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Abstract There are limited studies on the improvement of leaky gut with minor inflammation associated with various diseases. To explore the therapeutic potential of Lactiplantibacillus plantarum 22 A-3, a member of the Lactobacillus species, in addressing a leaky gut. Lactiplantibacillus plantarum 22 A-3 was administered to a leaky gut mice model with low dextran sulfate sodium concentrations. The Lactiplantibacillus plantarum 22 A-3-treated group exhibited amelioration of increased intestinal permeability, as indicated by lower blood fluorescein isothiocyanate-dextran levels compared with that of the control group. Furthermore, the messenger RNA expression of interleukin-10, an anti-inflammatory cytokine, was upregulated in the small intestine of Lactiplantibacillus plantarum 22 A-3-treated mice. Moreover, forkhead box P3 was upregulated in the small intestine and colon following Lactiplantibacillus plantarum 22 A-3 administration. Flow cytometry showed that forkhead box P3-positive regulatory T cells tended to increase in the small intestine and colon; however, this was not significant. Messenger RNA levels for the pro-inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha showed no significant changes in the small intestine; however, their expressions significantly decreased in the colon. Blood fluorescein isothiocyanate-dextran levels showed that intestinal permeability also decreased in Lactiplantibacillus plantarum 22 A-3-dead bacteria. The bacterial component of Lactiplantibacillus plantarum 22 A-3 ameliorates increased intestinal permeability through its anti-inflammatory effect in the intestinal tract and may be a novel treatment for leaky gut.

Background/Objectives: The usefulness of dual-energy computed tomography (DECT) for low absorption in the parenchymal phase and contrast effects in the delayed phase for pancreatic cancer is not clear. Therefore, the diagnostic capability of low-KeV images obtained using DECT for pancreatic cancer in the pancreatic parenchymal and delayed phases was evaluated quantitatively and qualitatively. Methods: Twenty-five patients with pancreatic cancer who underwent contrast-enhanced DECT were included. A total of 50 and 70 KeV CT images, classified as low-keV and conventional CT-equivalent images, were produced, respectively. The tumor-to-pancreas contrast (Hounsfield units [HU]) in the pancreatic parenchymal and delayed phases was calculated by subtracting the CT value of the pancreatic tumor from that of normal parenchyma. Results: The median tumor-to-pancreas contrast on 50 KeV CT in the pancreatic parenchymal phase (133 HU) was higher than that on conventional CT (68 HU) (p < 0.001). The median tumor-to-pancreas contrast in the delayed phase was −28 HU for 50 KeV CT and −9 HU for conventional CT (p = 0.545). For tumors < 20 mm, the tumor-to-pancreas contrast of 50 KeV CT (−39 HU) had a significantly clearer contrast effect than that of conventional CT (−16.5 HU), even in the delayed phase (p = 0.034). Conclusions: These 50 KeV CT images may clarify the low-absorption areas of pancreatic cancer in the pancreatic parenchymal phase. A good contrast effect was observed in small pancreatic cancers on 50 KeV delayed-phase images, suggesting that DECT is useful for the visualization of early pancreatic cancer with a small tumor diameter.

Background & Aims: Radiofrequency ablation (RFA) is the standard treatment for small hepatocellular carcinoma (HCC), specifically for tumors

Background & Aims: This study used the Global Burden of Disease data (2010–2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries. Methods: Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI). Results: Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5–16,361.4), annual incidence rates were 608.5 cases (598.8–617.7), and YLDs were 0.5 (0.3–0.8) years. MASLD point prevalence was higher in men than women (15,731.4 vs. 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45–49 for men and 50–54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1–34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5–34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5–33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%–18.9%), Sudan (13.3%, 95% UI 9.8%–16.7%) and India (13.2%, 95% UI 12.0%–14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels. Conclusions: MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing. Impact and implications: This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study’s reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.

Introduction Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH.Methods and analysis This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20–80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities.Ethics and dissemination Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. Participants wishing to understand the results of this study will be contacted directly on data publication.Trial registration number This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280).Protocol version V.1.9, 23 November 2023

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. Methods This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. Results Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P

Objectives: Chronic constipation is a common gastrointestinal disorder, and management is crucial. Computed tomography (CT) is useful for evaluating rectal fecal mass but limited owing to radiation exposure, cost, and inaccessibility at certain facilities. Ultrasonography (US) avoids these pitfalls, but it is unknown whether it accurately assesses rectal feces. In this study, we evaluated the diagnostic performance of US compared with CT as the gold standard for assessing rectal feces. Methods: We prospectively evaluated rectal fecal mass retention using US performed within 1 h of CT to assess the degree of agreement between methodologies. Rectal stool findings were evaluated on three levels: no stool (R1), presence of stool (R2), and hard stool filling (R3). Results: The sample included 100 patients (55 men, 45 women), of whom 47 were constipated. The kappa coefficients for rectal content detection were excellent between US and CT (p

Purpose The effect of hepatic fibrosis stage on quantitative ultrasound based on the attenuation coefficient (AC) for liver lipid quantification is controversial. The objective of this study was to determine how the degree of fibrosis assessed by magnetic resonance (MR) elastography affects AC based on the ultrasound-guided attenuation parameter according to the grade of hepatic steatosis, using magnetic resonance imaging (MRI)–derived proton density fat fraction (MRI-derived PDFF) as the reference standard. Methods Between February 2020 and April 2021, 982 patients with chronic liver disease who underwent AC and MRI-derived PDFF measurement as well as MR elastography were enrolled. Multiple regression was used to investigate whether AC was affected by the degree of liver stiffness. Results AC increased as liver stiffness progressed in 344 patients without hepatic steatosis (P=0.009). In multivariable analysis, AC was positively correlated with skin-capsule distance (P

Background: Refractory ascites affects the prognosis and quality of life in patients with liver cirrhosis. Peritoneovenous shunt (PVS) is a treatment procedure of palliative interventional radiology for refractory ascites. Although it is reportedly associated with serious complications (e.g., heart failure, thrombotic disease), the clinical course of PVS has not been thoroughly evaluated. Objectives: To evaluate the relationship between chronological course and complications after PVS for refractory ascites in liver cirrhosis patients. Materials and Methods: This was a retrospective study of 14 patients with refractory ascites associated with decompensated cirrhosis who underwent PVS placement between June 2011 and June 2023. The clinical characteristics, changes in cardiothoracic ratio (CTR), and laboratory data (i.e., brain natriuretic peptide (BNP), D-dimer, platelet) were evaluated. Follow-up CT images in eight patients were also evaluated for ascites and complications. Results: No serious complication associated with the procedure occurred in any case. Transient increases in BNP and D-dimer levels, decreased platelet counts, and the worsening of CTR were observed in the 2 days after PVS; however, they were improved in 7 days in all cases except one. In the follow-up CT, the amount of ascites decreased in all patients, but one patient with a continuous increase in D-dimer 2 and 7 days after PVS had thrombotic disease (renal and splenic infarction). The mean PVS patency was 345.4 days, and the median survival after PVS placement was 474.4 days. Conclusions: PVS placement for refractory ascites is a technically feasible palliative therapy. The combined evaluation of chronological changes in BNP, D-dimer, platelet count and CTR, and follow-up CT images may be useful for the early prediction of the efficacy and complications of PVS.

