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Abstract Background Eosinophilic gastrointestinal disorders (EGIDs) are chronic allergic diseases categorized as eosinophilic esophagitis (EoE) and non‐EoE EGIDs. Few studies regarding the association between EGIDs and coronavirus disease 2019 (COVID‐19) have been reported. Although most Japanese individuals received the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine, the incidence of COVID‐19 remained high in 2022. This study examines the incidence of COVID‐19 in patients with EGIDs during the vaccination era. Methods Patients with EGIDs who visited our department between October and December 2022 were enrolled in the study. The incidence and severity of COVID‐19 prior to October 1, 2022 were determined. Patients who reported having COVID‐19 also reported their hospitalization history, intensive care unit admissions, and EGID flares. The number of SARS‐CoV‐2 vaccinations received and treatment for EGIDs were obtained from the patients' medical records. Results Of 111 patients with EGIDs (65 with EoE and 46 with non‐EoE EGIDs) included in this study, 31 (28%) patients reported having COVID‐19, including 14 (22%) with EoE and 17 (37%) with non‐EoE EGIDs. Fifty‐nine (84%) patients received two or more vaccinations, and 11 (16%) patients received no vaccinations. COVID‐19 was mild in all but one patient who had moderate symptoms. COVID‐19 was not associated with EGID flares. EGID treatments and an unvaccinated status were not associated with an increased risk of COVID‐19. Conclusion COVID‐19 was mild in patients with EGIDs and not associated with EGIDs flares during the vaccination era. There was a relatively high incidence of COVID‐19 among patients with non‐EoE EGIDs.

Abstract Background and Aim Mental status such as anxiety and depression in patients with non‐esophageal eosinophilic gastrointestinal diseases (non‐EoE EGIDs) has not been studied. The aim of this study was to evaluate whether patients with non‐EoE EGIDs had mental disorders and decreased mental‐health‐related quality of life (QOL) similar to those in patients with disorders of gut–brain interaction (DGBI). Methods We enrolled patients with non‐EoE EGIDs and DGBI visiting the Osaka Metropolitan University Hospital, and the measures listed below were compared between the groups. We collected data using the following questionnaires: hospital anxiety and depression scale, and short form (SF)‐8 including mental component summary (MCS)‐8. Results We evaluated 21 and 17 patients with non‐EoE EGIDs and DGBI, respectively. The anxiety score was not significantly different between the groups. The proportion of patients with possible anxiety was not significantly different between the groups (19.0% vs 33.3%). These results show that patients with non‐EoE EGIDs had anxiety that might be equivalent to that of patients with DGBI. The depression score and proportion of patients with possible depression in the non‐EoE EGID group tended to be lower than those in the DGBI group. MCS‐8 scores were not significantly different between the non‐EoE EGID and DGBI groups, which might imply an equivalent decrease in mental‐health‐related QOL in both groups of patients. In patients with non‐EoE EGIDs, the anxiety score had a significant inverse association with the MCS‐8 score. Conclusions Patients with non‐EoE EGIDs may have anxiety that correlates with decreased mental‐health‐related QOL.

Abstract Background The Rome IV criteria have been established as an international standard for diagnosing disorders of gut–brain interaction. In this study, we aimed to examine the upper gastrointestinal (GI) endoscopic findings and symptoms of subjects with functional constipation (FC) and irritable bowel syndrome (IBS) of individuals undergoing a medical check-up. Methods A total of 13,729 subjects underwent a medical check-up at Osaka City University-affiliated clinic, MedCity21, between April 2018 and March 2019. Among the 5,840 subjects who underwent screening upper GI endoscopy and completed a questionnaire based on the Rome IV criteria, 5,402 subjects were consecutively enrolled after excluding subjects with a large amount of gastric residue (n = 6), those who had previously undergone partial or total gastrectomy (n = 40), or those with daily use of low-dose aspirin (n = 82), nonsteroidal anti-inflammatory drugs (n = 63), or acid secretion inhibitors (n = 308). Results Robust Poisson regression analyses adjusted for age, sex, Helicobacter pylori infection status, alcohol intake, and smoking habits showed a significant association between FC and corpus erosion (adjusted prevalence ratio [aPR], 2.93; 95% confidence interval [CI], 1.51–5.67; p

