Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis.

INTRODUCTION: Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED: This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION: Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.

Identification of differentially methylated regions associated with both liver fibrosis and hepatocellular carcinoma.

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.

No evidence for cross-paradigm transfer of abstract task knowledge in adults and school-aged children.

Cognitive control is a hallmark of human cognition. A large number of studies have focused on the plasticity of cognitive control and examined how repeated task experience leads to the improvement of cognitive control in novel task environments. However, it has been demonstrated that training-induced changes are very selective and that transfer occurs within one task paradigm but not across different task paradigms. The current study tested the possibility that cross-paradigm transfer would occur if a common cognitive control strategy is employed across different task paradigms. Specifically, we examined whether prior experience of using reactive control in one task paradigm (i.e., either the cued task-switching paradigm or the AX-CPT) makes adults (N = 137) and 9- to 10-year-olds (N = 126) respond in a reactive way in a subsequent condition of another task paradigm in which proactive control could have been engaged. Bayesian generalized mixed-effects models revealed clear evidence of an absence of cross-paradigm transfer of reactive control in both adults and school-aged children. Based on these findings, we discuss to what extent learned control could be transferred across different task contexts and the task-specificity of proactive/reactive control strategies.

Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD. APPROACH AND RESULTS: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort. CONCLUSIONS: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.

Meta-analysis of the diagnostic accuracy of serum type IV collagen 7S concentration for the staging of liver fibrosis in nonalcoholic fatty liver disease.

AIM: We aimed to evaluate the diagnostic accuracy of the measurement of serum type IV collagen 7S (T4C7S) concentration for the staging of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: A systematic search or published works was carried out using the PubMed, Cochrane Library, and Web of Science Core Collection databases for studies of the accuracy of serum T4C7S concentration for the staging of fibrosis using Fibrosis stage (F)0-4 in patients with NAFLD diagnosed by liver biopsy. RESULTS: Nine articles describing 1475 participants with NAFLD were included. For fibrosis ≥F1, with n = 849, summary estimates of sensitivity of 0.79, specificity of 0.69, and area under the curve (AUC) of 0.80 were obtained using a median T7C4S cut-off value of 4.6 ng/ml. For fibrosis ≥F2, with n = 1,090, summary estimates of sensitivity of 0.78, specificity of 0.78, and AUC of 0.84 were obtained using a median cut-off value of 4.9 ng/ml. For fibrosis ≥F3, with n = 1311 participants and a median cut-off value of 5.4 ng/ml, a pooled sensitivity of 0.82, specificity of 0.81, and AUC of 0.83 were obtained. For fibrosis ≥F4, with n = 753 and a median cut-off value of 6.6 ng/ml, a pooled sensitivity of 0.85, specificity of 0.81, and AUC of 0.85 were obtained. CONCLUSIONS: Serum T4C7S concentration was found to be an accurate method of staging liver fibrosis in patients with NAFLD.

M-PAST score is better than MAST score for the diagnosis of active fibrotic nonalcoholic steatohepatitis.

BACKGROUND: Clinical trials enroll patients with active fibrotic nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease [NAFLD] activity score ≥ 4) and significant fibrosis (F ≥ 2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). METHODS: We undertook prospective primary (n = 176), retrospective validation (n = 169), and University of California San Diego (UCSD; n = 234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP), or proton density fat fraction (PDFF), and aspartate aminotransferase (AST) were combined to develop a two-step strategy-FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)-and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. RESULTS: Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p = 0.004) and MAST (0.710, p < 0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. CONCLUSIONS: The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This study is registered with ClinicalTrials.gov (number, UMIN000012757).

Real-world assessment of SmartExam, a novel FibroScan computational method: A retrospective single-center cohort study.

BACKGROUND AND AIM: SmartExam is a novel computational method compatible with FibroScan that uses a software called SmartDepth and continuous controlled attenuation parameter measurements to evaluate liver fibrosis and steatosis. This retrospective study compared the diagnostic accuracy of conventional and SmartExam-equipped FibroScan for liver stiffness measurement (LSM). METHODS: The liver stiffness and the associated controlled attenuation parameters of 167 patients were measured using conventional and SmartExam-Equipped FibroScan as well as reference methods like magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) measurements to assess its diagnostic performance. M or XL probes were selected based on the probe-to-liver capsule distance for all FibroScan examinations. RESULTS: The liver stiffness and controlled attenuation parameter (CAP) correlation coefficients calculated from conventional and SmartExam-equipped FibroScan were 0.97 and 0.82, respectively. Using MRE/MRI-PDFF as a reference and the DeLong test for analysis, LSM and the area under the receiver operating characteristic curve for CAP measured by conventional and SmartExam-equipped FibroScan showed no significant difference. However, the SmartExam-equipped FibroScan measurement (33.6 s) took 1.4 times longer than conventional FibroScan (23.2 s). CONCLUSIONS: SmartExam has a high diagnostic performance comparable with that of conventional FibroScan. Because the results of the conventional and SmartExam-equipped FibroScan were strongly correlated, it can be considered useful for assessing the fibrosis stage and steatosis grade of the liver in clinical practice, with less variability but little longer measurement time compared with the conventional FibroScan.