Abstract Background Liver fibrosis is a major risk factor for hepatocellular carcinoma (HCC). We have previously reported that differentially methylated regions (DMRs) are correlated with the fibrosis stages of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the methylation levels of those DMRs in liver fibrosis and subsequent HCC were examined. Methods The methylation levels of DMRs were investigated using alcoholic cirrhosis and HCC (GSE60753). The data of hepatitis C virus-infected cirrhosis and HCC (GSE60753), and two datasets (GSE56588 and GSE89852) were used for replication analyses. The transcriptional analyses were performed using GSE114564, GSE94660, and GSE142530. Results Hypomethylated DMR and increased transcriptional level of zinc finger and BTB domain containing 38 (ZBTB38) were observed in HCC. Hypermethylated DMRs, and increased transcriptional levels of forkhead box K1 (FOXK1) and zinc finger CCCH-type containing 3 (ZC3H3) were observed in HCC. The methylation levels of DMR of kazrin, periplakin interacting protein (KAZN) and its expression levels were gradually decreased as cirrhosis progressed to HCC. Conclusions Changes in the methylation and transcriptional levels of ZBTB38, ZC3H3, FOXK1, and KAZN are important for the development of fibrosis and HCC; and are therefore potential therapeutic targets and diagnostic tools for cirrhosis and HCC.

Background and Aims: Although numerous noninvasive diagnostic methods have been developed to predict liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), they lack markers for predicting lobular inflammation, hepatocellular ballooning, or changes related to metabolic dysfunction-associated steatohepatitis (MASH). We examined serum cytokeratin 18 fragment (CK18F) as a noninvasive marker for predicting treatment response and “at-risk MASH” and “MASH resolution” in patients with MASLD. Methods: One-hundred-and-ten patients with MASLD who underwent repeated biopsy were enrolled (age, 4 [0.5–21] years) in this retrospective study. We investigated associations among serum CK18F levels, liver histology, and blood tests and compared them with changes in serum CK18F levels and liver histology and the resolution of MASH. Additionally, 565 biopsy-proven patients were analyzed for associations among serum CK18F levels, liver histology, and blood tests. Moreover, the Fibrosis-4 (FIB-4) index and CK18F were examined for their usefulness in predicting ''at-risk MASH.'' Results: CK18F changes were strongly correlated with changes in lobular inflammation, hepatocellular ballooning, and nonalcoholic fatty liver disease activity score. Multiple regression analysis showed that contributing to “MASH resolution” was associated with changes in CK18F levels as independent factors. Patients diagnosed with MASLD and an FIB-4 index >2.67, or those with an FIB-4 index ≤2.67 and CK18F > 200 U/L, were at high risk of developing MASH and should be referred to a hepatologist. Conversely, those with an FIB-4 index ≤2.67 and CK18F ≤ 200 U/L were effectively managed through regular follow-up appointments. Conclusion: CK18F changes are associated with nonalcoholic fatty liver disease activity score changes and are a promising noninvasive diagnostic marker for ''at risk MASH'' and ''MASH resolution.''

Abstract Objective To comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic constipation (CC). Design Systematic literature review (SLR) and meta-analysis (MA). Literature searches were conducted on PubMed and Embase using the Ovid platform. Methods SLR including randomized controlled trials (RCTs) and observational studies was conducted to identify the overall efficacy and safety of lubiprostone, linaclotide, and elobixibat. Thereafter, MA was performed using only RCTs. The number needed to treat (NNT) and number needed to harm (NNH) analyses were additionally conducted. Primary and secondary outcome measures The primary outcome was efficacy regarding change in spontaneous bowel movements. Secondary outcomes included safety, constipation-related symptoms, and QoL. Results Twenty-four studies met the inclusion criteria for the SLR: 17 RCTs, 4 observational studies, and 3 single-arm trials. Feasibility assessment for the MA resulted in 14 studies available for safety data analysis, and 8 available for efficacy analysis, respectively. Three drugs showed similar efficacy in the MA and NNT analysis. However, the NNH analysis revealed distinct safety profiles: lubiprostone, linaclotide, and elobixibat were linked to the highest risk of nausea, diarrhea, and abdominal pain, respectively. Conclusion The current study provides an updated overview of the efficacy, safety, patient symptoms, and QoL of the three drugs with different mechanisms of action for CC treatment.The findings could help physicians adopt an individualized approach for treating patients with CC in clinical practice.

Background and Aims: The clinical characteristics and risk factors involved in the development of liver fibrosis in the subtypes of steatotic liver disease (SLD) remain unknown. We examined the clinical characteristics of SLD subtypes using a large Japanese cohort. Methods: We performed a cross-sectional analysis (total n = 108,446). In this cohort, SLD was diagnosed by ultrasonography. Individuals with none of the cardiometabolic risk factors were excluded. Results: According to their nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) status based on the database, participants with cardiometabolic criteria were allocated to the MASLD, MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) with metabolic dysfunction groups. Of 30,857 subjects with SLD, 21,488 (69.6%) had NAFLD, and 20,922 (67.8%) had MASLD. There were few differences in the clinical characteristics between NAFLD and MASLD. After adjustment for clinical variables, we found that male patients with MetALD [odds ratio (OR) 2.26; 95% confidence interval (CI) 1.87–2.84] and ALD with metabolic dysfunction (OR 3.92; 95% CI 2.85–5.39) had a significantly higher risk for advanced liver fibrosis (diagnosed by Fibrosis-4 (FIB-4) index >2.67) compared to those with MASLD. In female patients with ALD, metabolic dysfunction (OR 5.80; 95% CI 2.51–13.4) and systemic blood pressure of ≥130 mmHg were significant risk factors for high FIB-4 (males: OR 3.38, 95% CI 2.51–4.55; females: OR 4.34, 95% CI 2.66–7.07, P < .001). Conclusion: Alcohol intake and systolic blood pressure are independent contributors to liver fibrosis progression assessed by FIB-4 in SLD.