The coronavirus disease (COVID-19) pandemic has had a considerable impact on the global healthcare system and potentially the clinical course of patients with inflammatory bowel disease (IBD). Although IBD is a chronic disease, its therapy (except steroid therapy) does not increase the risk of contracting or aggravating COVID-19. However, the clinical course of patients is significantly influenced by environmental factors. Social restrictions due to the pandemic or the fear of contracting the virus have influenced lifestyle and psychosocial behaviors that may worsen the clinical course of patients with IBD. This narrative literature review summarizes the current evidence on the impact of the COVID-19 pandemic on the lifestyle and psychosocial behaviors of patients with IBD. The COVID-19 pandemic negatively affected the lifestyle and psychosocial behaviors of patients with IBD. Furthermore, patients with IBD failed to maintain medication adherence, thus affecting the clinical course of their condition.

Endoscopic mucosal healing (MH) is an important treatment goal for patients with ulcerative colitis (UC). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and has been reported to be a useful predictive marker for UC. This study aimed to evaluate the clinical utility of the NLR for predicting clinical relapse in UC patients with MH. We retrospectively enrolled patients with UC who underwent colonoscopy at the Osaka City University Hospital between January 2010 and December 2010, whose Mayo Endoscopic Subscore was 0 or 1. The correlation between the incidence of relapse and demographic factors, including the NLR, was analyzed. We included 129 patients in the present study. The median NLR at the time of endoscopy was 1.98, and differences in the high NLR group and the low NLR group were compared. During a median follow-up period of 46.4 months, 58 patients (45.0%) experienced relapse. The cumulative relapse-free rate was significantly higher in the low NLR group than in the high NLR group (P = 0.03, log-rank test). Multivariate analysis identified high NLR as an independent prognostic factor for clinical relapse (hazard ratio, 1.74; 95% confidence interval, 1.02-2.98; P = 0.04). NLR is a novel and useful predictor of clinical relapse in UC patients with MH, and it can potentially be a strong indicator to determine the appropriate treatment strategy and decision-making in clinical practice.

Abstract Background and Aim Although chronic diarrhea is a major digestive disorder, it has not been well studied. The aims of this study were to investigate the prevalence and risk factors of chronic diarrhea in the Japanese population and to assess the relationship between stool type and frequency and symptoms related to chronic diarrhea. Method A total of 13 668 adults who underwent a medical checkup at MedCity21 were enrolled, and 9540 who met the inclusion criteria participated in the study. Participants with chronic diarrhea were defined as those who typically had a Bristol Stool Form Scale of type 6 or 7. Results The prevalence of chronic diarrhea was 3.0%. The risk factors for chronic diarrhea were younger age (odds ratio [OR] 0.984, 95% confidence interval [CI] 0.972–0.996), male sex (OR = 2.270, CI = 1.730–2.960), alcohol intake on ≥5 days per week (OR = 2.390, CI = 1.860–3.060), not getting adequate sleep (OR = 0.712, CI = 0.559–0.907), skipping breakfast ≥3 times a week (OR = 1.490, CI = 1.120–1.980), and absence of diabetes mellitus (OR = 0.384, CI = 0.179–0.824). Only 23.5% of the participants in the diarrhea group had ≥3 bowel movements per day. Chronic diarrhea was significantly associated with heartburn, nausea, stomach ache, abdominal bloating and distension, and feeling of stress. Conclusions Our study shows that chronic diarrhea is common in Japan with a prevalence of 3.0%; unique risk factors related to gender, age, and irregular lifestyle were identified. An understanding of bowel habit in the healthy population is helpful for the assessment of change in bowel habit associated with gastrointestinal disorders.

