.002,P = 0.023) (Table 4).

ESD-related adverse events

Two patients (1.5%) experienced delayed bleeding with tarry stool and only one patient received transfusion treatment after ESD treatment. Although the prevalence of patients received anti-coagulants was 16.7% and no cases with hematologically abnormal coagulation ability were observed (Table 1), intake of aspirin of non-steroidal anti-inflammatory drug did not increase incidence of gastric bleeding after ESD. There were no other major ESD-related adverse events.

DISCUSSION

The healing speed of ESD-induced ulcers may be akey factor in preventing ESD-related bleeding. In this study, we investigated possible risk factors associated with healing of ESD-induced ulcers and found that of all possible factors, severe gastric atrophy at 4 wk post-ESD and initial ulcer size at 8 wk were independent risk factors in multivariate analysis. However, we found no significant association of healing of ESD-induced ulcers and tumor location[15], initial ulcer size[17,18], coagulation abnormality[18], electrocoagulation during ESD[18], or kind of gastric acid suppressant[19]. Because the healing rate of ESD-induced ulcers was affected by tumor size,post-ESD ulcer size and severity of gastritis (e.g., gastric atrophy), attention should be paid to the incidence of complications (i.e., bleeding and perforation) in patients with severe gastric atrophy and a large size of gastric tumor.

In this study, we focused on the influence of the severity of gastric atrophy on the healing rate of ESD-induced ulcers. Previously, Fujiwara et al[24] reported improved healing at 8 wk post-ESD for patients with severe atrophic gastritis when treated concomitantly with a PPI and rebamipide. In this study, at 4 wk after ESD, we revealed that severe gastric atrophy, especially of the A2 type according to the Kyoto classification,slowed healing speed. Kakushima et al[23] failed to show a significant association between the severity of gastric atrophy and ESD-induced ulcer healing with administration with omeprazole and sucralfate for 8 wk post-ESD; our study also did not demonstrate significant differences at 8 wk post-ESD. At 8 wk, mean reduction rates were 99.8% ± 0.1% and ESD-induced ulcers were scarred in 83.3% (110/132). We therefore hypothesize that the severity of gastric atrophy may in fl uence healing of ESD-induced ulcers at 4 wk, but not at 8 wk.

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The healing speed of ESD-induced ulcers was affected by the severity of gastric atrophy, but not by H. pylori status, kinds of acid inhibitory drugs, or CYP2C19 genotype. Patients with severe gastric atrophy accompanied by intestinal metaplasia should be considered as likely candidates for ESD-related complication, due to delayed ulcer healing. Therefore, H. pylori eradication therapy is required to perform at younger age before progression of gastric mucosal atrophy to prevent development of H. pylori-related diseases and bleeding from ESD-induced ulcer.

In general, peptic ulcer healing has been correlated with intragastric pH[28], H. pylori infection[20], gastric motility[29], microcirculation in gastric mucosa[30-32],gastric mucosal levels of growth factors[33,34] and prostaglandins (PGs)[35]. The aggressive factors induced gastric mucosal injury resulting in loss of mucosal barrier can be quickly healed if adequate supply of PGE2,epidermal growth factor and tumor growth factor (TGF)α takes place. Although it is unclear whether peptic ulcers and ESD-induced ulcers share a similar healing mechanism, because severity of gastric mucosal atrophy reduced microcirculation in gastric mucosa and gastric mucosal levels of prostaglandin and growth factors,resulted that advanced gastric atrophy perturbs the process of ulcer healing in the presence of these above factors.

