Atsushi Nakajima’s research while affiliated with Yokohama City University and other places

Objective An interim analysis of postmarketing surveillance reported the safety and efficacy of elobixibat, a laxative medication that inhibits the ileal bile acid transporter, at 4 weeks in approximately 1000 patients with chronic constipation in Japan. However, its long-term safety and efficacy in elderly patients remain unclear. This study aimed to conclude and report the final analysis of postmarketing surveillance, including 52-week safety and efficacy profiles in a clinical practice setting, using approximately 3000 patients. Methods The overall survey period spanned from June 2018 to May 2022. Observation periods were set at 4 weeks (4-week treatment period) and 52 weeks (52-week treatment period). Adverse drug reactions and efficacy outcomes, including defecation frequency, Bristol Stool Form Scale scores, and patient satisfaction, were analyzed. Results The 4-week safety analysis set included 3638 patients with a mean age of 70.8 years, and 73.7% were aged ⩾65 years. Most patients (62.5%) were treated with elobixibat alone, while the rest received concomitant laxatives. In total, 231 patients (6.35%) experienced adverse drug reactions, with gastrointestinal disorders (6.02%) such as diarrhea (3.35%) and abdominal pain (2.06%), being the most common adverse drug reaction. The adverse drug reaction incidence in elderly patients aged ⩾65, ⩾75, and ⩾85 years was 5.49%, 4.85%, and 2.80%, respectively. In the 52-week treatment period, adverse drug reaction incidence was 5.40% (71/1315 patients), similar to that in the 4-week treatment period. Regarding efficacy, defecation frequency and Bristol Stool Form Scale scores significantly improved from week 2 onward, regardless of the age group and administration timing (before breakfast, lunch, or dinner). Most patients reported satisfaction from week 2 onward (6.0%, 66.9%, 78.6%, and 90.4% at baseline, weeks 2, 4, and 52, respectively). Conclusion This study confirmed the long-term safety and efficacy of elobixibat in patients with chronic constipation, including many elderly ones, in routine clinical practice.

Background Attenuation Imaging (ATI) and controlled attenuation parameter (CAP) are non-invasive ultrasound-based methods for diagnosing hepatic steatosis. However, reports on the clinical usefulness of ATI are limited. We aimed to compare the ability of ATI and CAP to diagnose hepatic steatosis with magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) as the reference standard. Methods We performed a prospective multicenter study of 562 patients with chronic liver disease who underwent ATI, CAP, and MRI-PDFF. Patients with skin-to-liver capsule distance (SCD) ≤ 25 mm underwent CAP with an M probe; those with SCD > 25 mm underwent CAP with an XL probe. MRI-PDFF was used as the reference standard: S0 corresponds to MRI-PDFF < 5.2%, S1 to 5.2% ≤ MRI-PDFF < 11.3%, S2 to 11.3% ≤ MRI-PDFF < 17.1%, and S3 to MRI-PDFF ≥ 17.1%. Results The correlation coefficients for ATI and MRI-PDFF stratified by body mass index (< 30, ≥ 30 kg/m ² ), SCD (< 25, ≥ 25 mm), 2-dimensional share wave elastography (< 1.8 m/s), fibrosis-4 index (≤ 2.67), albumin–bilirubin score (< − 2.60) and type IV collagen 7 s (< 5.0 ng/ml) were significantly higher than those for CAP and MRI-PDFF. Areas under the receiver operating characteristics (95% CI) for ATI and CAP were 0.895 (0.869–0.922) and 0.845 (0.809–0.881) for ≥ S1 steatosis, 0.944 (0.926–0.963) and 0.881(0.852–0.910) for ≥ S2 steatosis, and 0.928 (95% CI 0.906–0.950) and 0.860 (95% CI 0.829–0.890) for S3 steatosis. ATI had higher diagnostic performance for all hepatic steatosis grades than CAP. Conclusions ATI is a more useful non-invasive method for diagnosing hepatic steatosis than CAP.