Abstract Background/aims Functional dyspepsia (FD) is often comorbid with sleep disturbance. However, it is not fully understood how sleep disturbance affects the pathophysiology of FD. We aimed to investigate the relationship between FD and sleep disturbance. Methods We prospectively enrolled 20 FD patients with sleep disturbance between December 2018 and July 2019. Patients took sleep aids for 4 weeks and filled out questionnaires before and after taking sleep aids. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Athens Insomnia Scale (AIS) were used to evaluate the severity of their sleep disturbance. Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSG), Gastrointestinal Symptom Rating Scale (GSRS), and the Japanese version of Patient Assessment of Constipation Quality of Life (JPAC-QOL) were used to evaluate the severity of GI symptoms. Short-Form 36-Item Health Survey (SF-36) was used to evaluate QOL. Pre- and post-sleep medication values of questionnaires were compared. Results Among 20 enrolled patients, 16 completed the study protocol. Zolpidem, eszopiclone, and suvorexant were administered to six, nine, and one patient, respectively. Each median total score of questionnaires (pre-/post-sleep medication, respectively) was as follows: PSQI, 10.0/8.5; ESS, 12.5/5.0; AIS, 10.0/4.0; mFSSG, 21.0/16.0; GSRS, 44.0/31.0 (Pain in GSRS, 11.0/5.0); JPAC-QOL, 26.0/15.5; SF-36, 63.9/71.9. All of these results showed statistically significant differences between pre- and post-sleep medication (p

BackgroundAutonomic dysfunction is a factor in irritable bowel syndrome (IBS). However, there are no reports of autonomic nervous system (ANS) activity during natural defecation in patients with IBS. We aimed to clarify the relationship between ANS activity and life events, such as defecation and abdominal symptoms, using real-time recording.MethodsSix patients with IBS and 14 healthy controls were enrolled in this prospective multicenter study. ANS activity was recorded for 24 h using a T-shirt wearable device, and life events were recorded simultaneously in real time using a smartphone application software. Low frequency/high frequency (LF/HF) and HF calculated by power spectrum analysis were defined as activity indicators of the sympathetic and parasympathetic nerves, respectively.ResultsThe means of LF/HF and HF in the period with positive symptoms were comparable between the groups; however, the sum of LF/HF, sum of ΔLF/HF, and the maximum variation in ΔLF/HF were significantly higher in the IBS group. In the IBS group, the sum of ΔLF/HF and LF/HF increased significantly from 2 min before defecation, and the sum of LF/HF remained significantly higher until 9 min after defecation. The sum of ΔLF/HF at 2 min before defecation was significantly positively correlated with the intensity of abdominal pain and diarrhea and constipation scores. In contrast, it was significantly negatively correlated with defecation satisfaction and health-related quality of life.ConclusionsIn patients with IBS, sympathetic nerve activity was activated 2 min before defecation, which was correlated with abdominal symptoms and lower QOL.

Background: The government of Japan declared a state of emergency on April 16, 2020, owing to the coronavirus disease 2019 (COVID-19) pandemic. The subsequent lockdown altered lifestyles and worsened mental illnesses. Inflammatory bowel disease (IBD) is an intestinal disorder that is affected by environmental factors. Therefore, we aimed to assess the effects of COVID-19 and the state of emergency on the lifestyle and disease activity of patients with IBD.Methods: We conducted a questionnaire survey on patients with IBD from June 16 to August 21, 2020 during their regular follow-up at our hospital, 2 months after the state of emergency was declared.Results: Overall, 241 patients with ulcerative colitis (UC) and 210 with Crohn's disease (CD) completed the survey, of which 82 (34%) and 97 (46%) patients, respectively, reported disease exacerbation within 2 months after the lockdown. Multivariate logistic regression analysis identified age at enrollment (odds ratio, OR 0.98, 95% CI 0.96–0.99; P < 0.05), sleep hours (OR, 0.74; 95% CI, 0.57–0.97; P < 0.05), and increased stress due to the COVID-19 pandemic (OR, 6.06; 95% CI, 1.79–20.50; P < 0.01) as independent factors associated with UC exacerbation. Patients with exacerbated CD were younger at CD onset and had higher patient-reported outcome 2 scores before the state of emergency than patients with non-exacerbated CD. On multivariate analysis, age (OR, 0.97; 95% CI, 0.95–0.99; P < 0.01) and active disease before the state of emergency (OR, 2.20; 95% CI, 1.23–3.95; P < 0.01) were independently associated with CD exacerbation.Conclusions: Improving sleep quality and preventing psychological stress may be crucial in IBD management during a pandemic, especially in young patients.