Summary: Aim: Constipation is a common complication in patients receiving enteral nutrition, and fecal incontinence caused by laxative use can lead to a decrease in patients' quality of life and an increase in the burden on healthcare providers. This study aimed to investigate the effects of a high-fiber liquid diet on constipation and defecation care. Methods: An anonymous online survey of 184 healthcare providers was conducted on the use of ISOCAL® Fibecare (IF). Results: Many patients who used IF experienced underlying neurological disease (56.5%), and the number of days of use (mean ± standard deviation [SD]) was 41.6 ± 41.5 days. The intake of dietary fiber before and after IF use increased significantly from 11.2 ± 7.6 to 23.8 ± 5.6 g/day (P < 0.001), the number of normal bowel movements per week increased from 1.4 ± 1.8 to 1.9 ± 2.4 times/week (P < 0.01), and the number of people not receiving constipation treatment increased significantly from 19 (10.3%) to 47 (25.5%) (P < 0.001). With treatment, the use of osmotic laxatives, diphenylmethane derivatives, and enemas significantly decreased. Changes after the use of IF included decreased burden of defecation care for 31.0% of respondents, decreased frequency of bed sheet changes due to fecal soil in 22.2%, and decreased frequency of diaper exchange in 15.2%. Conclusions: Our findings suggest that the use of IF reduces the burden of healthcare providers at the time of defecation care due to the increased number of normal stools and decreased use of laxatives and enemas. Trial Registry: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055173.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and there has been a rapid increase in cases worldwide. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma and is also associated with an increased risk of cardiovascular disease or exacerbation of other organ diseases, thus posing a significant health problem from both a medical and a socioeconomic perspective. NAFLD is a systemic disease and requires the involvement of numerous medical professionals. Multidisciplinary collaboration, in which different professionals within different specialties come together and work together toward a common goal, supports better patient care by integrating perspectives of multiple experts and facilitating the exchange of opinions. Due to the large number of potential patients, gastroenterologists and hepatologists cannot manage the patients alone, and collaboration between specialists in various fields, including family doctors, dentists, nutritionists, and pharmacists is required for treatment of NAFLD. This review will discuss NAFLD from the perspective of various specialties and introduce multidisciplinary collaboration.

Abstract Background Surveillance colonoscopy decreases colorectal cancer mortality; however, lesions are occasionally missed. Although an appropriate surveillance interval is indicated, variations may occur in the methods used, such as scope manipulation or observation. Therefore, individual endoscopists may miss certain areas. This study aimed to verify the effectiveness of performing repeat colonoscopies with a different endoscopist from the initial procedure. Methods We retrospectively reviewed a database of 8093 consecutive colonoscopies performed in the Omori Red Cross Hospital from January 1st 2018 to June 30th 2021. Data from repeat total colonoscopies performed within three months were collected to assess missed lesions. The patients were divided into two groups according to whether the two examinations were performed by different endoscopists (group D) or the same endoscopist (group S). The primary outcome in both groups was the missed lesion detection rate (MLDR). Results Overall, 205 eligible patients were analyzed. In total, 102 and 103 patients were enrolled in groups D and S, respectively. The MLDR was significantly higher in group D (61.8% vs. 31.1%, P 6 min) (odds ratio, 3.10; 95% CI, 1.12–8.61) as significant variables. Conclusions Overall, our study showed a significant improvement in the detection of missed lesions when performed by different endoscopists. When performing repeat colonoscopy, it is desirable that a different endoscopist perform the second colonoscopy. Trial registration This study was approved by the Institutional Review Board of the Omori Red Cross Hospital on November 28, 2022 (approval number:22–43).

Background/Aims Endoscopic ultrasound gallbladder drainage (EUS-GBD) is gaining attention as a treatment method for cholecystitis. However, only a few studies have assessed the outcomes of permanent stenting with EUS-GBD. Therefore, we evaluated the clinical outcomes of permanent stenting using EUS-GBD. Methods This was a retrospective, single-center cohort study. The criteria for EUS-GBD at our institution are a high risk for surgery, inability to perform surgery owing to poor performance status, and inability to obtain consent for emergency surgery. EUS-GBD was performed using a 7-Fr double-pigtail plastic stent with a dilating device. The primary outcomes were the recurrence-free rate of cholecystitis and the late-stage complication-avoidance rate. Secondary outcomes were technical success, clinical success, and procedural adverse events. Results A total of 41 patients were included in the analysis. The median follow-up period was 168 (range, 10–1,238) days. The recurrence-free and late-stage complication-avoidance rates during the follow-up period were 95% (38 cases) and 90% (36 cases), respectively. There were only two cases of cholecystitis recurrence during the study period. Conclusions EUS-GBD using double-pigtail plastic stent was safe and effective with few complications, even in the long term, in patients with acute cholecystitis.

Abstract Background and Aim Ischemic colitis (IC) is a benign disease associated with acute lower gastrointestinal bleeding and frequent recurrence. While several studies have investigated risk factors for IC onset, few have assessed the risk factors for recurrent IC. This study aimed to identify risk factors for recurrent IC. Methods Potential risk factors for recurrence were assessed by examining medical records and laboratory findings in this single‐center retrospective study. We extracted the following data from the patients' medical records: patient characteristics, clinical signs and symptoms, laboratory findings, method of treatment, length of hospital stay, disease course, and the frequency of IC morbidities. Patients with IC were selected from a total of 439 312 patients over an 11‐year period. Patients were divided into recurrent and nonrecurrent IC groups. Results In total, 225 patients met the diagnostic criteria for IC during the specified study period; of these, 204 patients (90.7%) and 21 patients (9.3%) were included in the nonrecurrent and recurrent IC groups, respectively. Univariate and multivariate analyses showed a significant association between IC recurrence and both cerebral infarction (P = 0.008, odds ratio [OR] = 6.3) and history of appendectomy (P = 0.0005, OR = 6.2). The median (interquartile range [IQR]) follow‐up time for all patients was 1556 (353–2768) days; this was much longer than the median (IQR) time to recurrence of 291 (64–907) days in the recurrent IC group. Conclusion The results of this study suggest that prior cerebral infarction and appendicectomy may be risk factors for IC recurrence.

