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BackgroundClinical 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).MethodsWe 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.ResultsAreas 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

Although working memory (WM) is usually defined as a cognitive system coordinating processing and storage in the short term, in most WM models, memory aspects have been developed more fully than processing systems, and many studies of WM tasks have tended to focus on memory performance. The present study investigated WM functioning without focusing exclusively on short-term memory performance by presenting participants with an n-back task on letters, n varying from 0 to 2, each letter being followed by a tone discrimination task involving from one to three tones. Predictions regarding the reciprocal effects of these tasks on each other were motivated by the time-based resource-sharing (TBRS) theoretical framework for WM that assumes the temporal sharing of attention between processing and memory. Although, as predicted, increasing the n value had a detrimental effect on tone discrimination in terms of accuracy and response times, and increasing the number of tones disrupted speed and accuracy on n-back performance, the overall pattern of results did not perfectly fit the TBRS predictions. Nonetheless, the main alternative models of WM do not seem to offer a complete account. The present findings point toward the need to use a larger range of tasks and situations in designing and testing models of WM.

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.

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.

We analyzed a Japanese lexical database to investigate the structure of the lexical environment based on the hypothesis that the lexical environment is optimized for the functioning of verbal working memory. Our prediction was that, as a consequence of the cultural transmission of language, low-imageable meanings tend to be represented by frequent phonological patterns in the current vocabulary rather than infrequent phonological patterns. This prediction was based on two findings of previous laboratory studies on verbal working memory. (1) The quality of phonological (phonemic and accent) representations in verbal working memory depends on phonological regularity knowledge; therefore, short-term phonological representations are less robust for words with infrequent phonological patterns. (2) Phonological representations are underpinned by contributions from semantic knowledge; therefore, phonological representations of highly imageable words are more robust than those for low-imageable words. Our database analyses show that nouns with less imageable meanings tend to be associated with more frequent phonological patterns in Japanese vocabulary. This lexical structure can maintain the quality of phonological representations in verbal working memory through contributions of semantic and phonological regularity knowledge. Larger semantic contributions compensate for the less robust phonological representations of infrequent phonological forms. The quality of phonological representations is preserved by phonological regularity knowledge when larger semantic contributions are not expected.

Abstract Background The ideal medication for acid-related diseases should have a rapid onset of action to promote hemostasis and cause efficient resolution of symptoms. The aim of our study was to comparatively investigate the inhibitory effect on gastric acid secretion of a single oral administration of omeprazole plus mosapride with that of omeprazole alone. Methods Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 hours after a single oral administration of omeprazole 20 mg or that of omeprazole 20 mg plus mosapride 5 mg (the omeprazole being administered one hour after the mosapride). Each administration was separated by a 7-days washout period. Results The average pH during the 6-hour period after administration of omeprazole 20 mg plus mosapride 5 mg was higher than that after administration of omeprazole 20 mg alone (median: 3.22 versus 4.21, respectively; p = 0.0247). Conclusions In H. pylori -negative healthy male subjects, an oral dose of omeprazole 20 mg plus mosapride 5 mg increased the intragastric pH more rapidly than omeprazole 20 mg alone.

Abstract Background The association between obesity and the risk of Barrett's esophagus (BE) is unclear. Furthermore, the association between visceral obesity and the risk of BE is entirely unknown. Methods We conducted a retrospective study in 163 patients with non-alcoholic fatty liver disease (NAFLD) who underwent both endoscopy and abdominal CT at an interval of less than a year at our institution. BE was endoscopically diagnosed based on the Prague C & M Criteria. The surface areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated from CT images at the level of the umbilicus. The correlations between the BMI, VAT, and SAT and the risk of BE were examined by univariate and multivariate analyses. Results Sixty-nine of the 163 study participants (42.3%) were diagnosed to have endoscopic BE, which was classified as short-segment BE (SSBE) in almost all of the cases. There were no significant differences in the age or gender distribution between the groups with and without BE. According to the results of the univariate analysis, VAT was significantly associated with the risk of BE; the BMI tended to be higher in the group with BE than in the group without BE, but this relation did not reach statistical significance. VAT was independently associated with the risk of BE even after adjustment for the BMI. Conclusion In Japanese patients with NAFLD, obesity tended to be associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal visceral adiposity.

Abstract Background We aimed to estimate whether the macroscopic extent of gastric mucosal atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of CagA-positive H. pylori infection. Methods Two hundred and fifty-three patients who were diagnosed as having esophageal squamous cell carcinoma, and 253 sex- and age-matched controls were enrolled in the present study. The macroscopic extent of gastric mucosal atrophy was evaluated based on the Kimura and Takemoto Classification. A conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations. Results Body gastritis, defined endoscopically, was independently associated with an increased risk for esophageal squamous cell carcinoma. Conclusion Our findings suggest that macroscopic body gastritis may be a risk factor for esophageal squamous cell carcinoma in Japan. Further studies are needed to confirm these findings.