Objectives: Endoscopy confers high risk for acquiring coronavirus disease 2019. Although guidelines recommend that medical staff use personal protective equipment, no infection control equipment have been established for patients. This study aimed to clarify the usefulness of two face masks we had designed for transnasal and transoral endoscopy. Methods: The efficacy of the masks was evaluated by simulating coughing in a mannequin with fluorescent dyes and mapping the droplet trajectory and number. The number of aerosols generated during endoscopy was clinically evaluated in the endoscopy room. Overall, 4356 screening endoscopies were performed with the patients wearing our masks at Medcity21, a health checkup facility, between June and December 2020; the effects of the masks on the patient’s condition were evaluated retrospectively. An 11-item paper-based survey was performed by the endoscopy staff 6 months after the adoption of the mask-based infection control method. Results: Use of both masks reduced the number of droplets released during the simulation. Clinically, the use of both masks did not affect the patients’ conditions during endoscopy and prevented an increase in the aerosols in the endoscopy room. This mask-based infection control method was favorably received, and all staff indicated that understanding the efficacy of our mask-based infection control reduced their anxiety regarding infection. Until December 2020, none of our staff had contracted SARS-CoV-2. Conclusion: Our mask-based infection control method is easy to adopt, inexpensive, and effective; understanding its effectiveness may help ease the fear of infection among endoscopy staff.

The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase β2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model.

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors.

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1β, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect.

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

Background and study aims Eosinophilic gastrointestinal disorders are classified into eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis according to the site of eosinophilic infiltration. Although well established in eosinophilic esophagitis, endoscopic findings in eosinophilic gastritis and eosinophilic gastroenteritis with regard to gastric lesions have not been clearly described. The aim of this study was to identify endoscopic findings of gastric lesions associated with eosinophilic gastrointestinal disorders. Patients and methods Out of 278 patients with eosinophilic gastrointestinal disorders, 18 had eosinophilic gastritis or eosinophilic gastroenteritis confirmed by biopsy; their endoscopic images were analyzed retrospectively. The association between endoscopic findings and number of eosinophils in the gastric mucosa was investigated. Results Erythema was most frequently observed (72 %), followed by ulcers (39 %), discoloration (33 %), erosions (28 %), nodularity (28 %), and polyps (28 %). There were several unique endoscopic findings such as submucosal tumor-like deep large ulcers in three patients, antral Penthorum-like appearances (small nodules radially lined toward the pyloric ring) in three patients, “muskmelon-like appearances” (discolored mucosa-composed mesh pattern) in three patients, multiple white granular elevations in two patients, cracks (appearance of furrows similar to those in eosinophilic esophagitis) in five patients, and antral rings in one patient. No significant association was observed between endoscopic findings and number of gastric eosinophils. Conclusions Several unique endoscopic findings of gastric lesions were observed in patients with eosinophilic gastritis or eosinophilic gastroenteritis. Submucosal tumor-like ulcers, antral Penthorum-like appearances, muskmelon-like appearances, and cracks might be associated with eosinophilic gastrointestinal disorders.