Chronic constipation is a common gastrointestinal disorder, and its management is critical. However, it is extremely difficult to assess its subjective symptoms when patients are unable to report them due to cognitive or physical disabilities, especially in cases of patients with incurable geriatric, pediatric, palliative, psychiatric, or neurological diseases. We had previously established a protocol for observing and assessing rectal fecal retention using ultrasonography and for classifying cases into three categories based on the rectal findings: no fecal retention, fecal retention without hard stools, and fecal retention with hard stools. However, although the detection of rectal fecal retention using ultrasonography would be expected to lead to better therapeutic management, there is no standard algorithm for selecting specific treatments and defecation care options based on ultrasonographic findings. Therefore, we organized an expert consensus meeting of multidisciplinary professionals to develop such an algorithm based on rectal ultrasonography findings for patients with constipation in both residential and hospital settings.

Background and Objectives: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing worldwide, alongside the epidemic of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Materials and Methods: Forty-one patients with MASH and nineteen with MASH-HCC participated in the study, completing survey questionnaires, undergoing periodontal examinations, and providing samples of saliva, mouth-rinsed water, feces, and peripheral blood. The oral and fecal microbiome profiles were analyzed by 16S ribosomal RNA sequencing. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The genus Fusobacterium had a significantly higher occupancy rate (p = 0.002) in the intestinal microflora of the MASH-HCC group compared to the MASH group. However, Butyricicoccus (p = 0.022) and Roseburia (p < 0.05) had significantly lower occupancy rates. The Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusions: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.

Although handheld ultrasound devices (HUDs) are commonplace, their ability to diagnose fecal retention (FR) remains unclear. This prospective observational study examined HUDs’ usefulness in diagnosing FR in patients with constipation in a palliative care setting. Between 10 December 2020 and 30 June 2022, we compared rectal ultrasonographic findings obtained using HUDs with clinical manifestations in 64 males and 70 females (48%, 52%, 68 ± 11 years old) with constipation who had undergone computed tomography (CT). FR was diagnosed using a HUD and compared with CT and digital rectal examination (DRE) results. In total, 42 (31%), 42 (31%), and 41 (31%) patients were diagnosed using HUDs, CT, and DRE, respectively. Thirty-nine (93%) patients in the CT group were also diagnosed with FR using HUDs. A total of 89 of 92 patients with a negative CT diagnosis also had a negative HUD diagnosis. Among the 41 patients in the DRE group, 37 were also diagnosed with FR using HUDs. Among 93 patients with a negative DRE diagnosis, 86 had a negative HUD diagnosis. The sensitivity, specificity, positive predictive value, and negative predictive value of HUDs for CT were 93%, 97%, 93%, and 97%, respectively. Those of HUDs for DRE were 88%, 94%, 86%, and 95%, respectively. The concordance rates for FR diagnosis were 128/134 for CT and HUDs and 123/134 for DRE and HUDs. HUD was useful for diagnosing FR in this setting. HUDs could provide valuable support for appropriate treatment selection. Developing a constipation treatment algorithm based on rectal ultrasonographic findings is warranted in the future.

Abstract Background and Aim Detailed clinical information regarding drug‐induced constipation (DIC) is limited. This study aimed to investigate the real‐world situation of DIC. Methods This retrospective study used data from a Japanese claims database registered from 2014 to 2021. The constipation cohort included subjects with at least one record of treated constipation, while the non‐constipation cohort was selected through random stratified sampling method, to match the constipation cohort by gender. The study population and control with at least one history of a known causative drug (CD) were matched 1:1 using propensity scores. The proportion of potential DIC (pDIC), the timing of diagnosis for pDIC, and the proportion of prescriptions by drug class for both the CDs and the laxatives were calculated, while logistic regression analysis was performed to explore additional associated factors. Results Of the 4 533 905 subjects, 178 852 were eligible in both the study population and the control. The pDIC group comprised of 19 485 patients, which accounted for 10.9% of all treated constipation subjects, while the non‐constipation with CD group had 10 430 subjects. The median duration between the recorded CD prescription and treated constipation was 38.0 days. The most frequently prescribed CD was cardiovascular drugs (47.9%). All CD classes, being male, and some comorbidities were associated with the occurrence of pDIC. Conclusion The pDIC subjects accounted for about 11% of all treated constipation cases. Since DIC requires different treatment regimens compared to other constipation types, physicians should be cognizant to provide patients with optimized treatments.

ABSTRACT Fusobacterium nucleatum is associated with colorectal cancer (CRC), and identical F. nucleatum strains seemed to be detected in 75% of patients who exhibited the presence of F. nucleatum in both CRC and saliva samples in our previous study; however, the validation of strain identity and the development of a method for strain-level discrimination are required for etiological studies. We confirmed that F. nucleatum isolates obtained from CRC and saliva samples derived from patients with CRC originated from their identical strains using whole-genome sequencing. We evaluated the hypervariable region of the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (CRISPR–Cas) system in F. nucleatum strains isolated from the CRC and saliva specimens of CRC patients to develop a method for genotyping this bacterium at the strain level. The developed method consisted of two simple PCR steps to amplify the different lengths and sequences of the CRISPR–Cas regions from F. nucleatum strains using specific but common primers. This method could successfully detect identical strains present in both cryopreserved CRC samples and saliva obtained from the same CRC patient. Dynamic monitoring of F. nucleatum strains in saliva obtained from patients with colorectal adenoma before and after oral care showed interindividual variability in F. nucleatum strains during oral care. This study provided a simple and rapid method for comprehensively identifying F. nucleatum at the strain level in clinical samples, leading to a paradigm shift in CRC research, such as the investigation of pathogenic F. nucleatum strains and monitoring of pathogenic strains in clinical trials for preventing CRC recurrence. (This study was registered in the UMIN Clinical Trials Registry under ID UMIN000016229.) IMPORTANCE Fusobacterium nucleatum is one of the predominant oral bacteria in humans. However, this bacterium is enriched in colorectal cancer (CRC) tissues and may be involved in CRC development. Our previous research suggested that F. nucleatum is present in CRC tissues originating from the oral cavity using a traditional strain-typing method [arbitrarily primed polymerase chain reaction (AP-PCR)]. First, using whole-genome sequencing, this study confirmed an exemplary similarity between the oral and tumoral strains derived from each patient with CRC. Second, we successfully developed a method to genotype this bacterium at the strain level, targeting the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated system, which is hypervariable (defined as F. nucleatum-strain genotyping PCR). This method can identify F. nucleatum strains in cryopreserved samples and is significantly superior to traditional AP-PCR, which can only be performed on isolates. The new methods have great potential for application in etiological studies of F. nucleatum in CRC.