Association with intragastric pH and speed of post-ESD ulcer healing

Vonoprazan has a longer half-life (7.7 h) than PPIs,due to its slow dissociation from H+/K+-ATPase[36]. In addition, vonoprazan inhibits H+/K+-ATPase activity with 400-fold greater potency than lansoprazole at pH 6.6[37].Therefore, use of vonoprazan for treatment of ESD-induced ulcers is expected to confer an advantage over the conventional regimen with a PPI. This is despite the finding of Kagawa et al[5], who reported that the rates of ESD-related ulcer healing were 96.0% ± 6.7% at 6 wk with vonoprazan and 94.7% ± 11.6% at 8 wk with PPI,despite the fact the post-ESD bleeding incidence in the vonoprazan group (1.3%) was less than that in the PPI group (10.0%, P = 0.01). In a prospective randomized controlled trial, the rate of scar formation attained with vonoprazan at 8 wk was significantly higher than that for esomeprazole (94.9% vs 78.0%, P = 0.049), and in a multivariate analysis, only vonoprazan was correlated with scar formation (OR = 6.33; 95%CI: 1.21-33.20)[14].However, although we have two kinds of clinical pathways scheduled to use lansoprazole or vonoprazan after ESD treatment for gastric tumors and investigated to analyze the healing speed of ulcer after ESD by use of only the two kinds of acid inhibitory drugs,lansoprazole and vonoprazan, there was no significant difference between vonoprazan and lansoprazole at 4 wk and 8 wk after ESD in this study. Given that one factor associated with healing of ESD-induced ulcers at 8 wk in multivariate analysis was initial ulcer size,this discrepancy may be due to differences in the size of lesions. Although potent acid inhibition is required to heal ESD-induced ulcers, a 90% reduction in ESD-induced ulcers was achieved at 28 d, irrespective of acid inhibitors. It is important to investigate whether the kind of acid inhibitor influences the speed of artificial ulcer reduction in an earlier phase (i.e., within 2 wk).

使用SPSS 19.0软件进行数据分析，计量资料使用均数±标准差(±s)进行表示，使用Student's t test检验及one-way ANOVA对数据进行检验，P＜0.05被认为差异具有统计学意义。

Limitations

Several limitations of this study warrant mention. First,the sample size is not large. Second, we did not gather data regarding the reduction rate at 2 wk post-ESD. In this study, most ESD-induced ulcers had already healed by 4 wk post-ESD, which means evaluation at an earlier phase is required. Third, although we investigated the influence of CYP2C19 genotype, which impacts the pharmacodynamics of PPI, on the healing of ulcers, we did not clarify whether the CYP3A4/5 genotype, which is related to vonoprazan-dependent pharmacodynamics,influenced healing[38]. Forth, although minerals (e.g.,Zn) and vitamins (e.g., Vitamin C) may affect the healing speed of ulcer after ESD, unfortunately, we have no data of minerals and vitamins in all patients[39,40].

In conclusions, we conducted a study to investigate factors influencing the healing speed of ESD-induced ulcers. Healing speed was affected by the severity of gastric atrophy, but not by H. pylori status, kinds of acid inhibitory drugs, or CYP2C19 genotype. These results suggest that eradication of H. pylori can be carried out at any time in terms of ulcer healing and that PPI or vonoprazan treatment for ESD-induced ulcers can be administrated at the standard dose irrespective of CYP2C19 genotype.

ARTICLE HIGHLIGHTS

Research background

The endoscopic submucosal dissection (ESD) for early-stage gastric cancer is first-line therapy in Japan, because of en bloc resection and a lower local recurrence rate of gastric cancer. However, bleeding from ESD-induced ulcer is a major complication of ESD treatment. When ESD is performed for gastric cancer, PPIs or vonoprazan are used to treat ESD-induced ulcers in Japan.It remains unclear whether vonoprazan with more potent and sustained acid inhibition than PPIs, H. pylori infection and characteristics of gastric mucosa(e.g., inflammation and atrophy) are associated with improved ulcer healing speed and prevention of post-ESD bleeding. Rapid healing of ESD-induced ulcers is key to the prevention of delayed bleeding.

Research motivation

Of many possible factors related to ESD-induced ulcer healing, such as location of the tumor, submucosal fibrosis, initial ulcer size, diabetes, coagulation abnormality, electrocoagulation during ESD, and method of gastric acid suppression, it is unclear whether above parameters actually affect the healing of ESD-induced ulcers and the incidence of gastrointestinal bleeding after ESD treatment. Especially, there was no report investigated with the healing speed of ulcer after ESD and characteristics of gastric mucosa (e.g., in fl ammation and atrophy).

Research objectives

The main objective was to clarify factors that might be associated with healing of post-ESD ulcers and bleeding, including H. pylori status, pro file of the gastric tumor, kinds of acid inhibitory drugs, and severity of gastritis including of gastric atrophy and intestinal metaplasia.

Research methods

We retrospectively enrolled 132 patients with gastric tumors scheduled for ESD, irrespective to H. pylori infection. Following ESD, patients were treated with daily lansoprazole 30 mg or vonoprazan 20 mg for 8 wk. Ulcer size was endoscopically measured on the day after ESD and at 4 and 8 wk. The gastric mucosa was endoscopically graded according to the Kyoto gastritis scoring system. We assessed the number of patients with and without a 90% reduction in ulcer area at 4 wk post-ESD and scar formation at 8 wk, and looked for risk factors for slower healing.