Ultrafast transient absorption (TA) spectroscopy has been one of the most powerful experimental tools to study the mechanism of photoinduced electron transfer (ET) as in photosynthetic and flavin photoreceptor systems in plants. However, no work has been reported on their quantitative mechanisms. Apparent rates of charge separation (CS) from tryptophans (Trps) to the excited isoalloxazine (Iso*) and charge recombination (CR) from the produced ion pairs to Trps and Iso in the ground states are reported to be 0.25 ps and 3.2 ps in medium-chain acyl-CoA dehydrogenase (MCAD), and 0.15 ps and 6.6 ps in flavin mononucleotide binding protein (FMN-bp), obtained by an ultrafast TA method. The decays of the CS and CR processes were for the first time simultaneously analyzed with an ET theory and structures obtained by molecular dynamics simulation. MCAD and FMN-bp form a tetramer and dimer, respectively. The CS and CR rates of an individual donor and various related physical quantities were numerically obtained. It was found that both CS and CR rates were fastest from Trp166 among four Trps in MCAD and those from Trp106 among two Trps in FMN-bp. Logarithmic CS rates in MCAD were dependent on the donor–acceptor distance (Rc) with parabolic functions, while those of CR rates linearly decreased with Rc. Reasons why CS rates were faster than CR rates in both MCAD and FMN-bp were elucidated in terms of pre-exponential factors in the theory. The present method could be useful to understand the precise mechanisms of initial steps of biological functions of photoreceptors in plants.

Background: Inflammation-based scoring has been reported to be useful for predicting the recurrence and prognosis of various carcinomas. This study retrospectively investigated the relationship between inflammation-based score and intraductal papillary mucinous neoplasms (IPMNs). Methods: Between January 2013 and October 2018, we enrolled 417 consecutive patients with pancreatic tumors who received surgical resections at our hospital. The main outcome was the association between the preoperative inflammation-based score and their accuracy in predicting malignant transformation of IPMN. Results: Seventy six patients were eligible. Pathological findings indicated that 35 patients had low-grade dysplasia, 18 had high-grade dysplasia, and 23 had invasive carcinomas. As the C-reactive protein albumin ratio (CAR) was higher, malignant transformation of IPMNs also increased (p = 0.007). In comparing CARhigh and CARlow using cutoff value, the results using a propensity score analysis showed that the CARhigh group predicted malignant transformation of IPMNs (odds ratio, 4.18; 95% confidence interval, 1.37–12.8; p = 0.01). In the CARhigh group, disease-free survival (DFS) was significantly shorter (p = 0.04). In the worrisome features, the AUC for the accuracy of malignant transformation with CARhigh was 0.84 when combining with the MPD findings. Conclusions: Preoperative CAR could be a predictive marker of malignant transformation of IPMNs.

We determined the bone mineral density (BMD) and the expression of serum bone formation marker (procollagen type I N-terminal propeptide: PINP) and bone resorption marker (C-terminal telopeptide of collagen: CTX) by ELISA to evaluate ovariectomy-induced osteoporosis in ovariectomized (OVX) mice. The intestinal microbiota of the mice was assessed using 16S rRNA gene sequencing. OVX mice exhibited a lower BMD of 87% with higher serum levels of CTX and PINP compared to sham-operated (sham) mice. The cecum microbiome of OVX mice showed lower bacterial diversity than that of sham mice. TNFα mRNA levels in the colon were 1.6 times higher, and zonula occludens-1 mRNA and protein expression were lower in OVX mice than in sham mice, suggesting that ovariectomy induced inflammation and increased intestinal permeability. Next, we used antibiotic treatment followed by fecal microbiota transplantation (FMT) to remodel the gut microbiota in the OVX mice. A decrease in PINP was observed in antibiotic-treated mice, while there was no change in BMD or CTX between mice with and without antibiotic treatment. Oral transplantation of the luminal cecal content of OVX or sham mice to antibiotic-treated mice did not affect the BMD or PINP and CTX expression. Additionally, transplantation of the luminal contents of OVX or sham mice to antibiotic-treated OVX mice had similar effects on BMD, PINP, and CTX. In conclusion, although ovariectomy induces dysbiosis in the colon, the changes in the gut microbiota may only have a minor role in ovariectomy-induced osteoporosis.

Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD). However, the acceptance of COVID-19 vaccines has not been sufficiently evaluated in patients with IBD. We aimed to assess the acceptance and hesitancy of COVID-19 vaccination and related factors among these patients. A retrospective cohort study using a self-reported questionnaire was performed among patients with IBD between 22 June 2021 and 30 August 2021. Of the 187 participants, 10.2% (n = 19) were hesitant to be vaccinated. Patients in the vaccine-hesitant group were younger (p = 0.009) and had a shorter disease duration (p = 0.020). Vedolizumab was prescribed more frequently (p = 0.024) and immunomodulators were less frequently used (p = 0.027) in this group. Multivariable logistic regression analysis identified age (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.92–1.00, p = 0.042) and the use of immunomodulators (OR: 0.08, 95% CI: 0.01–0.66, p = 0.019) as independent significant factors for vaccine hesitancy. The COVID-19 vaccine hesitancy rate in patients with IBD in Japan was 10% in this study. The Japanese COVID-19 vaccination campaign appears to be successful. The risk of COVID-19 among patients with IBD requires adequate measures to ensure that vaccines are accepted by vaccine-hesitant patients. These findings may be helpful in achieving adequate vaccination rates.

Background and study aims Esophageal fistulas after esophagectomy are associated with high mortality and poor quality of life. They are sometimes intractable to conservative management and surgery that increases mortality. Few studies have assessed use of polyglycolic acid (PGA) sheets with fibrin glue for esophageal fistulas. We investigated the safety of using PGA sheets with fibrin glue for esophageal fistulas after esophagectomy. Patients and methods This was a single-center prospective pilot study. Patients who had refractory esophageal fistulas after esophagectomy were included. PGA sheets were filled in the fistula using biopsy forceps. Fibrin glue was applied to the PGA sheets. We repeated the procedure 1 week later. The outcome measures were the incidence of adverse events (AEs) and closure of the fistula. Results Five patients were assessed. No adverse events were observed. The esophageal fistula was closed with the application of PGA sheets four times in 40 % (2/5) of the cases. Conclusions PGA sheets with fibrin glue were safe for esophageal fistula closure after esophagectomy and do not involve the risk of AEs.

ObjectivesPouchitis is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). Although there have been many investigations of the neutrophil-to-lymphocyte ratio (NLR) in various diseases, its role in predicting the development of pouchitis remains unclear. We aimed to evaluate the clinical utility of the NLR for predicting the development of pouchitis after IPAA in UC patients.Materials and methodsUC patients who underwent IPAA at Osaka City University Hospital between May 2006 and March 2019 were included. The incidence of pouchitis was estimated using the Kaplan-Meier method. Potential preoperative, intraoperative, and postoperative predictors for pouchitis, including various demographic and clinical variables, were analyzed. The combined impact of the NLR and other known prognostic factors were investigated using Cox proportional hazard regression with inverse probability of treatment weighting (IPTW).ResultsForty-nine patients with UC who underwent IPAA were included. The median follow-up period was 18.3 months (interquartile range: 10.7-47.2 months). Eighteen patients (36.7%) developed pouchitis. The incidence of pouchitis was 19.2%, 32.6%, and 45.9% at 1, 2, and 5 years, respectively. NLR was significantly associated with the development of pouchitis in the univariate Cox regression analysis (hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.01-1.28; P = 0.03). The NLR cutoff value of 2.15 was predictive of the development of pouchitis according to receiver operating characteristic analysis (specificity: 67.7%, sensitivity: 72.2%). The incidence of pouchitis was significantly lower in the low NLR group than that in the high NLR group (P = 0.01, log-rank test). Cox regression analyses using IPTW also identified NLR as a prognostic factor for the development of pouchitis by statistically adjusting for background factors (HR, 3.60; 95% CI, 1.31-9.89; P = 0.01).ConclusionsNLR may be a novel and useful indicator for predicting the development of pouchitis after IPAA in UC and should be introduced in clinical practice.