Abstract Introduction Opioid-induced constipation (OIC) is one of the most common side effects in patients with cancer treated with opioid analgesics. The actual use of laxatives for OIC in Japan remains unelucidated. This study aimed to investigate the real-world patterns of laxative use for patients with cancer who newly initiated opioid analgesic therapy. Methods We used a Japanese nationwide hospital claims database (January 2018–December 2019). Patients with cancer newly receiving opioid analgesic therapy were included and classified on the basis of opioid classes (weak or strong) and route of administration (oral or transdermal) at initiation. The patients were divided into two groups on the basis of whether they received early medication (starting laxatives within 3 days after initiating opioid analgesic therapy), and patterns of laxative use were analyzed. Results There were 26,939 eligible patients, with 50.7% of them initiated with strong opioids. The proportion of patients who received early medication was 25.0% for weak opioids and 57.3% for strong opioids. Osmotic laxatives were most frequently used as first-line therapy in the early medication group (oral weak opioids: 12.3%, oral strong opioids: 29.4%, transdermal strong opioids: 12.8%). Stimulant laxatives were frequently used as first-line therapy, to the same extent or more than osmotic laxatives in the non-early medication group (oral weak opioids: 13.7%, oral strong opioids: 7.7%, transdermal strong opioids: 15.1%). Peripherally acting μ-opioid receptor antagonists were the second most frequently used in the early medication group for those on oral strong opioids (9.4%). Conclusion This study demonstrated for the first time that the patterns of laxative use for OIC in Japanese patients with cancer were different, depending on the opioid types at initiation and the timing of laxative medication.

Abstract Background and Aim A number of basic and clinical studies have confirmed that the traditional Japanese herbal medicine, Daikenchutou (DKT) has a pharmacological effect on cholinergic and serotonergic mechanisms with a favorable safety profile and an improving effect on lower gastrointestinal (GI) symptoms including abdominal pain or bloating. The purpose of this study is to evaluate the efficacy and safety of DKT on chronic constipation. Methods This multicenter, randomized, placebo‐controlled, double‐blinded clinical trial enrolled 67 patients with chronic constipation fulfilling Rome III criteria. After a 2‐week observation period, 63 patients with persistent symptoms were finally randomized to a 4‐week course of treatment with DKT or placebo. The primary endpoint consisted of a global assessment of overall treatment effect (OTE), while the secondary endpoints consisted of improvements in stool consistency, spontaneous bowel movements, lower GI symptoms related to constipation, and quality of life. Factors associated with OTE were also investigated. Results After 4 weeks administration of DKT, OTE was significantly higher than placebo. No side effects were observed. Significant improvement in stool consistency and lower GI symptoms was observed in the DKT group. The improvements in lower GI symptoms as well as stool consistency were associated with OTE. OTE was higher in patients with greater improvement in lower GI symptoms with mental component summary scores close to normal before treatment. Conclusion DKT was effective and safe in treating chronic constipation, especially in patients having symptoms related to constipation with no impaired mental component summary score.

Abstract Diagnosing distal bile duct obstruction remains challenging. This study aimed to examine the diagnostic ability of artificial intelligence (AI) based on clinical biomarkers in diagnosing malignant distal bile duct obstruction. A total of 206 patients with distal bile duct obstruction were included in this study. Clinical laboratory parameters were collected from the patients and evaluated using AI. All clinical parameters were input into the AI algorithm, and the AI value for malignant distal bile duct obstruction was calculated. The benign and malignant diagnostic capabilities of AI and other factors (alkaline phosphatase [ALP], intrahepatic bile duct [IHBD] diameters, and total bile duct [CBD] diameters) were compared. Benign and malignant bile duct obstruction were diagnosed in 142 and 64 patients, respectively. The median AI value of malignant distal bile duct obstruction was significantly greater than that of benign distal bile duct obstruction (0.991 vs. 0.002, p

Background and Aims: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. Methods: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin–bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. Results: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6–402.0) and 110.3 (95% CI, 16.3–2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7–199.8) and 93.1 (95% CI, 16.3–1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. Conclusion: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.

Abstract Non-invasive imaging techniques have greatly advanced the assessment of liver fibrosis and steatosis but are not fully evaluated in overweight patients. We evaluated the diagnostic performance of vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) to assess fibrosis and controlled attenuation parameter (CAP) and MR imaging (MRI)-proton density fat fraction (MRI-PDFF) to assess steatosis in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD). We included 163 biopsy-proven patients with NAFLD who underwent VCTE, MRE/MRI-PDFF, and liver biopsy (years 2014–2020) who were classified according to their body mass index (BMI) as normal (BMI

Abstract A 2-step approach, Fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE), has been proposed to predict advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to develop a novel 3-step approach for predicting advanced fibrosis. We enrolled 284 biopsy-confirmed NAFLD patients from two tertiary care centers and developed subgroups (n = 190), including 3.7% of patients with advanced fibrosis, assuming a primary care setting. In the 3-step approach, patients with intermediate-to-high FIB-4 in the first step underwent an enhanced liver fibrosis test or measurement of type IV collagen 7S domain as the second step, and VCTE was performed if the second step value was higher than the cutoff. In 284 cases, a tertiary care cohort with 36.3% advanced fibrosis, the 3-step approach showed significantly higher specificity and positive predictive value than the 2-step approach. In the subgroup with 3.7% advanced fibrosis, the 3-step approach significantly reduced the referral rate to specialists, the number of high-risk patients (i.e., liver biopsy candidates), and healthcare costs by 12.5% to 15.8%. The 3-step approach may improve the diagnostic performance to predict advanced fibrosis in NAFLD, which could lower rates of referrals to specialists, liver biopsies, and medical costs.

Abstract Background and Aim Non‐alcoholic fatty liver disease (NAFLD) can progress in non‐obese patients as in obese patients. Reports on long‐term prognosis in non‐obese NAFLD patients are controversial. Therefore, we aimed to examine the long‐term prognosis of non‐obese patients with NAFLD. Methods This single‐center, retrospective cohort study enrolled biopsy‐proven non‐obese and obese NAFLD patients between January 2002 and December 2011 and followed them up until 31 March 2021, for death and clinical events (cardiovascular and liver‐related events and extrahepatic cancers). Results Of the 223 NAFLD patients, 58 (26.0%) were non‐obese. Compared with obese patients, they had a lower fibrosis stage (0.8 ± 0.80 vs 1.2 ± 0.91; P = 0.004), milder lobular inflammation (0.9 ± 0.7 vs 1.1 ± 0.7; P = 0.02), and significantly lower serum creatinine, total bilirubin, ferritin, and type IV collagen 7S and higher high‐density lipoprotein levels. After a median follow‐up of 8.9 years, no significant difference was noted in mortality between the two groups (2 [3.4%] non‐obese vs 5 [3.0%] obese; log‐rank test, P = 0.63). Twelve patients (20.7%) in the non‐obese group and 32 (19.4%) in the obese group had clinical events. Although the obese group had a higher incidence of clinical events during the first 10 years of follow‐up, the non‐obese group had a higher incidence after that (log‐rank test, P = 0.67). The non‐obese group had a high incidence of malignancy (9 [15.5%] non‐obese vs 14 [8.3%] obese; P = 0.13). Conclusion Non‐obese NAFLD does not necessarily have a good prognosis, and some cases have a poor prognosis such as extrahepatic cancers. Further validation is required in the future.

