Search

Summary: Backgrounds and Aims: Alcohol use leads to disabilities and deaths worldwide. It not only harms the liver but also causes alcohol use disorder (AUD) and heart disease. Additionally, alcohol consumption contributes to health disparities among different socio‐economic groups. Methods: We estimated global and regional trends in the burden of AUD, liver disease, and cardiovascular disease from alcohol using the methodology of the Global Burden of Disease study. Results: In 2019, the highest disability‐adjusted life years rate per 100,000 population was due to AUD (207.31 [95% Uncertainty interval (UI) 163.71–261.66]), followed by alcohol‐associated liver disease (ALD) (133.31 [95% UI 112.68–156.17]). The prevalence rate decreased for AUD (APC [annual percentage change] −0.38%) and alcohol‐induced cardiomyopathy (APC −1.85%) but increased for ALD (APC 0.44%) and liver cancer (APC 0.53%). Although the mortality rate for liver cancer from alcohol increased (APC 0.30%), mortality rates from other diseases decreased. Between 2010 and 2019, the burden of alcohol‐associated complications increased in countries with low and low‐middle sociodemographic index (SDI), contributing more significantly to the global burden. Conclusion: The global burden of AUD, liver, and cardiovascular disease has been high and increasing over the past decade, particularly for liver complications. Lower SDI countries are contributing more to this global burden. There is a pressing need for effective strategies to address this escalating burden. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels of growth differentiation factor‐15 (GDF15), a cell stress‐responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods: Serum GDF15 levels were measured in 518 biopsy‐performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results: In the biopsy‐MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib‐4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high‐GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib‐4 index <1.3 or low‐GDF15 rarely developed liver cancer, high‐GDF15 patients with a Fib‐4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high‐GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low‐GDF15 patients, whether limited to high‐Fib‐4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib‐4 index >1.3, 2.7% had a Fib‐4 index >1.3 and >1.75 ng/mL GDF15. Conclusions: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance. [ABSTRACT FROM AUTHOR]

This retrospective cohort study explored the prevalence of substantial weight loss (≥10% per year) in independent older individuals in order to develop and validate a scoring system for high-risk group identification and targeted intervention against malnutrition. We used insurance claims and the Kokuho Database (KDB), a nationwide repository of Japanese-specific health checkups and health assessments for the older people. The study included 12,882 community-dwelling individuals aged 75 years and older who were self-supported in their activities of daily living in Saga Prefecture, Japan. Health evaluations and questionnaires categorized weight-loss factors into organic, physiological, psychological, and non-medical domains. The resulting scoring system (SAGA score), incorporating logistic regression models, predicted ≥ 10% annual weight-loss risk. The results revealed a 1.7% rate of annual substantial weight loss, with the SAGA score effectively stratifying the participants into low-, intermediate-, and high-risk categories. The high-risk category exhibited a weight-loss rate of 17.6%, highlighting the utility of this scoring system for targeted prevention. In conclusion, the validated SAGA score is a crucial tool for identifying individuals at high risk of significant weight loss, enabling tailored interventions and social support benefiting both older individuals and their relatives. This retrospective cohort study explored the prevalence of substantial weight loss (≥10% per year) in independent older individuals in order to develop and validate a scoring system for high-risk group identification and targeted intervention against malnutrition. We used insurance claims and the Kokuho Database (KDB), a nationwide repository of Japanese-specific health checkups and health assessments for the older people. The study included 12,882 community-dwelling individuals aged 75 years and older who were self-supported in their activities of daily living in Saga Prefecture, Japan. Health evaluations and questionnaires categorized weight-loss factors into organic, physiological, psychological, and non-medical domains. The resulting scoring system (SAGA score), incorporating logistic regression models, predicted ≥ 10% annual weight-loss risk. The results revealed a 1.7% rate of annual substantial weight loss, with the SAGA score effectively stratifying the participants into low-, intermediate-, and high-risk categories. The high-risk category exhibited a weight-loss rate of 17.6%, highlighting the utility of this scoring system for targeted prevention. In conclusion, the validated SAGA score is a crucial tool for identifying individuals at high risk of significant weight loss, enabling tailored interventions and social support benefiting both older individuals and their relatives. [ABSTRACT FROM AUTHOR]

Summary: Aims: A multi‐stakeholder consensus has proposed MASLD (metabolic dysfunction‐associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid‐term mortality of patients with biopsy‐proven MASLD in Japan. Methods: We enrolled 1349 patients with biopsy‐proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data‐mining analysis. Results: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty‐five patients with MASLD died. Of these, liver‐related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9‐fold and 1.8‐fold risk of mortality, respectively. In the decision‐tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid‐term prognosis of patients with MASLD. Conclusions: In patients with biopsy‐proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver‐related events. Hepatic inflammation and fibrosis were significant factors influencing mid‐term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD. [ABSTRACT FROM AUTHOR]

Next-generation sequencing has transformed the acquisition of vast amounts of genomic information, including the rapid identification of target gene sequences in metagenomic databases. However, dominant species can sometimes hinder the detection of rare bacterial species. Therefore, a highly sensitive amplification technique that can selectively amplify bacterial genomes containing target genes of interest was developed in this study. The rolling circle amplification (RCA) method can initiate amplification from a single locus using a specific single primer to amplify a specific whole genome. A mixed cell suspension was prepared using Pseudomonas fluorescens ATCC17400 (targeting nonribosomal peptide synthetase [NRPS]) and Escherichia coli (non-target), and a specific primer designed for the NRPS was used for the RCA reaction. The resulting RCA product (RCP) amplified only the Pseudomonas genome. The NRPS was successfully amplified using RCP as a template from even five cells, indicating that the single-priming RCA technique can specifically enrich the target genome using gene-specific primers. Ultimately, this specific genome RCA technique was applied to metagenomes extracted from sponge-associated bacteria, and NRPS sequences were successfully obtained from an unknown sponge-associated bacterium. Therefore, this method could be effective for accessing species-specific sequences of NRPS in unknown bacteria, including viable but non-culturable bacteria. [ABSTRACT FROM AUTHOR]