Asymmetric negative transfer effects of working memory training.

Gathercole et al. (Journal of Memory and Language, 105, 19-42, 2019) presented a cognitive routine framework for explaining the underlying mechanisms of working memory (WM) training and transfer. This framework conceptualizes training-induced changes as the acquisition of novel cognitive routines similar to learning a new skill. We further infer that WM training might not always generate positive outcomes because previously acquired routines may affect subsequent task performance in various ways. Thus, the present study aimed to demonstrate the negative effects of WM training via two experiments. We conducted Experiment 1 online using a two-phase training paradigm with only three training sessions per phase and replicated the key findings of Gathercole and Norris (in prep.) that training on a backward circle span task (a spatial task) transferred negatively to subsequent training on a backward letter span task (a verbal task). We conducted Experiment 2 using a reversed task order design corresponding to Experiment 1. The results indicated that the transfer from backward letter training to backward circle training was not negative, but rather weakly positive, suggesting that the direction of the negative transfer effect is asymmetric. The present study therefore found that a negative transfer effect can indeed occur under certain WM training designs. The presence of this asymmetric effect indicates that backward circle and backward letter tasks require different optimal routines and that the locus of negative transfer might be the acquisition process of such optimal routines. Hence, the routines already established for backward circle might hinder the development of optimal routines for backward letter, but not vice versa.

Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE). METHODS: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day. RESULTS: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE. CONCLUSIONS: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.

Cultures Crossing: The Power of Habit in Delaying Gratification.

Resisting immediate temptations in favor of larger later rewards predicts academic success, socioemotional competence, and health. These links with delaying gratification appear from early childhood and have been explained by cognitive and social factors that help override tendencies toward immediate gratification. However, some tendencies may actually promote delaying gratification. We assessed children's delaying gratification for different rewards across two cultures that differ in customs around waiting. Consistent with our preregistered prediction, results showed that children in Japan (n = 80) delayed gratification longer for food than for gifts, whereas children in the United States (n = 58) delayed longer for gifts than for food. This interaction may reflect cultural differences: Waiting to eat is emphasized more in Japan than in the United States, whereas waiting to open gifts is emphasized more in the United States than in Japan. These findings suggest that culturally specific habits support delaying gratification, providing a new way to understand why individuals delay gratification and why this behavior predicts life success.

MRI-Based Quantitative R2* Mapping at 3 Tesla Reflects Hepatic Iron Overload and Pathogenesis in Nonalcoholic Fatty Liver Disease Patients.

BACKGROUND: The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated. PURPOSE: This study aimed to investigate the effect of HIO and examine the diagnostic usefulness of magnetic resonance imaging (MRI)-based R2* quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD. STUDY TYPE: Prospective and retrospective. POPULATION: A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver-biopsy-confirmed NAFLD were performed. FIELD STRENGTH/SEQUENCE: 3 T; chemical-shift encoded multi-echo gradient echo. ASSESSMENT: Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2* for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed. STATISTICAL TESTS: Student's t-test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P-value less than 0.05 is statistically significant. RESULTS: HIC was significantly correlated with HIB grades (r = 0.407). R2* was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2* mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s-1 . In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s-1 . When R2* was <62.5 s-1 , R2* correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2* was ≥62.5 s-1 , a significant correlation of R2* with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition. DATA CONCLUSION: R2* ≥ 62.5 s-1 is a promising modality for non-invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Two differentially methylated region networks in nonalcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma.

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.

Prior task experience increases 5-year-old children's use of proactive control: Behavioral and pupillometric evidence.

Children engage cognitive control reactively when they encounter conflicts; however, they can also resolve conflicts proactively. Recent studies have begun to clarify the mechanisms that support the use of proactive control in children; nonetheless, sufficient knowledge has not been accumulated regarding these mechanisms. Using behavioral and pupillometric measures, we tested the novel possibility that 5-year-old children (N = 58) learn to use proactive control via the acquisition of abstract task knowledge that captures regularities of the task. Participants were assigned to either a proactive training group or a control training group. In the proactive training group, participants engaged in a training phase where using proactive control was encouraged, followed by a test phase using different stimuli where both proactive and reactive control could be used. In the control training group, participants engaged in a training phase where both cognitive control strategies could be used, followed by a similarly-structured test phase using different stimuli. We demonstrated children in the control training group responded more quickly and accurately and showed greater cue-related pupil dilation in the test phase than in the training phase. However, there were no differences in response times, accuracies, and pupil dilation between the proactive and control training groups in the training and test phases. These findings suggest that prior task experience, that goes beyond specific knowledge about the timing of task goal activation, can lead children to engage more proactive control endogenously, even if they are not directly encouraged to do so.

The Hebb repetition effect in complex span tasks: Evidence for a shared learning mechanism with simple span tasks.