Abstract The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM) and metabolic syndromes. This trial follows up on our previous work and forms part of the ToPiND study. We aimed to combine tofogliflozin and pioglitazone treatment for hepatic steatosis in patients with NAFLD and T2DM. In this open‐label, prospective, single‐center, randomized clinical trial, patients with NAFLD with T2DM and a hepatic fat fraction of ≥10% were assessed based on magnetic resonance imaging proton density fat fraction. Eligible patients received either 20 mg tofogliflozin or 15–30 mg pioglitazone orally, once daily for 24 weeks, followed by combination therapy with both medicines for an additional 24 weeks. The effects on diabetes mellitus and hepatic steatosis were examined at baseline and after the completion of monotherapy and combination therapy. Thirty‐two eligible patients received the combination therapy of tofogliflozin and pioglitazone. The combination therapy showed additional improvement in glycated hemoglobin compared with each monotherapy group and showed improvement in steatosis, hepatic stiffness, and alanine aminotransferase levels compared with the tofogliflozin monotherapy group. Pioglitazone monotherapy–mediated increase in body weight decreased following concomitant use of tofogliflozin. The combination therapy resulted in lower triglyceride, higher high‐density lipoprotein cholesterol, higher adiponectin, and higher ketone body levels. Conclusion: In addition to the additive effects of tofogliflozin and pioglitazone in patients with T2DM and NAFLD, combination therapy was suggested to reduce weight gain and induce cardioprotective effect. Further studies with more patients are needed to investigate the combination therapy of various drugs.

Abstract The risk factors for non-alcoholic fatty liver disease (NAFLD) progression are not completely known. Porphyromonas gingivalis infection is a risk factor for systemic diseases. We investigated the association of P. gingivalis infection with the risk of non-alcoholic steatohepatitis progression. Here, hematological tests, periodontal examination, and saliva collection were performed for 164 patients with NAFLD. P. gingivalis was identified in saliva using polymerase chain reaction. Hepatic steatosis and stiffness were evaluated using vibration-controlled transient elastography (VCTE) and magnetic resonance imaging. In patients with NAFLD, P. gingivalis positivity (P. gingivalis ratio ≥ 0.01%) in saliva correlated with liver stiffness determined using magnetic resonance elastography (MRE; p 10 periodontal pockets with depths ≥ 4 mm had significantly increased hepatic stiffness on both VCTE and MRE.

Abstract Background We previously reported that two differentially methylated region (DMR) networks identified by DMR and co-methylation analyses are strongly correlated with the fibrosis stages of nonalcoholic fatty liver disease (NAFLD). In the current study, we examined these DMR networks in viral hepatitis and hepatocellular carcinoma (HCC). Methods We performed co-methylation analysis of DMRs using a normal dataset (GSE48325), two NAFLD datasets (JGAS000059 and GSE31803), and two HCC datasets (GSE89852 and GSE56588). The dataset GSE60753 was used for validation. Results One DMR network was clearly observed in viral hepatitis and two HCC populations. Methylation levels of genes in this network were higher in viral hepatitis and cirrhosis, and lower in HCC. Fatty acid binding protein 1 (FABP1), serum/glucocorticoid regulated kinase 2 (SGK2), and hepatocyte nuclear factor 4 α (HNF4A) were potential hub genes in this network. Increased methylation levels of the FABP1 gene may be correlated with reduced protection of hepatocytes from oxidative metabolites in NAFLD and viral hepatitis. The decreased methylation levels of SGK2 may facilitate the growth and proliferation of HCC cells. Decreased methylation levels of HNF4A in HCC may be associated with tumorigenesis. The other DMR network was observed in NAFLD, but not in viral hepatitis or HCC. This second network included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation, which are specifically related to fibrosis and/or tumorigenesis in NAFLD. Conclusions Our results suggest that one DMR network was associated with fibrosis and tumorigenesis in both NAFLD and viral hepatitis, while the other network was specifically associated with NAFLD progression. Furthermore, FABP1, SGK2, and HNF4A are potential candidate targets for the prevention and treatment of HCC.

Anionic aluminium clusters are promising candidates for the fabrication of superatom-assembled nanomaterials. Here, the authors report enhanced stability for Al13 − and boron-doped B@Al12 − on a molecularly decorated p-type organic substrate.

Abstract Background Pancreato‐biliary endoscopic procedures often need to be performed under deep intravenous sedation. The patients are at an increased risk of respiratory depression influenced by the anatomical dead space of the upper respiratory system. We aimed to evaluate the benefit of oxygen delivery through a single‐sided trans‐nasal catheter (TC) for patients undergoing pancreato‐biliary endoscopy. Methods Oxygen supplementation during the procedure was provided either by insertion of a single‐sided TC or insertion of a conventional nasal catheter (NC). A prospective, single‐blind, randomized controlled study was conducted in two groups. Results The number of patients who indicated a decrease in the peripheral transcutaneous oxygen saturation (SpO2; desaturation) was significantly lower in the TC group than in the counterpart (8/58; 13.8% vs. 26/58; 44.8% p < 0.001). The efficient oxygen delivery in the safe range was better conserved in the TC group than in the NC one. There was no adverse effect on both groups. The maximum SpO2 while the endoscopic procedure was significantly higher in the TC group (99.7% vs. 99.3% p = 0.016) and the minimum SpO2 was also significantly higher in the same group (97.7% vs. 94.1% p < 0.0001), which meant that the efficient oxygen delivery was better maintained in TC group than the NC group. Conclusions A single‐sided TC placed in the pharynx in patients undergoing pancreato‐biliary endoscopy prepares a superior condition of the patients for venous sedation, maintained hyper‐oxygen saturation and a relatively higher SpO2 level to be maintained in limited conditions to reduce the dead space with acceptable tolerance, as compared to the placement of a conventional NC.