Key message: We proposed models to predict the effects of genomic and environmental factors on daily soybean growth and applied them to soybean growth data obtained with unmanned aerial vehicles. Advances in high-throughput phenotyping technology have made it possible to obtain time-series plant growth data in field trials, enabling genotype-by-environment interaction (G × E) modeling of plant growth. Although the reaction norm is an effective method for quantitatively evaluating G × E and has been implemented in genomic prediction models, no reaction norm models have been applied to plant growth data. Here, we propose a novel reaction norm model for plant growth using spline and random forest models, in which daily growth is explained by environmental factors one day prior. The proposed model was applied to soybean canopy area and height to evaluate the influence of drought stress levels. Changes in the canopy area and height of 198 cultivars were measured by remote sensing using unmanned aerial vehicles. Multiple drought stress levels were set as treatments, and their time-series soil moisture was measured. The models were evaluated using three cross-validation schemes. Although accuracy of the proposed models did not surpass that of single-trait genomic prediction, the results suggest that our model can capture G × E, especially the latter growth period for the random forest model. Also, significant variations in the G × E of the canopy height during the early growth period were visualized using the spline model. This result indicates the effectiveness of the proposed models on plant growth data and the possibility of revealing G × E in various growth stages in plant breeding by applying statistical or machine learning models to time-series phenotype data. [ABSTRACT FROM AUTHOR]

Nutritropism is a positive tropism toward nutrients in plant roots. An NH4+ gradient is a nutritropic stimulus in rice (Oryza sativa L.). When rice roots are exposed to an NH4+ gradient generated around nutrient sources, root tips bend toward and coil around the sources. The molecular mechanisms are largely unknown. Here, we analyzed the transcriptomes of the inside and outside of bending root tips exhibiting nutritropism to reveal nutritropic signal transduction. Tissues facing the nutrient sources (inside) and away (outside) were separately collected by laser microdissection. Principal component analysis revealed distinct transcriptome patterns between the two tissues. Annotations of 153 differentially expressed genes implied that auxin, gibberellin and ethylene signaling were activated differentially between the sides of the root tips under nutritropism. Exogenous application of transport and/or biosynthesis inhibitors of these phytohormones largely inhibited the nutritropism. Thus, signaling and de novo biosynthesis of the three phytohormones are necessary for nutritropism. Expression patterns of IAA genes implied that auxins accumulated more in the inside tissues, meaning that ammonium stimulus is transduced to auxin signaling in nutritropism similar to gravity stimulus in gravitropism. SAUR and expansin genes, which are known to control cell wall modification and to promote cell elongation in shoot gravitropism, were highly expressed in the inside tissues rather than the outside tissues, and our transcriptome data are unexplainable for differential elongation in root nutritropism. [ABSTRACT FROM AUTHOR]

Summary: Background: Although alcohol abstinence may be an effective intervention for alcohol‐associated cirrhosis, its association with prognosis has not been systematically assessed or quantified. Aims: To determine the prevalence of alcohol abstinence, factors associated with alcohol abstinence and the impact of abstinence on morbidity and overall survival in people with alcohol‐associated cirrhosis. Methods: We searched Medline and Embase from inception to 15 April 2023 for prospective and retrospective cohort studies describing alcohol abstinence in people with known alcohol‐associated cirrhosis. Meta‐analysis of proportions for pooled estimates was performed. The method of inverse variance, employing a random‐effects model, was used to pool the hazard ratio (HR) comparing outcomes of abstinent against non‐abstinent individuals with alcohol‐associated cirrhosis. Results: We included 19 studies involving 18,833 people with alcohol‐associated cirrhosis. The prevalence of alcohol abstinence was 53.8% (CI: 44.6%–62.7%). Over a mean follow‐up duration of 48.6 months, individuals who continued to consume alcohol had significantly lower overall survival compared to those who were abstinent (HR: 0.611, 95% CI: 0.506–0.738). These findings remained consistent in sensitivity/subgroup analysis for the presence of decompensation, study design and studies that assessed abstinence throughout follow‐up. Alcohol abstinence was associated with a significantly lower risk of hepatic decompensation (HR: 0.612, 95% CI: 0.473–0.792). Conclusions: Alcohol abstinence is associated with substantial improvement in overall survival in alcohol‐associated cirrhosis. However, only half of the individuals with known alcohol‐associated cirrhosis are abstinent. [ABSTRACT FROM AUTHOR]

Aim: To compare the effects of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) versus dipeptidyl peptidase‐4 inhibitors (DPP4is) on liver function in patients with type 2 diabetes (T2D) in Japan. Materials and Methods: This was a Japanese retrospective cohort study using the RWD Database (1 January 2015 to 24 September 2021). Patients newly treated with an SGLT2i or a DPP4i were matched 1:4 (SGLT2i:DPP4i) using propensity score. The primary endpoint was the change from baseline to 1 year after the index date in alanine aminotransferase (ALT). Secondary endpoints included change from baseline in various laboratory test results, including the Fibrosis‐4 (FIB‐4) index, aspartate aminotransferase, gamma‐glutamyl transpeptidase (GGT), albumin and HbA1c. Endpoints were compared between treatment groups using Welch's t‐test in the full population and in subgroups stratified by baseline characteristics. Results: Baseline characteristics of 955 and 3063 matched patients newly treated with an SGLT2i and a DPP4i, respectively, were well balanced. Patients receiving an SGLT2i had significantly greater reductions in ALT, FIB‐4 index and GGT and a significantly greater increase in albumin than patients receiving a DPP4i. A significantly greater change from baseline in ALT was observed in the SGLT2i group than in the DPP4i group among subgroups with lower baseline FIB‐4 index and HbA1c. Conclusions: In this study, improvements in various measures, including ALT, the FIB‐4 index, GGT and albumin, were observed with SGLT2is compared with DPP4is, suggesting that SGLT2is may provide hepatoprotective benefits, including the prevention of liver fibrosis, in patients with T2D in Japan. [ABSTRACT FROM AUTHOR]