11 Sakurai Y, Mori Y, Okamoto H, Nishimura A, Komura E, Araki T, Shiramoto M. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects--a randomised open-label crossover study. Aliment Pharmacol Ther 2015; 42: 719-730 [PMID:26193978 DOI: 10.1111/apt.13325]

Research results

After ESD, mean healing rates of ESD-related ulcer were 90.4% ± 0.8% at 4 wk and 99.8% ± 0.1% at 8 wk. The reduction rate was associated with the Kyoto grade of gastric mucosal atrophy at 4 wk and ESD-induced ulcers with≥ 90% healing at 4 wk were associated with absence of atrophy, depth of gastric tumor, and procedure time. In the univariate analysis to identify possible factors related to achievement of 90% healing at 4 wk, healing was associated with gastric atrophy, procedure time and initial ESD-induced ulcer size. In the multivariate analysis, the factor associated with 90% healing at 4 wk was gastric mucosal atrophy (OR = 5.678, 95%CI: 1.190-27.085, P = 0.029).

Research conclusions

Intestinal metaplasia is often observed in patients with severe gastric atrophy and is a well-known risk factor for gastric cancer, similar to severe gastric atrophy alone. The prevalence of intestinal metaplasia in H. pylori-positive patients is 57% in Japanese aged approximately 70 years[26]. Although we saw no significant association between the severity of intestinal metaplasia and ulcer healing speed in this study, Chen et al[27] reported that patients with intestinal metaplasia had a higher healing rate of gastric ulcers than those without intestinal metaplasia, suggesting that patients with severe gastric atrophy accompanied by intestinal metaplasia should be considered as likely candidates for ESD-related complication, due to delayed ulcer healing.

Research perspectives

Eradication of H. pylori can be carried out at any time in terms of ulcer healing and that PPI or vonoprazan treatment for ESD-induced ulcers can be administrated at the standard dose irrespective of CYP2C19 genotype.However, because this is a preliminary small study, further study is required to plan whether the healing speed of ESD-induced ulcers was affected by the severity of gastric atrophy in prospective multicenter study. In addition, we will clarify the potential mechanism about association with the healing of ESD-induced ulcer and severity of gastric atrophy as further study.

REFERENCES

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俗话说，实践是检验真理的唯一标准。但在我国由于管理会计引进的时间较短，且一开始是照搬国外的理论，我国自己的管理会计理论仍处于发展阶段，在许多方面都没有的到研究和论证。没有合理的管理会计理论，不能将管理会计的理念与实际的工作相结合起来。在很多时候只是单独的讨论管理会计的重要性，却忽略了管理会计在实际工作中的应用方法，使管理会计与企业出现脱节，无法发挥其真正的作用。

宝宝是父母的心头肉，时时牵挂、疼爱有加。宝宝要是有个头疼脑热的，或者小伤小病，父母看在眼里，疼在心里，恨不得病生在自己身上。有时一场疾病之后，宝宝瘦了，父母也累坏了。许多宝宝大病一场之后，连性格也发生了转变。

29 Takeuchi K, Ueki S, Okabe S. Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats.Dig Dis Sci 1986; 31: 1114-1122 [PMID: 3463496]

13 Andersson K, Carlsson E. Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases. Pharmacol Ther 2005; 108: 294-307 [PMID: 16000224 DOI: 10.1016/j.pharmthera.2005.05.005]

此外，根据高考成绩和英语入学测试成绩，进行“分级教学”。尊重教学规律和学生个体差异，努力做到因材施教，满足学生个性发展需求。让英语基础较好的学生更加拔尖出色，挖掘他们的潜力，为同学们树立榜样作用，激发学习的积极性和热情，调动各层次的学生学习动力。

14 Tsuchiya I, Kato Y, Tanida E, Masui Y, Kato S, Nakajima A, Izumi M. Effect of vonoprazan on the treatment of artificial gastric ulcers after endoscopic submucosal dissection: Prospective randomized controlled trial. Dig Endosc 2017; 29: 576-583 [PMID: 28267236 DOI: 10.1111/den.12857]