Abstract Background The appropriate delivery of death pronouncements potentially affects bereaved families’ wellbeing positively. Although younger physicians need to learn the competencies and entrustable professional activities (EPAs) to conduct death pronouncement independently, both of which have not been clarified. Therefore, this study aimed to develop a list of competencies and EPAs necessary for death pronouncement practice, which resident physicians need to acquire by the end of their residency training (postgraduate year 2). Methods An anonymous modified Delphi study was conducted with a panel of 31 experts. The experts were invited online from general wards in hospitals with resident physicians across Japan to participate in the study using the purposive and snowball sampling method. A non-anonymous web conference was held with three additional external evaluators to finalize the item list. The consensus criterion was defined as a mean response of at least 4 points on a 5-point Likert scale for each competency and EPA item and a rating of 4 or 5 points by at least 80% of the participants. Results Consensus was achieved, with consistently high levels of agreement across panel members, on 11 competencies and 9 EPA items. Additionally, a correspondence matrix table between competencies and EPAs was developed. Conclusions This study clarified the standardized educational outcomes as competencies in death pronouncement practice and the unit of professional practice of physicians who can perform this independently (EPAs), serving as a blueprint to aid the development of an educational model and evaluation method for clinical educational institutions and developers of medical school curriculums.

Abstract Background and Aim Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM@50 Hz) using standard vibration‐controlled transient elastography (VCTE) have been studied as a noninvasive test for screening of gastroesophageal varices (GEV) in chronic liver disease (CLD). Recently, a novel spleen‐dedicated VCTE (SSM@100 Hz) has been developed. We evaluated the diagnostic performance of SSM@100 Hz, SSM@50 Hz, LSM, and other noninvasive tests using esophagogastroduodenoscopy (EGD) as the reference as well as the correlation with hepatic venous pressure gradient (HVPG). Methods A total of 123 patients with CLD enrolled in this cross‐sectional study. SSM@100 Hz, SSM@50 Hz, and LSM were determined by VCTE. EGD and HVPG were performed within 12 weeks before or after VCTE. Results GEV were present in 60 patients. Failure or suboptimal SSM were fewer at 100 Hz (4.0%) than at 50 Hz (17.7%). All SSM values obtained at 100 Hz were lower than the 100 kPa ceiling threshold, but 10 patients reached the 75 kPa ceiling threshold for SSM@50 Hz. SSM@100 Hz was most accurate (area under the receiver operating characteristic [AUROC] = 0.944) for the diagnosis of GEV compared to SSM@50 Hz, LSM, and scoring systems. AUROC of SSM@100 Hz for diagnosis of high‐bleeding risk varices (HRV) was 0.941, which was significantly higher than that of SSM@50 Hz (AUROC = 0.842, P = 0.002). SSM@100 Hz showed higher specificity (82.0%) for diagnosis of HRV than SSM@50 Hz (specificity = 67.1%). SSM@100 Hz was significantly correlated with HVPG (r = 0.71, P

Sodium glucose cotransporter‐2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon‐like peptide‐1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, −0.41%, P

Abstract Fusobacterium nucleatum is associated with the progression of colorectal cancer. Thus, the possibility of preventing colorectal cancer or its progression by targeting F. nucleatum has been explored. As F. nucleatum is associated with periodontitis, we analysed whether treating periodontitis could influence F. nucleatum abundance in the colon. Patients with colorectal tumours who underwent colonoscopy were recruited. Patients diagnosed with periodontitis by a dentist were treated for approximately 3 months. Endoscopic resection of colorectal tumours was performed after periodontitis treatment, and resected tumours were pathologically classified as high-(HGD) or low-grade dysplasia (LGD). Saliva and stool samples were collected before and after the treatment. Of the 58 patients with colorectal tumours, 31 were included in the study, 16 showed improvement in periodontitis, and 11 showed no improvement. Stool F. nucleatum levels before treatment were significantly lower in the LGD group than in the HGD group. A significant decrease in faecal F. nucleatum levels was observed in patients who underwent successful treatment but not in those whose treatment failed. Salivary F. nucleatum levels were not altered in patients despite periodontal treatment. Thus, successful periodontitis treatment reduces stool F. nucleatum levels and may aid research on periodontitis and suppression of colorectal cancer development.

Non-alcoholic fatty liver disease is currently the most common chronic liver disease, affecting up to 25% of the global population. Simple fatty liver, in which fat is deposited in the liver without fibrosis, has been regarded as a benign disease in the past, but it is now known to be prognostic. In the future, more emphasis should be placed on the quantification of liver fat. Traditionally, fatty liver has been assessed by histological evaluation, which requires an invasive examination; however, technological innovations have made it possible to evaluate fatty liver by non-invasive imaging methods, such as ultrasonography, computed tomography, and magnetic resonance imaging. In addition, quantitative as well as qualitative measurements for the detection of fatty liver have become available. In this review, we summarize the currently used qualitative evaluations of fatty liver and discuss quantitative evaluations that are expected to further develop in the future.

Background: Chronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide. Methods: This is an exploratory multicenter open-label study. The target number of patients is 64: 32 patients with and 32 without abdominal symptoms. Patients with chronic idiopathic constipation or irritate bowel syndrome with constipation diagnosed according to the Rome-IV criteria are eligible. Patients prescribed 0.99–2 g/day of magnesium oxide for at least 4 weeks will be included. Those who consent to the study will continue taking magnesium oxide for 2–4 weeks, and defecation will be documented. Patients who meet the criteria will be prescribed linaclotide (0.5 mg) daily for 12 weeks. The primary endpoint is a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score after 12 weeks of treatment. Conclusion: This is the first study to investigate the usefulness of linaclotide as a second-line treatment for chronic constipation. We will test the efficacy of treatment of constipation in patients with inadequate response to magnesium oxide. Trial registration: This study is registered with the Japan Registry of Clinical Trials (jRCT, jRCTs031200048).