The Hebb repetition effect on serial-recall task refers to the improvement in the accuracy of recall of a repeated list (e.g., repeated in every 3 trials) over random non-repeated lists. Previous research has shown that both temporal position and neighboring items need to be the same on each repetition list for the Hebb repetition effect to occur, suggesting chunking as one of its underlying mechanisms. Accordingly, one can expect absence of the Hebb repetition effect in a complex span task, given that the sequence is interrupted by distractors. Nevertheless, one study by Oberauer, Jones, and Lewandowsky (2015, Memory & Cognition, 43[6], 852-865) showed evidence of the Hebb repetition effect in a complex span task. Throughout four experiments, we confirmed the Hebb repetition effect in complex span tasks, even when we included distractors in both encoding and recall phases to avoid any resemblance to a simple span task and minimized the possibility of chunking. Results showed that the Hebb repetition effect was not affected by the distractors during encoding and recall. A transfer cycle analysis showed that the long-term knowledge acquired in the complex span task can be transferred to a simple span task. These findings provide the first insights on the mechanism behind the Hebb repetition effect in complex span tasks; it is at least partially based on the same mechanism that improves recall performance by repetition in simple span tasks.

Retrieval stopping can reduce distress from aversive memories.

Aversive memories have the potential to impair one's psychological well-being. It is desirable to reduce the anguish over such memories, as well as the chance that they will be retrieved. In two experiments, we investigated whether retrieval stopping reduces the distress elicited by negative memories retrieved from cues and how the effects of retrieval stopping are modulated by mental disorders, such as depression and anxiety. Participants engaged in retrieval stopping of aversive scene memories without any diversionary thoughts (direct suppression, Experiment 1) or with diversionary positive thoughts (thought substitution, Experiment 2). Direct suppression reduced arousal elicited by the retrieval of aversive memories, while thought substitution did not only reduce arousal but also increased positive valence. Self-reported anxious/depressive symptoms negatively modulated the effects of direct suppression. For no or mild anxious/depressed individuals, direct suppression alleviated negative valence and high arousal when retrieving aversive memories. The negative relationship was not observed between the severity of the symptoms and the effect of thought substitution. These findings suggest that both retrieval stopping strategies can reduce distress from aversive memories.

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.

BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice.

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.

Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease. METHODS: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m2 ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m2 ) who underwent pathological examination and 87 controls at five hospitals in Japan. RESULTS: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease. CONCLUSIONS: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).

Relationship between Stool Form and Quality of Life in Patients with Chronic Constipation: An Internet Questionnaire Survey.

INTRODUCTION: Chronic constipation (CC) is a highly prevalent functional bowel disorder with low treatment satisfaction and impaired quality of life (QOL). However, physicians tend to emphasize only "stool frequency," and relationship between "stool form" and QOL remains unclear. In this study, we aimed to investigate the actual situation of CC treatment in Japan and elucidate the relationship between stool form and QOL in patients with CC. METHODS: We conducted an online questionnaire survey in September 2018 targeting Japanese adult patients already diagnosed with CC and taking prescribed drugs. Assessments included the type of drug treatment, treatment duration, frequency of drug use, frequency of bowel movements (BMs), Bristol Stool Form Scale (BSFS), and Japanese version of the Patient Assessment of Constipation QOL (PAC-QOL) scores. Relationship between BSFS and Japanese PAC-QOL scores was analyzed, and most important factor that influences QOL was investigated. RESULTS: A total of 614 subjects were enrolled. Of these, 398 (64.8%) regularly used magnesium oxide and 162 (26.4%) used stimulant laxative, especially 81 (50.0%) used stimulant laxative "everyday." Mean score of the PAC-QOL was 1.29 ± 0.74, and the lowest score (highest QOL) of 0.94 ± 0.61 was observed in BSFS type 4. Significant difference was seen between BSFS type 4 and all the other types except type 7. Multivariate analysis revealed that normal stool form (BSFS type 4) and BMs ≥3/week are strongly related to decreases of PAC-COL score. In BSFS types 6 and 7, 36% of individuals experienced self-discontinuation of prescribed drugs and 53% self-reduced drug intake because of excessive effects. CONCLUSIONS: Stool form and frequency of BMs are relevant to QOL, especially normal stool form (BSFS type 4) is important for improving the QOL in patients with constipation. Physicians should focus on "stool form" and reconsider the prescription especially in BSFS types 6-7 patients.

Contribution of Executive Functions to Learning Sequential Actions in Young Children.

This study examined whether executive functions impact how flexibly children represent task context in performing repeated sequential actions. Japanese children in Experiments 1 (N = 52; 3-6 years) and 2 (N = 50, 4-6 years) performed sequential actions repeatedly; one group received reminders. Experiment 1 indicated that reminders promote flexible changes in contextual representations. Experiment 2 observed such effects in younger children and showed executive functions were associated with the flexible representation of task context. Reminders did not perfectly compensate for the role of executive functions but wiped out individual differences in executive functions that contribute to children's acquisition of routines. Therefore, setting goals before context-dependent actions is necessary, but not sufficient, to modulate contextual representations in routines.