15 Yoshizawa Y, Sugimoto M, Sato Y, Sahara S, Ichikawa H, Kagami T, Hosoda Y, Kimata M, Tamura S, Kobayashi Y, Osawa S,Sugimoto K, Miyajima H, Furuta T. Factors associated with healing of artificial ulcer after endoscopic submucosal dissection with reference to Helicobacter pylori infection, CYP2C19 genotype, and tumor location: Multicenter randomized trial. Digest Endosc 2016;28: 162-172 [PMID: 26331711 DOI: 10.1111/den.12544]

16 Horikawa Y, Mimori N, Mizutamari H, Kato Y, Shimazu K,Sawaguchi M, Tawaraya S, Igarashi K, Okubo S. Proper muscle layer damage affects ulcer healing after gastric endoscopic submucosal dissection. Dig Endosc 2015; 27: 747-753 [PMID:26043759 DOI: 10.1111/den.12501]

减压和CO2处理对金瓶柿脱涩保脆效果的影响………… 张雪丹，杨娟侠，木志杰，辛 力，刘 涛，孙 山，王 丹，王传增（118）

17 Oh TH, Jung HY, Choi KD, Lee GH, Song HJ, Choi KS,Chung JW, Byeon JS, Myung SJ, Yang SK, Kim JH. Degree of healing and healing-associated factors of endoscopic submucosal dissection-induced ulcers after pantoprazole therapy for 4 weeks.Dig Dis Sci 2009; 54: 1494-1499 [PMID: 19005762 DOI: 10.1007/s10620-008-0506-5]

18 Lim JH, Kim SG, Choi J, Im JP, Kim JS, Jung HC. Risk factors of delayed ulcer healing after gastric endoscopic submucosal dissection. Surg Endosc 2015; 29: 3666-3673 [PMID: 25740642 DOI: 10.1007/s00464-015-4123-z]

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通过信息网络与生物的本质特点进行光学理念和声学理念的融合，使高科技技术通过反应人的基本生理特性和基本行为习惯进行个人系统的识别。生物识别系统的引入优势是能够通过个人的不同的特征进行不同身份的识别，使学生或教师的身份具有安全性和唯一性。且通常生物特征是不会发生大体改变的，如指纹、虹膜特征。另外，生物识别的使用识别可以优化智慧校园的校园管理环节，具体是由于每个人都具有指纹、虹膜的特征，因此，生物识别技术具有大众性和广泛性。所以，生物识别平台的引进有利于高校处理学生个人信息。

21 Satoh K, Yoshino J, Akamatsu T, Itoh T, Kato M, Kamada T, Takagi A, Chiba T, Nomura S, Mizokami Y, Murakami K, Sakamoto C,Hiraishi H, Ichinose M, Uemura N, Goto H, Joh T, Miwa H, Sugano K, Shimosegawa T. Evidence-based clinical practice guidelines for peptic ulcer disease 2015. J Gastroenterol 2016; 51: 177-194[PMID: 26879862 DOI: 10.1007/s00535-016-1166-4]

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We enrolled 132 Japanese patients who underwent ESD for clinical early-stage gastric cancer and adenoma between March 2013 and October 2016 at our institution. Approval for the study protocol was given in advance by the Institutional Review Board of the Shiga University of Medicine Science (Number 27-36). This trial was registered in the University Hospital Medical Information Network, UMIN000018188.

25 Sugimoto M, Ban H, Ichikawa H, Sahara S, Otsuka T, Inatomi O,Bamba S, Furuta T, Andoh A. Efficacy of the Kyoto Classification of Gastritis in Identifying Patients at High Risk for Gastric Cancer.Intern Med 2017; 56: 579-586 [PMID: 28321054 DOI: 10.2169/internalmedicine.56.7775]

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“我们相信(Xe-100的)安全案例已得到充分证明，我们认为这是一种内在安全的反应堆。”X能源主管反应堆研发的副总裁马丁·范斯塔登表示，“我们不需要任何操纵员行动和能动电力系统来确保电厂或公众安全”或“确保任何厂区边界(辐射照射)限值均不会被超出”。

37 Hori Y, Imanishi A, Matsukawa J, Tsukimi Y, Nishida H, Arikawa Y, Hirase K, Kajino M, Inatomi N. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassiumcompetitive acid blocker for the treatment of acid-related diseases.J Pharmacol Exp Ther 2010; 335: 231-238 [PMID: 20624992 DOI: 10.1124/jpet.110.170274]

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