Abstract Background Spontaneous rupture is rare complication of hepatocellular carcinoma (HCC) with high mortality rate in cirrhotic cases. The aim of this study was to determine the factors influencing prognosis in cases of spontaneously ruptured HCC and to investigate the outcomes of the treatments employed, especially transcatheter arterial embolization (TAE). Methods A retrospective multicenter study was conducted in 48 cirrhotic patients with spontaneous rupture of HCC. Conservative treatment was employed in 32 patients (ConT group) and TAE was performed in 16 patients (TAE group). Results The median survival time (MST) in the ConT group was only 13.1 days and the survival rate was extremely poor: 59.4% at 7 days, 37.5% at 14 days, and 6.3% at 30 days. On the other hand, the MST in the TAE group was 244.8 days and the survival rate was 87.5% at 1 month, 56.3% at 3 months, 23.4% at 12 months, and 15.6% at 24 months. According to the results of univariate analyses, factors associated with poor hepatic function and poor suitability for TAE was important determinants of short-term death (less than 3 weeks) among the patients (p < 0.05). On the other hand, among the patients in whom initial TAE was successfully performed (n = 15), a multivariate analysis showed that a maximum tumor size not exceeding 7 cm was the only independent factor determining long-term survival (p = 0.0130). Conclusion Despite the inherent limitations of this retrospective study, TAE appears to be a useful treatment strategy for cirrhotic patients with spontaneous HCC rupture, as it yielded a longer survival period compared with conservative treatment in patients with ruptured HCC. Among the patients with ruptured HCC in whom initial TAE was successfully performed, the maximum tumor size was an important factor influencing survival.

Abstract Background Evidence regarding the association between alcohol consumption and the gastro-esophageal reflux disease (GERD) spectrum has been conflicting. We examined the association between alcohol consumption and erosive esophagitis and Barrett's epithelium in Japanese men. Methods The study population comprised 463 men subjects who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The presence of erosive esophagitis and Barrett's epithelium was diagnosed based on the Los Angeles Classification and the Prague C and M Criteria, respectively. We divided the study population into four groups: never drinkers, light drinkers (less than 25.0 g of ethanol per day), moderate drinkers (25.0 to 50.0 g of ethanol per day), and heavy drinkers (more than 50.0 g of ethanol per day). A linear regression of the logistic regression analysis was used to analyze the dose-response trends. Results Compared with never drinkers, light drinkers (less than 25.0 g ethanol per day), moderate drinkers (25.0 to 50.0 g per day), and heavy drinkers (more than 50.0 g per day) had ORs for erosive esophagitis of 1.110 (95% CI: 0.553 – 2.228, p = 0.7688), 1.880 (95% CI: 1.015 – 3.484, p = 0.0445) and 1.988 (95% CI: 1.120 – 3.534, p = 0.0190), respectively. These groups had ORs for Barrett's epithelium of 1.278 (95% CI: 0.752 – 2.170, p = 0.3643), 1.458 (95% CI: 0.873 – 2.433, p = 0.1500), and 1.912 (95% CI: 1.185 – 3.086, p = 0.0079), respectively. The odds ratios/grams (alcohol)/day of dose response trends for erosive esophagitis and Barrett's epithelium were 1.015 (95% CI: 1.004–1.026, p = 0.0066) and 1.012 (95% CI: 1.003–1.021, p = 0.0079), respectively. Conclusion These findings suggest that alcohol consumption in Japanese men tends to be associated with an increased risk of erosive esophagitis and Barrett's epithelium.

Abstract Background The changes in the liver in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However it has remained difficult to differentiate between NASH and non-progressive NAFLD on the basis of the clinical findings alone. Aims In this study we investigated the clinical usefulness of plasma Pentraxin3 (PTX3) levels to predict NASH. Plasma PTX3 was measured in 70 patients with histologically verified NAFLD (28 with non-NASH and 42 with NASH) and 10 healthy control subjects. Results The plasma PTX3 level was significantly higher in the NASH cases than in the non-NASH cases (p = 0.0021) and control subjects (p = 0.045). And the plasma PTX3 level was significantly higher in the stages 3–4 NAFLD cases than in the stages 0–2 NAFLD cases (p < 0.0001). The PTX3 values were closely correlated with the stages of liver fibrosis (p < 0.0001, Kruskal-Wallis test). To detect NASH compared with non-NASH, the area under the curve for plasma PTX3 were 0.755, and to detect stages 3–4 NAFLD compared with stages 0–2 NAFLD, the area under the curve for plasma PTX3 were 0.850. Conclusion This is the first study to demonstrate consistent and profound elevation of plasma PTX3 levels in NASH in comparison with non-NASH. The results suggest that plasma PTX3 levels may not only be laboratory values that differentiate NASH from non-NASH, but marker of the severity of hepatic fibrosis in NASH.