It remains unclear whether alcohol intake and cardiometabolic factors are simultaneously associated with liver fibrosis progression in Japanese obese patients. This study investigated factors influencing liver fibrosis progression using the Aspartate Aminotransferase/Platelet Ratio Index (APRI), which does not include age. We conducted a cross‐sectional study of 26 737 obese (BMI ≥ 25 kg/m ² ) adults undergoing health checkups. Steatotic liver disease (SLD) was diagnosed via ultrasonography. Clinical characteristics were analysed according to BMI category and APRI to identify risk factors for advanced liver fibrosis (APRI > 1.0). The prevalence of type 2 diabetes, hypertension, and SLD increased with increasing BMI. On multivariable analysis in male, significant risk factors for advanced liver fibrosis included increased BMI (BMI 30–34.9 kg/m ² : OR 2.64, 95% CI 1.89–3.69, p < 0.001; BMI 35–39.9 kg/m ² : OR 2.67, 95% CI 1.89–3.69, p = 0.002; BMI ≥ 40 kg/m ² : OR 3.51, 95% CI 1.24–9.96, p = 0.018), SLD (OR 2.13, 95% CI 1.49–3.05, p < 0.001), moderate alcohol intake (OR 1.36, 95% CI 1.03–1.79, p = 0.031), heavy alcohol intake (OR 4.31, 95% CI 2.90–6.40, p < 0.001), high blood pressure (OR 1.30, 95% CI 1.01–1.67, p = 0.044), and high fasting blood glucose (OR 1.61, 95% CI 1.12–2.28, p = 0.008). In female, only age > 65 years (OR 3.02, 95% CI1.93–4.73, p < 0.001), BMI, and high uric acid (OR 2.06, 95% CI 1.15–3.68, p = 0.015) were extracted. In an obese male, alcohol intake and cardiometabolic factors were associated with liver fibrosis progression based on APRI, independent of elevated BMI and SLD.

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.

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: Although contrast-enhanced endoscopic ultrasound (CH-EUS) plays an important role in the ultrasound imaging-based diagnosis of intra-abdominal hypervascular tumors, detective flow imaging EUS (DFI-EUS), which can detect micro-blood flow without using a contrast agent, has recently emerged. In this study, we investigated the usefulness of DFI-EUS for detecting intra-abdominal hypervascular tumors. Methods: Thirteen patients with intra-abdominal hypervascular tumors detected on contrast-enhanced computed tomography who underwent DFI-EUS and CH-EUS were included. The lesions were classified into non-enhancement, hypo-enhancement, iso-enhancement, and hyper-enhancement patterns. Vascular structural patterns were classified as non-enhancement, homogeneous or heterogeneous enhancement. On DFI-EUS, patients who showed heterogeneous enhancement were evaluated for the presence or absence of dendritic and peritumoral capsule-like structures. Contrast patterns, vascular structure patterns, and detection capabilities of DFI-EUS and CH-EUS were examined. Results: The final diagnoses were pancreatic neuroendocrine neoplasm in 10 patients (76.9%), gastrointestinal neuroendocrine neoplasm in one patient (7.6%), gastrointestinal stromal tumor in one patient (7.6%), and metastatic pancreatic tumor in one patient (7.6%). The contrast patterns (DFI-EUS vs. CH-EUS) were non-enhancement in 7.7% vs. 0%, iso-enhancement in 15.3% vs. 23.0%, and hyper-enhancement in 76.9% vs. 76.9%. The vascular structure patterns (DFI-EUS vs. CH-EUS) showed a homogeneous enhancement of 0% vs. 100% and a heterogeneous enhancement of 92% vs. 0%. Patients with heterogeneous enhancement on DFI-EUS showed a dendritic structure in 91.6% and capsule-like structures in 75.0% of patients. Conclusions: DFI-EUS and CH-EUS showed comparable iso-enhancement or hyper-enhancement patterns. In contrast, DFI-EUS revealed the characteristic heterogeneous patterns of dendritic and capsular-like vascular structures.