Cry4Aa, produced by Bacillus thuringiensis subsp. israelensis, exhibits specific toxicity to larvae of medically important mosquito genera. Cry4Aa functions as a pore-forming toxin, and a helical hairpin (α4-loop-α5) of domain I is believed to be the transmembrane domain that forms toxin pores. Pore formation is considered to be a central mode of Cry4Aa action, but the relationship between pore formation and toxicity is poorly understood. In the present study, we constructed Cry4Aa mutants in which each polar amino acid residues within the transmembrane α4 helix was replaced with glutamic acid. Bioassays using Culex pipiens mosquito larvae and subsequent ion permeability measurements using symmetric KCl solution revealed an apparent correlation between toxicity and toxin pore conductance for most of the Cry4Aa mutants. In contrast, the Cry4Aa mutant H178E was a clear exception, almost losing its toxicity but still exhibiting a moderately high conductivity of about 60% of the wild-type. Furthermore, the conductance of the pore formed by the N190E mutant (about 50% of the wild-type) was close to that of H178E, but the toxicity was significantly higher than that of H178E. Ion selectivity measurements using asymmetric KCl solution revealed a significant decrease in cation selectivity of toxin pores formed by H178E compared to N190E. Our data suggest that the toxicity of Cry4Aa is primarily pore related. The formation of toxin pores that are highly ion-permeable and also highly cation-selective may enhance the influx of cations and water into the target cell, thereby facilitating the eventual death of mosquito larvae. [ABSTRACT FROM AUTHOR]

Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D. TYK2 is a candidate susceptibility gene for type 1 diabetes (T1D) and a beneficial effect has been reported for TYK2 inhibitors for other autoimmune diseases. In this study, the authors generate Tyk2 KO mice on a NOD background and demonstrate that TYK2 signaling drives CD8+ T cell autoreactivity and T1D. [ABSTRACT FROM AUTHOR]

Summary: Background: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. Aims: To assess the treatment and renal/bone safety outcomes following the switch to TAF. Methods: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T‐scores (L‐spine) by bone absorptiometry by 24 months after switch to TAF. Results: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T‐score improved significantly from −1.43 ± 1.36 to −1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9–89.5 ± 16.3 mL/min/1.73 m2, p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T‐score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T‐score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). Conclusions: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable. [ABSTRACT FROM AUTHOR]

Background: People with schizophrenia have a lower colorectal screening rate than the general population. A previous study reported an intervention using case management to encourage colorectal cancer screening for patients with schizophrenia in psychiatric outpatient settings. In this feasibility study, we developed provider-level implementation strategies and evaluated the feasibility of conducting a definitive trial in terms of the penetration of the intervention assessed at the patient level. Additionally, we examined the fidelity of strategies to implement the intervention at the provider level in a routine clinical psychiatric setting. Methods: This was a multicenter, single-arm feasibility study with medical staff at psychiatric hospitals in Japan. The provider-level implementation strategies developed in this study included three key elements (organizing an implementation team appointed by the facility director, interactive assistance using a clear guide that outlines who in the hospital should do what, and developing accessible educational materials) to overcome major barriers to implementation of the intervention and four additional elements (progress monitoring, joint meetings and information sharing among participating sites, adaptation of encouragement methods to specific contexts, and education of on-site staff), with reference to the elements identified in the Expert Recommendations for Implementing Change (ERIC). The feasibility of the strategies was evaluated by the proportion of patients who were eligible for encouragement (patients with schizophrenia aged 40, 50, or 60) who received encouragement. We set the goal of providing encouragement to at least 40% of eligible patients at each site. Results: Two public and four private psychiatric hospitals in Okayama and Shimane prefectures participated in this study. Regarding fidelity, all elements of the strategies were conducted as planned. Following the procedures in the guide, each team prepared and provided encouragement according to their own facility and region. Penetration, defined as the proportion of eligible patients who received encouragement, ranged from 33.3 to 100%; five of the six facilities achieved the target proportion. Conclusions: The provider-level implementation strategies to implement encouragement were feasible in terms of penetration of the intervention assessed at the patient level. The results support the feasibility of proceeding with a future definitive trial of these strategies. Trial registration: jRCT, jRCT1060220026. Registered on 06/04/2022. [ABSTRACT FROM AUTHOR]

SUMMARY: Understanding how nutrient stress impacts plant growth is fundamentally important to the development of approaches to improve crop production under nutrient limitation. Here we applied single‐cell RNA sequencing to shoot apices of Pisum sativum grown under boron (B) deficiency. We identified up to 15 cell clusters based on the clustering of gene expression profiles and verified cell identity with cell‐type‐specific marker gene expression. Different cell types responded differently to B deficiency. Specifically, the expression of photosynthetic genes in mesophyll cells (MCs) was down‐regulated by B deficiency, consistent with impaired photosynthetic rate. Furthermore, the down‐regulation of stomatal development genes in guard cells, including homologs of MUTE and TOO MANY MOUTHS, correlated with a decrease in stomatal density under B deficiency. We also constructed the developmental trajectory of the shoot apical meristem (SAM) cells and a transcription factor interaction network. The developmental progression of SAM to MC was characterized by up‐regulation of genes encoding histones and chromatin assembly and remodeling proteins including homologs of FASCIATA1 (FAS1) and SWITCH DEFECTIVE/SUCROSE NON‐FERMENTABLE (SWI/SNF) complex. However, B deficiency suppressed their expression, which helps to explain impaired SAM development under B deficiency. These results represent a major advance over bulk‐tissue RNA‐seq analysis in which cell‐type‐specific responses are lost and hence important physiological responses to B deficiency are missed. The reported findings reveal strategies by which plants adapt to B deficiency thus offering breeders a set of specific targets for genetic improvement. The reported approach and resources have potential applications well beyond P. sativum species and could be applied to various legumes to improve their adaptability to multiple nutrient or abiotic stresses. Significance Statement: Using single‐cell RNA‐seq, our study uncovers cell‐specific responses in peas that enhance adaptability to nutrient stresses, guiding breeders in crop improvement. These insights can extend to other legumes, amplifying our research's reach. [ABSTRACT FROM AUTHOR]

Summary: Background: Non‐alcoholic fatty liver disease (NAFLD) represents a significant health threat worldwide. The growing trend towards an aging population, along with an alarming rise in obesity and diabetes, may have significant implications for the burden of NAFLD. Aim: To assess the impact of NAFLD on the elderly. Methods: We utilised data from the Global Burden of Disease study between 2010 and 2019 to conduct a comprehensive analysis of the prevalence, mortality, and disability‐adjusted life years (DALYs) associated with NAFLD in the elderly (65–89 years), stratified by region, nation, sociodemographic Index and sex. Results: Globally, there were an estimated 228 million cases, 87,230 deaths and 1.46 million DALYs attributed to NAFLD in the elderly. Geographically, the Western Pacific region had the highest burden of NAFLD in the elderly. From 2010 to 2019, there was an increasing prevalence rate in all areas, with the most pronounced change observed in the Western Pacific region (annual percentage change (APC) +0.95%, p < 0.001). Over the study period, there was a more rapid increase in NAFLD prevalence in men (APC +0.74%, p < 0.001) than in women (APC +0.63%, p < 0.001). In most regions, death and DALYs rates have declined, with the exception of the Americas, where there was a slight increase (APC +0.25%, p = 0.002 and 0.38%, p < 0.001, respectively). Conclusion: Over the past decade, the burden of NAFLD in the elderly has been increasing, necessitating immediate and inclusive measures to tackle the rising burden. [ABSTRACT FROM AUTHOR]