Abstract Background Genetic factors as well as environmental factors are important in the development of NAFLD and in this study we investigated associations between polymorphisms of peroxisome proliferators-activated receptor γ coactivator 1α polymorphism (PPARGC1A) and NAFLD. Aims We recruited 115 patients with biopsy-proven NAFLD, 65 with NASH and 50 with simple steatosis, and 441 healthy control subjects and investigated 15 SNPs of PPARGC1A. Results SNP rs2290602 had the lowest p value in the dominant mode (p = 0.00095), and the odds ratio for NAFLD (95% CI) was 2.73 (1.48 – 5.06). rs2290602 was significantly associated with NAFLD even when the most conservative Bonferroni's correction was applied (p = 0.0143). The frequency of the T allele of rs2290602 was significantly higher in the NASH patients than in the control subjects (p = 0.00093, allele frequency mode), and its frequency in the NASH patients tended to be higher than in the simple steatosis patients (p = 0.09). The results of the real-time RT-PCR study showed that intrahepatic mRNA expression of PPARGC1A was lower in the TT group than in the GG or GT group at SNP rs2290602 (p = 0.0454). Conclusion This is the first study to demonstrate a significant association between genetic variations in PPARGC1A and NAFLD. This finding suggested that PPARGC1A polymorphism and lower expression of PPARGC1A mRNA in the liver are an important genetic contribution to etiology of NAFLD.

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.

The Hebb repetition paradigm has recently attracted attention as a measure of serial order learning, which underlies word-form learning abilities. Although children are good vocabulary learners, it is surprising that previous Hebb learning studies with young children show rather weak Hebb effects. In this study, we conducted two experiments to identify developmental factors that drive an increase of the size of the Hebb effect in young children. Motivated by evidence from adult work, we focused on an ability to group a sequence into consistent subsequences and on phonological short-term memory (STM) capacity. In Experiment 1 (N = 98), it was shown that 3- to 5-year-old children with high phonological STM capacity showed a Hebb effect, particularly in the later experimental trials. In Experiment 2 (N = 97), temporal grouping of the sequences in 2-2 subsequences further encouraged children with high phonological STM capacity to show the Hebb effect even in the earlier experimental trials and children with low STM capacity to show a trend toward a Hebb effect in the later trials. Moreover, across Experiments 1 and 2 we found robust evidence of transfer of the Hebb effect to recall of new sequences that partially overlapped in item-by-item pairings with the Hebb sequence, indicating that children use consistent grouping strategies when learning above-span Hebb sequences. These findings indicate that phonological STM, grouping consistency, and their interaction are developmental requirements for the Hebb effect to emerge.

The purpose of this study was to examine the role and nature of phonology in silent reading of Japanese sentences. An experiment was conducted using a Japanese sentence acceptability judgment task. One important finding was that participants more rapidly rejected homophonic sentences in which one two-kanji compound word was replaced by its homophone word than non-homophonic sentences. In the latter, the word was replaced by a non-homophone spelling control; that is, we observed a homophone advantage. Participants were able to identify the correct word easily through foil's homophonic mate. This indicated that activated phonology played a role in the Japanese sentence acceptability judgment task and it contributed to the error detection/recovery process. Another important finding was that the homophone facilitation effect remained under articulatory suppression. It confirmed that phonology was activated at an early stage as abstract, non-articulatory phonology.

A wealth of developmental research suggests that preschoolers are capable of reporting, imitating, and performing sequential actions they engage in routinely. However, few studies have explored the developmental and cognitive mechanisms required for learning how to perform such routines. A previous computational model of routines argued that a representation of task contexts underlying routines could change flexibly. This position was supported by the empirical evidence that if adults are interrupted in the course of a routine, they make fewer errors if they are interrupted just before the selection of context-dependent action than if they are interrupted earlier. Another computational model examined how efficiently adults learned to perform routines and suggested the relationship of learning efficacy with executive functions. The present study aimed to examine whether the above-mentioned models and evidence from adults can be extended to preschoolers by using an experimental task, in which children were required to play the role of a baker and repeatedly make toast for either a cat or mouse, with momentary distractions. Experiment 1 showed that earlier interruption tended to cause older children to produce more branch point errors than interruption immediately before the branch points, whereas younger children tended to be vulnerable to both interruptions. Further, across 2 experiments, this study showed that the developmental differences in how young children represent task contexts were associated with their executive functions. These findings indicate that the representational flexibility of task contexts underlies children's performance of repeated sequential actions and its association with executive functions.