Objective Endoscopic sphincterotomy (EST), especially when anticoagulants are used, carries a significant risk of delayed bleeding. However, the relationship between the use of antithrombotic agents, including direct oral anticoagulants, and post‐EST bleeding remains unclear. This study aimed to identify the risk factors for post‐EST delayed bleeding when antithrombotic agents were administered according to the guidelines. Methods We analyzed cases of patients who underwent endoscopic retrograde cholangiopancreatography and EST between January 2018 and August 2022, focusing on those with normal anatomy and naïve papillae. We examined the incidence of post‐EST bleeding, endoscopic retrograde cholangiopancreatography procedure details, severity and timing of post‐EST delayed bleeding, hemostatic interventions, and factors related to post‐EST delayed bleeding. Results Among the 502 patients included, 76 (15%) were taking antithrombotic agents. Post‐endoscopic retrograde cholangiopancreatography delayed bleeding was noted in seven patients (1.4%). Mild, moderate, and severe delayed bleeding occurred in four, one, and two cases, respectively. Hemostatic injection completely controlled cases of delayed bleeding. Multivariate analysis identified a 1‐day direct oral anticoagulants interruption (odds ratio: 20.5, 95% confidence interval: 3.33–125, p = 0.0011) and dialysis (odds ratio: 38.7, 95% confidence interval: 2.4–624, p = 0.0099) as significant risk factors for delayed bleeding. No thromboembolic events related to the discontinuation of antithrombotic drugs were observed. Conclusion A 1‐day direct oral anticoagulants interruption and dialysis are independent risk factors for post‐EST delayed bleeding, necessitating careful consideration.

Aim The risk of lymph node metastasis after endoscopic resection of high‐risk T1 colorectal cancer prompts additional resection. However, age and comorbidities are considered in decision‐making and some surgeons opt for observation. We compared the long‐term outcomes of these approaches with the aim of clarifying the need for additional resection. Method This multicentre retrospective study included high‐risk T1 colorectal cancer patients treated with endoscopic submucosal dissection (ESD) between January 2013 and April 2021. Patients who met one or more of the following criteria were eligible for inclusion: submucosal invasion depth ≥1000 μm, vessel invasion, poor differentiation, budding grade 2/3 or a positive vertical margin. Patients were divided into resection (R) and observation (O) groups. Outcomes were evaluated based on overall survival (OS) and 5‐year cancer‐specific survival (CSS), with an additional stratified analysis using the age‐adjusted Charlson comorbidity index (ACCI). Results The study included 178 patients (group R, n = 131; group O, n = 47). Patients in group O were significantly older and had more comorbidities. Group R showed better 5‐year OS and CSS (OS 87.0% vs. 58.9%, p = 0.001; CSS 98.8% vs. 78.4%, p = 0.002). Stratification by ACCI revealed that benefits of additional resection remained for patients with ACCI ≤ 6 (OS 91.2% vs. 58.3%, p = 0.013; CSS 98.4% vs. 61.7%, p < 0.001) but not for those with ACCI ≥7 (OS 75.9% vs. 59.8%, p = 0.289; CSS 100% vs. 100%, p = 0.617). Conclusions Significant survival benefits were demonstrated in group R patients with high‐risk T1 cancer. However, the survival benefit of additional surgical resection was unconfirmed in patients with ACCI ≥ 7.

Aim: In the PEMA-FL study in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), pemafibrate was shown to significantly decrease low-density lipoprotein cholesterol (LDL-C) levels. We aimed to investigate the mechanisms of pemafibrate-induced LDL-C reduction in patients with MASLD by conducting an additional sub-analysis of the PEMA-FL study. Methods: The PEMA-FL study randomized 118 patients with MASLD to receive pemafibrate or placebo for 72 weeks. This sub-analysis examined the percentage change in LDL-C and related lipid markers by tertile of baseline LDL-C levels and the correlation between these changes in the pemafibrate group. Results: Pemafibrate significantly decreased LDL-C levels approximately 25% (p＜0.001 at all timepoints) from baseline in the highest tertile of baseline LDL-C levels (≥ 137.5 mg/dL), with similar trends for non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) levels. Lipoprotein (a) [Lp(a)] levels decreased only in patients with the highest baseline LDL-C levels. Regardless of the baseline LDL-C levels, pemafibrate altered the LDL particle profile (increased LDL particle size and decreased the number); reduced lathosterol, β-sitosterol, and campesterol; and increased angiopoietin-like protein 3 (ANGPTL3). The percentage change in LDL-C positively correlated with that in ApoB, non-HDL-C, Lp(a), lathosterol, β-sitosterol, and campesterol but not HDL-C and ANGPTL3. Conclusion: Pemafibrate reduced LDL-C, ApoB, and non-HDL-C levels in patients with MASLD, and the effect was greater in those with higher baseline LDL-C levels. Pemafibrate may clinically benefit patients with MASLD by improving LDL-C levels and the LDL particle profile.