Background and Aims: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis‐4 (FIB‐4) index and body mass index (BMI) using an unsupervised machine learning method. Methods: We conducted a multicenter study of 1335 biopsy‐proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB‐4 index and BMI, we investigated prognosis for these clusters. Results: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3–4) as assessed from liver biopsy. Median values of BMI and FIB‐4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all‐cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB‐4 index (median 5.23 and 2.23), cluster a presented the lowest FIB‐4 index (median 0.78), and cluster c was associated with moderate FIB‐4 level (median 1.30) and highest BMI (median 34.3 kg/m2). Clusters a and c had lower mortality rates than clusters b and d. However, all‐cause of death in clusters a and c was unrelated to liver disease. Conclusions: Our clustering approach found that the FIB‐4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non‐liver‐related diseases were identified as the causes of death in NAFLD patients with low FIB‐4 index. [ABSTRACT FROM AUTHOR]

Nitratireductor sp. OM-1 can accumulate butenoic acid, which is a short-chain unsaturated carboxylic acid utilized for chemical products. So far, we have predicted the thioesterase gene, te, as a candidate gene for butenoic acid biosynthesis, based on comparative transcriptome analysis. To confirm the function of te, the gene transfer system in Nitratireductor sp. OM-1 was required. Thus, in this study, we used electroporation as a transformation system and pRK415, a broad host range plasmid, and optimized the conditions. As a result, a maximum transformation efficiency of 7.9 × 104 colonies/µg DNA was obtained at 22.5 kV/cm. Moreover, an expression vector, pRK415-te, was constructed by insertion of te, which was successfully transferred into strain OM-1, using electroporation. The recombinant OM-1 strain produced butenoic acid at 26.7 mg/g of dried cell weight, which was a 254% increase compared to transformants harboring an empty vector. This is the first report of a gene transfer system for Nitratireductor sp., which showed that the te gene was responsible for butenoic acid production. [ABSTRACT FROM AUTHOR]

Background & Aims: PNPLA3 rs738409 has been associated with an increased risk of liver‐related events in patients with non‐alcoholic fatty liver disease (NAFLD). In this study, we investigated the epidemiology of NAFLD and the impact of PNPLA3 on prognosis in Japan. Methods: A longitudinal multicentre cohort study, the JAGUAR study, includes 1550 patients with biopsy‐proven NAFLD in Japan. We performed genetic testing and evaluated outcomes from this cohort. Liver‐related events were defined as hepatocellular carcinoma (HCC) and decompensated liver cirrhosis events. Results: During follow‐up (median [range], 7.1 [1.0–24.0] years), 80 patients developed HCC, 104 developed liver‐related events, and 59 died of any cause. The 5‐year rate of liver‐related events for each single‐nucleotide polymorphism was 0.5% for CC, 3.8% for CG, and 5.8% for GG. Liver‐related deaths were the most common (n = 28); only three deaths were due to cardiovascular disease. Multivariate analysis identified carriage of PNPLA3 CG/GG (hazard ratio [HR] 16.04, p =.006) and FIB‐4 index >2.67 (HR 10.70, p <.01) as predictors of liver‐related event development. No HCC or liver‐related death was found among patients with PNPLA3 CC. There was a significantly increased risk of HCC, liver‐related events, and mortality for CG/GG versus CC, but no difference between the CG and GG genotypes. Conclusions: In Japanese individuals, the main cause of death from NAFLD is liver‐related death. The greater risk of liver‐related events incurred by PNPLA3 G allele was shown in Japan. Risk stratification for NAFLD in Japan is best accomplished by integrating PNPLA3 with the FIB‐4 index. [ABSTRACT FROM AUTHOR]

Aim: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3–4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra‐/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra‐/extrahepatic events in Asian patients with biopsy‐proven NAFLD. Methods: We undertook a retrospective multicenter cohort study to investigate associations between intra‐/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography. Results: Among 403 enrolled patients, 11 had liver‐related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3–4), Agile 3+ rule‐in (F3–4, highly suspected), and Agile 4 rule‐in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule‐in, and Agile 4 rule‐in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer. Conclusions: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment. [ABSTRACT FROM AUTHOR]