Endoscopic ultrasonography (EUS) is useful for detecting early-stage pancreatic cancer. Because the detection of small lesions is difficult, it is important to detect indirect findings, namely caliber change, retention cysts, and dilatation of the branch duct, during the procedure. Although two types of EUS endoscopes are frequently used, there is no comparative study on their efficacy for detecting indirect findings. Therefore, we aimed to compare the diagnostic efficacy of these two types for indirect findings. We retrospectively analyzed 316 consecutive patients who had undergone EUS for pancreaticobiliary disease at a single center between January 2017 and December 2018. The main outcome was the detection rate of indirect findings and its comparison between the two echoendoscope types. This outcome was achieved using the inverse probability of treatment weighting (IPTW) analysis. The detection rate of indirect findings was higher for the radial-arrayed endoscope than for the convex-arrayed echoendoscope (9.2% vs. 2.3% (p = 0.02)). The univariate analysis also revealed that the radial-arrayed echoendoscope was significantly superior to the convex-arrayed echoendoscope in terms of the detection of indirect findings (odds ratio, 5.94; 95% confidence interval, 1.68–21.10; p = 0.01) after IPTW. After adjustment for magnetic resonance imaging (MRI) and computed tomography (CT), radial-arrayed echoendoscope remained an independent factor for indirect finding detection (odds ratio, 6.04; 95% confidence interval, 1.74–21.00; p = 0.01). Finally, five patients who had indirect EUS findings were diagnosed with pancreatic cancer. Our results indicate that the radial-arrayed echoendoscope is useful for the detection of indirect findings.

Background and study aims Endoscopic findings of esophageal eosinophilia sometimes localize to small areas of the esophagus. A previous study suggested that pathogenesis of localized-type eosinophilic esophagitis (LEoE) was associated with acid reflux. However, LEoE treatment outcomes have not been studied. We aimed to analyze the clinical and histologic significance of LEoE in comparison with diffuse-type eosinophilic esophagitis (DEoE). Patients and methods This study included 106 patients with esophageal eosinophilia. Esophageal eosinophilia was defined as a condition where the maximum number of intraepithelial eosinophils was ≥ 15 per high-power field. LEoE was defined as an endoscopic lesion confined to one-third of the esophagus: upper, middle, or lower. Esophageal eosinophilia encompassing more than two-thirds of the esophagus was defined as DEoE. We retrospectively compared LEoE and DEoE in terms of clinical characteristics, histologic findings, and proportion of proton pump inhibitor (PPI) responders. Results Of 106 patients, 12 were classified as having LEoE and 94 were classified as having DEoE. The proportion of asymptomatic patients was significantly higher in the LEoE group than the DEoE group (42 % vs 7 %, P

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

ObjectivesAlthough tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection.Materials and methodsPatients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression.ResultsAmong 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72-0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05-0.66, P = 0.01) as independent predictors of clinical relapse.ConclusionsThe pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus.

Advanced techniques have been developed to overcome difficult cannulation cases in endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic duct guidewire placement method (PGW) is performed in difficult cannulation cases; it is possible that it places patients at risk of post-ERCP pancreatitis (PEP). The mechanism of PEP is still unclear, but pancreatic duct pressure and injury of pancreatic duct are known causes of PEP. Therefore, we hypothesized a relationship between pancreatic duct diameter and PEP and predicted that PGW would increase the risk of PEP in patients with non-dilated pancreatic ducts. This study aimed to investigate whether PGW increased the risk of PEP in patients with pancreatic duct diameter ≤ 3 mm.We analyzed 332 patients with pancreatic duct ≤ 3 mm who performed first time ERCP session. The primary endpoint was the rate of adverse event of PEP. We evaluated the risk of PEP in patients who had undergone PGW compared to those who had not, using the inverse probability of treatment weighting (IPTW) analysis.PGW was found to be an independent risk factor for PEP by univariate analysis (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.12-5.38; p = 0.03) after IPTW in patients with pancreatic duct diameter ≤ 3 mm. Adjusted for all covariates, PGW remained an independent risk factor for PEP (OR, 3.12; 95% CI, 1.33-7.33; p = 0.01).Our results indicate that PGW in patients with pancreatic duct diameter ≤ 3 mm increases the risk of PEP.