Background/Aims The use of endoscopic intervention (EI) for acute biliary pancreatitis (ABP) remains controversial because the severity of biliary obstruction/cholangitis/pancreatitis is not reflected in the indications for early EI (EEI). Methods A total of 148 patients with ABP were included to investigate 1) the differences in the rate of worsening cholangitis/pancreatitis between the EEI group and the early conservative management (ECM) group, especially for each severity of cholangitis/pancreatitis, and 2) the diagnostic ability of imaging studies, including endoscopic ultrasound (EUS), to detect common bile duct stones (CBDSs) in the ECM group. Results No differences were observed in the rate of worsening cholangitis between the EEI and ECM groups, regardless of the severity of cholangitis and/or the existence of impacted CBDSs. Among patients without impacted CBDSs and moderate/severe cholangitis, worsening pancreatitis was significantly more frequent in the EEI group (18% vs. 4%, p=0.048). In patients in the ECM group, the sensitivity and specificity for detecting CBDSs were 73% and 98%, respectively, for EUS, whereas the values were 13% and 92%, respectively, for magnetic resonance cholangiopancreatography. Conclusions EEI should be avoided in the absence of moderate/severe cholangitis and/or impacted CBDSs because of the high rate of worsening pancreatitis. EUS can contribute to the accurate detection of residual CBDSs, for the determination of the need for elective EI.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium–glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD. Methods: Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model. Results: SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol. Conclusions: SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.

Background: Many health care workers around the world tackled with COVID-19, however sadly, the infection of many medical care workers were reported. To reduce the risk of infection, we launched selected team (Team COVID) of non-specialists and brought in active telemedicine method and computed tomography (CT)-first protocol. We describe our actual practice and the health status of medical doctors dealing with COVID-19 patients. Methods: Between April 17, 2020 and May 24, 2020, 10 doctors worked with COVID-19 patients as part of Team COVID. The Team COVID doctors used a CT-first triage protocol for outpatients and telemedicine for inpatients and outpatients. We evaluated paired serum-specific antibodies for SARS-CoV-2 at the initial and end of the study duration and PCR results for SARS-CoV-2 at the end of the study duration. Furthermore, 36-item short-form of the Medical Outcome Study Questionnaire (SF-36) at the beginning and end of the study period were evaluated. Results: Ten doctors worked as Team COVID: seven internal medicine doctors and three surgeons. During the study period, Team COVID treated 165 individuals in the outpatient clinic and isolated hospitalized patients for 315 person-days. There were no positive results of serum-specific antibody testing and PCR testing for SARS-CoV-2 in Team COVID doctors. Furthermore, the SF-36 showed no deterioration in physical and mental QOL status. No in-hospital infection occurred during the study period. Conclusions: The Team COVID fulfilled the treatment using the active telemedicine and CT-first triage protocol without in hospital infection and excess stress. The combination strategy seems acceptable for both the protection and stress relief among the medical staff.

Background: It is unclear which laxatives are appropriate to prevent opioid-induced constipation (OIC). This study will evaluate whether prophylactic use of naldemedine prevents OIC in patients with cancer who start opioid administration. Methods: This study is a multicenter, double-blinded, randomized, placebo-controlled trial. Patients who meet the eligibility criteria and give consent will be randomly assigned to the naldemedine or placebo group. Both groups will take each drug once a day after breakfast for 14 days. Results: The primary endpoint is the proportion of patients with a Bowel Function Index of less than 28.8 on Day 14. The secondary endpoints include assessment scales of the impact of constipation on comprehensive quality of life. Conclusions: This is the first study proposed to assess the superiority of naldemedine over placebo in the prevention of OIC. If naldemedine is found to be effective in reducing OIC compared with the placebo, it will be regarded as a new standard for OIC prophylaxis at opioid initiation. Trial registration: jRCT identifier: jRCTs031200397. Registered March 5, 2021, https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031200397.

Abstract Genetically engineered mice (GEM) are the gold standard for cancer modeling. However, strict recapitulation of stepwise carcinogenesis from a single tumor-initiating epithelial cell among genetically intact cells in adults is not feasible with the currently available techniques using GEM. In previous studies, we partially overcame this challenge by physically isolating organs from adult animals, followed by genetic engineering in organoids and subcutaneous inoculation in nude mice. Despite the establishment of suitable ex vivo carcinogenesis models for diverse tissues, tumor development remained ectopic and occurred under immunodeficient conditions. Further refinement was, therefore, necessary to establish ideal models. Given the poor prognosis and few models owing to the lack of gall bladder (GB)-specific Cre strain, we assumed that the development of authentic models would considerably benefit GB cancer research. Here, we established a novel model using GB organoids with mutant Kras and Trp53 loss generated in vitro by lentiviral Cre transduction and CRISPR/Cas9 gene editing, respectively. Organoid-derived subcutaneous tumor fragments were sutured to the outer surface of the GB in syngeneic mice, which developed orthotopic tumors that resembled human GB cancer in histological and transcriptional features. This model revealed the infiltration of similar subsets of immune cells in both subcutaneous and orthotopic tumors, confirming the appropriate immune environment during carcinogenesis. In addition, we accurately validated the in vivo efficacy of gemcitabine, a common therapeutic agent for GB cancer, in large cohorts. Taken together, this model may serve as a promising avatar of patients with GB cancer in drug discovery and precision medicine.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy‐proven NAFLD were enrolled. After propensity‐score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis‐4 (FIB‐4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4‐7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB‐4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4‐7S. The AUROCs in patients with diabetes were 0.790 for the FIB‐4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4‐7S. The AUROC of COL4‐7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4‐7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4‐7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4‐7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

Background: Approximately 60% of patients with chronic constipation (CC) have a significantly higher rate of loss of defecation desire (LODD). Bile acids are expected to have a restorative effect on defecation desire (DD) because they lower the rectal sensory threshold, which is an objective index of DD. Elobixibat (EXB) specifically inhibits the ileal bile acid transporter/apical sodium-dependent bile acid transporter, which is a transporter involved in the reabsorption of bile acids in the terminal ileum. This study aims to investigate the LODD improvement rate in patients with CC after 4 weeks of EXB treatment. Methods: A total of 40 adult patients with CC who meet the eligibility criteria will be enrolled. Patients will receive oral EXB (10 mg/day) for 4 weeks. A patient diary will be provided daily at 4 weeks after treatment. The primary endpoint will be the percentage LODD improvement at week 4 of the treatment period from week 2 of the observation period using questionnaires. Ethics and dissemination: Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board prior to participant enrolment (approval number: CRB21-008). The results of this study will be submitted for publication in international peer-reviewed journals, and key findings will be presented at international scientific conferences. Participants desiring the results of this study will be directly contacted for data dissemination. Trial registration: This trial was registered at ClinicalTrials.gov (NCT05165199). Protocol version: 1.0, September 21, 2021.

Introduction Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH.Methods and analysis A total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication.Trial registration number This trial is registered with ClinicalTrials.gov (number: NCT05084404).Protocol version V.1.1, 19 August 2021.