Aim: This study was undertaken to investigate the utility of the fatty liver index (FLI) as a noninvasive tool for predicting hepatic steatosis based on alcohol consumption and sex in a large Asian population. Methods: We carried out a single‐center observational cohort study at the HITO Medical Center in Japan and enrolled 1976 Asian subjects. The subjects were categorized into nondrinkers and light drinkers (0–19 g/day) and moderate drinkers (20–59 g/day) based on their self‐reported alcohol intake. We used physical examinations, laboratory tests, and a questionnaire to collect information on various factors related to the FLI, including body mass index, waist circumference, and levels of γ‐glutamyl transferase and triglycerides. Results: The diagnostic accuracy of the FLI was assessed by calculating the area under the receiver operating characteristic curve (AUROC), and optimal cut‐off values were determined using Youden's index. The FLI had an acceptable performance index of >0.7 both overall and in all subgroups, with an overall AUROC of 0.844. The AUROCs were higher in women and moderate drinkers of both sexes. We also compared the cut‐off values obtained in the present study with the previously reported values of 30 and 60. Optimal cut‐off values for the FLI were calculated for the total population and subgroups and were found to differ from the previously established values in other countries. Conclusions: Our study suggests that the FLI is a useful noninvasive marker for predicting hepatic steatosis in a large Asian population, irrespective of alcohol consumption and sex. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Background: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. Case presentation: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. Conclusions: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Summary: Soybeans (Glycine max) develop newly differentiated aerenchymatous phellem (AP) in response to waterlogging stress. AP is formed in the hypocotyl and root, thus contributing to internal aeration and adaptation to waterlogging for several legumes. Extensive accumulation of triterpenoids – lupeol and betulinic acid – has been identified in AP. However, their physiological roles in plants remain unclarified. Lupeol is converted from 2,3‐oxidosqualene by lupeol synthase (LUS) and oxidized to betulinic acid. Notably, soybeans have two LUS genes (GmLUS1 and GmLUS2).Functional analysis was performed to reveal the biological and physiological functions of triterpenoids in AP using lus mutants.The AP cells of lus1 mutant lacked triterpenoid accumulation and epicuticular wax. Lupeol and betulinic acid were the major components of epicuticular wax and contributed to tissue hydrophobicity and oxygen transport to the roots. Tissue porosity in AP was lower in the lus1 mutant than in the wild‐type, which resulted in reduced oxygen transport to the roots via AP. This reduction in oxygen transport resulted in shallow root systems under waterlogged conditions.Triterpenoid accumulation in AP contributes to effective internal aeration and root development for adaptation to waterlogging, suggesting the significance of triterpenoids in improving waterlogging tolerance. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major complication of diabetes. Nonalcoholic fatty liver disease (NAFLD) is common in diabetes, and liver fibrosis is a prognostic risk factor for NAFLD. The interaction between DN and liver fibrosis in NAFLD remains unclear. In 189 patients with DN and NAFLD who received an education course about diabetic nephropathy, liver fibrosis was evaluated using the fibrosis-4 (FIB-4) index. The association between the outcome of DN and changes in liver fibrosis was examined. The FIB-4 index was maintained at the baseline level in patients with improved DN, while it was increased in other patients. The ΔFIB-4 index was positively correlated with changes in albuminuria and proteinuria (ρ = 0.22, p = 0.004). In a multivariate analysis, changes in albuminuria and proteinuria were associated with the ΔFIB-4 index (p = 0.002). Patients with a progressive FIB-4 index category from baseline to 5 years showed a lower event-free survival rate after 5 years than patients with an improved FIB-4 index category (p = 0.037). The outcome of DN is associated with changes in liver fibrosis in patients with diabetes, NAFLD and DN. Developing a preventive and therapeutic approach for these conditions is required. [ABSTRACT FROM AUTHOR]

Self-organized criticality (SoC) may optimize information transmission, encoding, and storage in the brain. Therefore, the underlying mechanism of the SoC provides significant insight for large-scale neuromorphic computing. We hypothesized that noise and stochastic spiking plays an essential role in SoC development in spiking neural networks (SNNs). We demonstrated that under appropriate noise levels and spike-time-dependent plasticity (STDP) parameters, an SNN evolves a SoC-like state characterized by a power-law distribution of neuronal avalanche size in a self-organized manner. Consistent with the physiological findings, the development of SNN was characterized by a transition from a subcritical state to a supercritical state and then to a critical state. Excitatory STDP with an asymmetric time window dominated the early phase of development; however, it destabilized the network and transitioned to the supercritical state. Synchronized bursts in the supercritical state enable inhibitory STDP with a symmetric time window, induce the development of inhibitory synapses, and stabilize the network toward the critical state. This sequence of transitions was observed when the appropriate noise level and STDP parameters were set to the initial conditions. Our results suggest that noise or stochastic spiking plays an essential role in SoC development and self-optimizes SNN for computation. Such neural mechanisms of noise harnessing would offer insight into the development of energy-efficient neuromorphic computing. [ABSTRACT FROM AUTHOR]

The information processing capacity (IPC) measure is gaining traction as a means of characterizing reservoir computing. This measure offers a comprehensive assessment of a dynamical system's linear and non-linear memory of past inputs by breaking down the system states into orthogonal polynomial bases of input series. In this study, we demonstrate that IPCs are experimentally measurable in the auditory cortex in response to a random sequence of clicks. In our experiment, each input series had a constant inter-step interval (ISI), and a click was delivered with a 50% probability at each time step. Click-evoked multi-unit activities in the auditory cortex were used as the state variables. We found that the total IPC was dependent on the test ISI and reached a maximum at around 10- and 18-ms ISI. This suggests that the IPC reaches a peak when the stimulus dynamics and intrinsic dynamics in the brain are matched. Moreover, we found that the auditory cortex exhibited non-linear mapping of past inputs up to the 6th degree. This finding indicates that IPCs can predict the performance of a physical reservoir when benchmark tasks are decomposed into orthogonal polynomials. Thus, IPCs can be useful in measuring how the living brain functions as a reservoir. These achievements have opened up future avenues for bridging the gap between theoretical and experimental studies of neural representation. By providing a means of quantifying a dynamical system's memory of past inputs, IPCs offer a powerful tool for understanding the inner workings of the brain. [ABSTRACT FROM AUTHOR]

Summary: The root barrier to radial O2 loss (ROL) is a key root trait preventing O2 loss from roots to anoxic soils, thereby enabling root growth into anoxic, flooded soils.We hypothesized that the ROL barrier can also prevent intrusion of hydrogen sulphide (H2S), a potent phytotoxin in flooded soils. Using H2S‐ and O2‐sensitive microsensors, we measured the apparent permeance to H2S of rice roots, tested whether restricted H2S intrusion reduced its adverse effects on root respiration, and whether H2S could induce the formation of a ROL barrier.The ROL barrier reduced apparent permeance to H2S by almost 99%, greatly restricting H2S intrusion. The ROL barrier acted as a shield towards H2S; O2 consumption in roots with a ROL barrier remained unaffected at high H2S concentration (500 μM), compared to a 67% decline in roots without a barrier. Importantly, low H2S concentrations induced the formation of a ROL barrier.In conclusion, the ROL barrier plays a key role in protecting against H2S intrusion, and H2S can act as an environmental signalling molecule for the induction of the barrier. This study demonstrates the multiple functions of the suberized/lignified outer part of the rice root beyond that of restricting ROL. [ABSTRACT FROM AUTHOR]