Neutrophil-to-lymphocyte ratio (NLR) has been used to determine the outcome in malignancies and coronary heart disease. Some reports considered the value of NLR as a predictor of response to infliximab in patients with Crohn's disease or rheumatoid arthritis; however, no similar studies have been reported for ulcerative colitis (UC). This study aimed to evaluate the clinical significance of the baseline NLR in patients with UC treated by infliximab.Patients with moderate-to-severe active UC who received the first infliximab infusion in our hospital between 2010 and 2015, who showed clinical response during the induction period, were retrospectively evaluated for long-term outcomes and risk factors for loss of response (LOR) during infliximab maintenance therapy. Baseline inflammatory markers including NLR were measured within one week before the initiation of infliximab.Fifty-nine patients with moderate-to-severe active UC started treatment with infliximab and 37 patients (62.7%) experienced clinical response after induction therapy. Fourteen of 37 patients on maintenance therapy lost the response during follow-up. Baseline NLR of patients with LOR was significantly higher than in patients with sustained response. The NLR cut-off value of 4.488 was predictive of LOR, using receiver operating characteristic analysis (sensitivity: 78.6%, specificity: 78.3%). A univariate analysis revealed a significant relationship between relapse-free survival and the NLR (P = 0.018). Multivariate analysis indicated the NLR as an independent prognostic factor for LOR (hazard ratio = 3.86, 95% confidence interval: 1.20-12.4, P = 0.023).Baseline NLR is a useful prognostic marker in patients with moderate-to-severe active UC treated with infliximab, and may contribute to appropriate use of infliximab.

Background and study aim: The incidence of stricture formation caused by endoscopic submucosal dissection (ESD) for widespread lesions is high, and stricture formation can reduce quality of life. We evaluated the prophylactic efficacy of hybrid therapy using a locoregional steroid injection and polyglycolic acid (PGA) sheets with fibrin glue to prevent stricture formation after esophageal ESD in high risk patients in whom we predicted stricture formation would be difficult to prevent with a single prophylactic steroid injection. Methods: Ten patients who underwent esophageal ESD were enrolled (entire-circumference: n = 6; sub-circumference, more than 5/6 of the circumference: n = 4). A single locoregional steroid injection and PGA sheets with fibrin glue were used after ESD. We evaluated the incidence of stricture formation, the number of endoscopic balloon dilation (EBD) procedures needed to treat the stricture formation, and adverse events of the therapy. Results: Esophageal stricture formation occurred in 50.0 % of patients (5/10) (median EBD sessions 0.5, range 0 – 16). Subanalysis showed that stricture formation occurred in 37.5 % of patients (3/8) excluded the lesions located near a previous scar from ESD or surgical anastomosis site (median EBD sessions 0, range 0 – 4). Conclusion: Hybrid therapy using a locoregional steroid injection and PGA sheets with fibrin glue may have the potential to prevent esophageal stricture formation after esophageal ESD in high risk patients.

Gastroesophageal reflux disease (GERD) is a common upper gastrointestinal disease. However, the role of exosomal microRNAs (miRNAs) and esophageal miRNAs in GERD has not been studied. A rat model of acid reflux esophagitis was used to establish a novel diagnosis marker for GERD and examine dynamics of miRNA expression in GERD. Rats were sacrificed 3 (acute phase), 7 (sub-acute phase) and 21 days (chronic phase) after induction of esophagitis. Exosomes were extracted from serum, and the expression patterns of serum miRNAs were analyzed. Four upregulated miRNAs (miR-29a-3p, 128-3p, 223-3p and 3473) were identified by microarray analysis. The expression levels of exosomal miR-29a-3p were significantly higher in the chronic phase of reflux esophagitis compared with controls, and increased expression of miR-29a-3p was specific to chronic reflux esophagitis. Esophageal miR-223-3p expression was higher compared with controls, and gradually decreased from acute to chronic phase in esophagitis. In conclusion, exosomal miR-29a-3p and esophageal miR-223-3p might play roles in GERD.