Background: Health literacy (HL) has gained increasing attention as a factor related to health behaviors and outcomes. This study aimed to investigate geographic differences in HL levels and effect modification by geographic area on their relationship with self-rated health in the Japanese population using a nationwide sample. Methods: Data for this study were derived from a nationally representative cross-sectional survey on health information access for consumers in Japan using a mailed self-administered questionnaire in 2020 (INFORM Study 2020). Valid responses from 3,511 survey participants, selected using two-stage stratified random sampling, were analyzed in this study. HL was measured using the Communicative and Critical Health Literacy Scale (CCHL). Multiple regression and logistic regression analyses were conducted to examine the associations between geographic characteristics and HL and effect modification on the association between HL and self-rated health by geographic area, controlling for sociodemographic characteristics. Results: The mean HL score was 3.45 (SD = 0.78), somewhat lower compared with previous studies on the Japanese general population. HL was higher in Kanto area than in Chubu area, after controlling for sociodemographic factors and municipality size. Furthermore, HL was positively associated with self-rated health after controlling for sociodemographic and geographic factors; however, this association was more evident in eastern areas than in western areas. Conclusion: The findings indicate geographic differences in HL levels and effect modification by geographic area on the relationship between HL and self-rated health in the general Japanese population. HL was more strongly associated with self-rated health in eastern areas than in western areas. Further investigation is needed to explore the moderating effects of areal features, including the distribution of primary care physicians and social capital, when formulating strategies to improve HL in different contexts. [ABSTRACT FROM AUTHOR]

The relationship between baseline serum albumin level and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) remains unknown. This is a sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) study. The main outcomes were: death or orthotopic liver transplantation (OLT), liver-related death, and liver-related events (hepatocellular carcinoma [HCC], decompensated cirrhosis, and gastroesophageal varices/bleeding). 1383 Japanese patients with biopsy-confirmed NAFLD were analyzed. They were divided into 3 groups based on serum albumin: high (>4.0 g/dL), intermediate (3.5–4.0 g/dL), and low (<3.5 g/dL). Unadjusted hazard ratio [HR] of the intermediate albumin group, compared with the high albumin group, were 3.6 for death or OLT, 11.2 for liver-related death, 4.6 for HCC, 8.2 for decompensated cirrhosis, and 6.2 for gastroesophageal varices (all risks were statistically significant). After adjusting confounding factors, albumin remained significantly associated with death or OLT (intermediate vs. high albumin group: HR 3.06, 95% confidence interval [CI] 1.59–5.91, p < 0.001; low vs. high albumin group: HR 22.9, 95% CI 8.21–63.9, p < 0.001). Among biopsy-confirmed NAFLD patients, those with intermediate or low serum albumin had a significantly higher risk of death or OLT than those with high serum albumin. [ABSTRACT FROM AUTHOR]

Aim: The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan. Methods: We analyzed 371 Japanese patients with biopsy‐proven NAFLD. We constructed area under the receiver operator characteristic curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac‐2‐binding protein glycosylation isomer (M2BPGi), the Fibrosis‐4 (FIB‐4) index, and combinations of these indices. Results: In patients with F0/F1/F2/F3/F4 fibrosis, the median values of the ELF test were 8.98/9.56/10.39/10.92/11.41, respectively. The AUROCs of the ELF test for patients with F0 versus F1–4, F0–1 versus F2–4, F0–2 versus F3–4, and F0–3 versus F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB‐4 index and M2BPGi at each fibrosis stage. Respective low and high cut‐off values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8%, and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB‐4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%. Conclusions: In Japan, the ELF test predicts NAFLD‐related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate. [ABSTRACT FROM AUTHOR]

Although programmed cell death 4 (PDCD4) was initially reported as a tumor suppressor and has been shown to inhibit cancer cell growth and metastasis, recent studies have demonstrated that loss of PDCD4 expression also induces growth inhibition by inducing apoptosis and/or cellular senescence. At present, the roles of PDCD4 in the activation and profibrogenic properties of myofibroblasts, which are critically involved in organ fibrosis, such as that in the liver, are unclear. We, therefore, investigated the roles of PDCD4 in myofibroblasts using human hepatic stellate cell line Lieming Xu-2 (LX-2). PDCD4 knockdown inhibited LX-2 proliferation and induced a senescent phenotype with increased β-galactosidase staining and p21 expression in a p53-independent manner together with downregulation of the notch signaling mediator RBJ-κ/CSL. During PDCD4 knockdown, alpha smooth muscle actin (α-SMA; an activation marker of myofibroblasts), matrix metalloproteinases MMP-1 and MMP-9, and collagen IV were upregulated, but the expression of collagen1α1 and collagen III was markedly downregulated without any marked change in the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). These results demonstrated that knockdown of PDCD4 induced the cellular senescence phenotype and activated myofibroblasts while suppressing the profibrogenic phenotype, suggesting roles of PDCD4 in cellular senescence and fibrogenesis in the liver. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter to the editor regarding a recent publication on the Agile3+ and Agile4 scores for diagnosing advanced fibrosis and cirrhosis. The authors address three issues raised in the letter, including a statistical error, the diagnostic performance of the scores in a Brazilian cohort, and the inability to reduce patients with uncertain diagnoses using the scores. The authors clarify that patients with indeterminate scores were not excluded from the analyses and that the diagnostic performance of the scores may be influenced by patient characteristics. They suggest further analysis to examine the impact of patient backgrounds on the scores' diagnostic performance. The authors declare no conflicts of interest. [Extracted from the article]

Aim: Patients often do not respond truthfully to physicians' interviews concerning alcohol. Few reports regarding the level of alcohol dependence in patients with chronic liver disease (CLD) have been presented. This study aimed to elucidate severity distribution in patients with CLD using the alcohol use disorders identification test (AUDIT). Methods: From March to June 2022, 2034 Japanese outpatients with CLD, including 415 cases associated with hepatitis C virus, 436 with hepatitis B virus, 173 with alcohol‐related liver disease (ARLD), and 1010 with other factors, were interviewed using AUDIT. Clinical features related to alcohol use in these patients were then retrospectively evaluated. Results: In all patients, an AUDIT score 8–14 (harmful use) was noted in 5.8% of hepatitis C virus, 8.9% of hepatitis B virus, 24.3% of ARLD, and 4.4% of other groups, respectively (P < 0.001), while a score ≥15 (dependency) was noted in 3.4%, 3.0%, 27.7%, and 1.9%, respectively (P < 0.001). When the country was divided into regions, the percentages remained similar. Comparisons between patients with and without an AUDIT score ≥8 (n = 1412), performed after exclusion of those without related data (n = 622), showed no significant differences for hepatic reserve function, while those with harmful alcohol use were significantly younger (66 vs. 70 years, P = 0.006) and had a larger percentage of men (80.4% vs. 45.1%, P < 0.001). Conclusion: Harmful alcohol and alcohol dependency were observed in approximately 10% of patients with viral or non‐viral CLD, after excluding patients with ARLD. Assessment of alcohol intake by use of the AUDIT questionnaire as well as adequate intervention should be considered necessary. [ABSTRACT FROM AUTHOR]

Aims: The real‐world efficacy of sofosbuvir/velpatasvir treatment for patients with hepatitis C virus‐related decompensated cirrhosis is unclear. We aimed to identify factors that improve liver functional reserve after treatment. Methods: This was a multicenter retrospective study of 12‐week sofosbuvir/velpatasvir treatment. A total of 48 patients with Child–Pugh (CP) class B or C were enrolled at 11 institutions. We evaluated changes in liver functional reserve at 24 weeks post‐treatment. Results: At baseline, 40 and eight patients were CP class B and C, respectively. The overall rate of sustained virologic response 12 weeks post‐treatment was 95.8% (46/48). Serum albumin, alanine aminotransferase and α‐fetoprotein levels, and the FIB‐4 index were significantly improved post‐treatment (P < 0.05). Among patients who achieved sustained virologic response 12 weeks post‐treatment, those with CP class A increased from 0 to 24 patients (56%) at 24 weeks post‐treatment. In multivariate analysis, body mass index (BMI) ≥25 was an independent factor that inhibited CP class improvement (P < 0.05). In decision tree analysis, after treatment, the initial divergent variable for CP class improvement was hepatic encephalopathy, followed by serum sodium level and BMI. Conclusion: Sofosbuvir/velpatasvir treatment improved the liver functional reserve in patients with hepatitis C virus‐related decompensated cirrhosis at 24 weeks post‐treatment. However, BMI ≥25 inhibited improvement in CP class. Additionally, decision tree analysis revealed that a combination of hepatic encephalopathy, serum sodium levels, and BMI were diversity profiles associated with no improvement in liver functional reserve after the treatment. [ABSTRACT FROM AUTHOR]

Introduction: NAFLD is increasingly prevalent in Asia, where people suffer more metabolic comorbidities at a lower body mass index (BMI), suggesting potential differences in their clinical profile. Therefore, we attempted to characterize the clinical profile of Asians with NAFLD via a meta-analytic approach. Methods: We searched PubMed, EMBASE, and Cochrane databases from January 1, 2000, to January 17, 2019. Two authors independently reviewed and selected 104 articles (2,247,754 persons) that identified NAFLD in Asians and reported relevant data, especially BMI and ALT, and excluded individuals with other liver disease and excessive alcohol consumption. Individual patient-level data were obtained from seven cohorts in Asia to complement meta-analyzed data. Results: Overall, the mean age was 52.07 (95% CI: 51.28–52.85) years, with those from Southeast Asia (42.66, 95% CI: 32.23–53.11) being significantly younger. The mean BMI was 26.2 kg/m2, higher in moderate-severe versus mild hepatic steatosis (28.3 vs. 25.7) patients and NFS ≥ −1.455 versus <−1.455 (27.09 vs. 26.02), with 34% having nonobese NAFLD. The mean ALT was 31.74 U/L, higher in NFS < −1.455 versus ≥−1.455 (33.74 vs. 27.83), though no differences were found by obesity or steatosis severity. The majority of males (85.7%) and females (60.7%) had normal to minimally elevated ALT (1–1.5 × 95% ULN). Individual patient-level data analysis (N = 7,668) demonstrated similar results. Conclusion: About one-third of Asians with NAFLD were nonobese, and the majority did not have markedly elevated ALT. Therefore, abnormal ALT or BMI is not recommended as a criterion for NAFLD screening in this population. Additionally, there were significant differences in the clinical profiles of NAFLD among the different regions of Asia. [ABSTRACT FROM AUTHOR]

Background: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear. Objective: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC. Patients and Methods: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed. Results: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007). Conclusions: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN. [ABSTRACT FROM AUTHOR]

This article, titled "Featured Cover," discusses a study conducted by Shusuke Kumazaki et al. on the use of serum growth differentiation factor 15 (GDF15) as a biomarker for liver cancer occurrence in patients with metabolic-associated fatty liver disease (MASLD), regardless of liver fibrosis. The study found that GDF15 showed high predictive capability for liver cancer in these patients. The authors of the study include a diverse group of researchers from various institutions. The article provides a valuable resource for library patrons researching liver cancer and its biomarkers. [Extracted from the article]

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 FROM AUTHOR]

That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. Here, male and female breeders were fed a high-fat diet and housed with or without running wheels before breeding (males) and before and during gestation (females). Offspring were sedentary and chow fed, with parents as follows: sedentary (Sed), maternal exercise (MatEx), paternal exercise (PatEx), or maternal+paternal exercise (Mat+PatEx). Adult offspring from all parental exercise groups had similar improvement in glucose tolerance and hepatic glucose production. Targeted metabolomics was performed in offspring serum, liver, and triceps muscle. Offspring from MatEx, PatEx, and Mat+PatEx each had a unique tissue metabolite signature, but Mat+PatEx offspring had an additive phenotype relative to MatEx or PatEx alone in a subset of liver and muscle metabolites. Tissue metabolites consistently indicated that the metabolites altered with parental exercise contribute to enhanced fatty acid oxidation. These data identify distinct tissue-specific adaptations and mechanisms for parental exercise-induced improvement in offspring metabolic health. Further mining of this data set could aid the development of novel therapeutic targets to combat metabolic diseases. [ABSTRACT FROM AUTHOR]

Objectives: Weight loss improves the liver pathophysiological status of nonalcoholic fatty liver disease (NAFLD) patients. However, there are few studies that investigate the accurate relationships between nutritional intake and disease progression in NAFLD patients. Methods: A total of 37 biopsy-confirmed NAFLD patients were enrolled in this study. Clinical and nutritional control data of 5074 persons were obtained from the National Institute of Health and Nutrition. Each NAFLD subject recorded dietary intake for seven consecutive days using a dietary questionnaire and photographs of each meal. A dietitian analyzed and quantified the nutritional data in each patient. We further analyzed the nutritional intake of NAFLD patients in three groups according to the following criteria: (1) liver fibrosis degree (advanced, early), (2) gender (male, female), and (3) body mass index (BMI) (high, low). Results: Excesses or deficiencies of multiple nutrients were found in NAFLD patients compared with control subjects. In addition, there were variations in nutritional intake. (1) The intake of vitamins A, B6, and E, pantothenic acid, soluble dietary fiber, and salt was lower in the advanced fibrosis group than in the early fibrosis group. (2) Fat intake was higher in male patients, and dietary fiber intake was lower in both male and female patients compared with control subjects. (3) Saturated fatty acid intake was higher, and copper and vitamin E intakes were lower in patients with high BMI than with low BMI. Conclusions: Our study demonstrates that differences were found in some nutrient intake of NAFLD patients and controls and according to the severity of the conditions (liver fibrosis degree, BMI). [ABSTRACT FROM AUTHOR]

Background and aim: Metabolic dysfunction and associated systemic inflammation are risk factors for chronic obstructive pulmonary disease (COPD) and COPD is highly prevalent in men. We investigated the impact of metabolic-associated fatty liver disease (MAFLD) and MAFLD-related systemic inflammation on COPD in men. Methods: We enrolled 2,041 men with fatty liver. Patients were classified into the COPD (n = 420/2041) and non-COPD (n = 1621/2041) groups. COPD and its high-risk group were diagnosed using the Japanese Respiratory Society Disease statement. Systemic inflammation was evaluated using the C-reactive protein (CRP)/albumin ratio. Independent factors for COPD were investigated by multivariate analysis and decision-tree analysis. Results: The prevalence of MAFLD was significantly higher in the COPD group than in the non-COPD group. In multivariable analysis, in addition to heavy smoking and aging, MAFLD was identified as an independent factor for COPD (OR 1.46, 95% CI 1.020–2.101, P = 0.0385). Decision-tree analysis showed that MAFLD, rather than heavy smoking, was the most influential classifier for COPD in non-elderly men (14% in MAFLD vs 6% in non-MAFLD groups). MAFLD was also the second most influential factor in elderly men who were not heavy smokers. In both groups, the CRP/albumin ratio was the first classifier for COPD (16% in the high CRP/albumin ratio group vs 3% in the low CRP/albumin ratio group of non-elderly men). Conclusions: MAFLD is an independent predictor of COPD in men. MAFLD had a significant impact on COPD through systemic inflammation in men of all ages who were not heavy smokers. MAFLD may be useful to broadly identify COPD in men. [ABSTRACT FROM AUTHOR]

Lakes Reservoir Res Manag 3:123-133 Hanazato T (1998) Response of a zooplankton community to insecticide application in experimental ponds: a review and the implications of the effects of chemicals on the structure and functioning of freshwater communities. Environ Res A 77:43-48 Recknagel F, Fukushima T, Hanazato T, Takamura N, Wilson H (1998) Modelling and prediction of phyto- and zooplankton dynamics of Lake Kasumigaura by artificial neural networks. Jpn J Environ Toxicol 4:67-72 Hanazato T, Arakawa T, Sakuma M, Chang KH, Okino T (2001) Zooplankton community in Lake Suwa: community structure and its role in the ecosystem (in Japanese). J Jpn Soc Water Policy Integr River Basin Manag 5:3-7 Chang KH, Hanazato T (2005) Heterogeneous distribution of zooplankton in a shallow eutrophic lake: species composition and diversity of zooplankton community associated with habitat structure in littoral area. [Extracted from the article]

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients. [ABSTRACT FROM AUTHOR]

In Japan, risk behaviors for cancer remain inadequately controlled, often due to a lack of necessary information and support to guide consumers in cancer control decisions. The use of strategic health communication efforts based on social marketing has substantial potential to provide groups of consumers who are underinformed or misinformed with relevant cancer information, both to reinforce their cancer awareness, knowledge, attitudes, and beliefs and to strengthen behaviors to prevent cancer. The INFORM Study monitors these variables nationally and identifies populations most in need of cancer‐related information. A nationally representative cross‐sectional mail survey was used to investigate consumer behaviors related to cancer prevention and screening, as well as cancer knowledge, attitudes and beliefs, and access to and use of trusted cancer information. A total of 10,000 Japanese aged 20 years or older were selected by two‐stage stratified random sampling. The self‐administered questionnaire consisted of core items from the Health Information National Trends Survey in the United States with some additional items not covered in HINTS but important in Japan. This national survey is expected to play an important role in promoting effective dissemination of evidence‐based recommendations. Key points: 1.This is the first nationwide survey of cancer control in Japan to monitor communication channel, personal characteristics such as knowledge and attitude, behavioral characteristics, socioeconomic and geographical characteristics.2.We identify the populations who are in most need of cancer‐related information and their access to and use of cancer information, and provide the basis for tailoring of messages to each segmented group's needs and interests.3.This national survey can play an important role in promoting effective dissemination of evidence‐based recommendations and implementation of evidence‐based interventions to prevent cancer. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to develop a self-check programme as a tool for multidisciplinary teams to improve the quality of care provided in outpatient chemotherapy centres. Methods We used the modified Delphi method to reach a group consensus. Potential indicators were submitted to each panel member, who was asked to rate each using a 9-point scale (1, extremely inappropriate; 5, equivocal; 9, extremely appropriate). The panellists rated a list of indicators over four iterative rounds according to two perspectives. (1) From a short-term perspective, if the indicators are not achieved, improvement is required in 6 months to 1 year; (2) from a medium-term perspective, although indicators are less crucial, efforts should be made to operate a higher-quality outpatient chemotherapy centre. Key findings Our Delphi panel comprised 12 experts: 4 physicians, 4 pharmacists and 4 nurses. All 12 panellists responded to the first- and second-round surveys and 11 (92%) responded to the third- and fourth-round surveys. Moreover, nine (75%) experts participated in each panel meeting. After the Delphi survey, 49 indicators were selected from a short-term perspective and 16 from a medium-term perspective for the self-check programme. Finally, the selected indicators were accepted by the consensus of all members. Conclusions We developed a self-check programme to improve the quality of care related to outpatient chemotherapy centres. It comprises 65 indicators across nine domains. We plan to conduct a pilot study to assess the usefulness and uptake of the self-check programme. [ABSTRACT FROM AUTHOR]