Publications by authors named "Hirokazu Takahashi"

462 Publications

Predictive value of cytokeratin-18 fragment levels for diagnosing steatohepatitis in patients with nonalcoholic fatty liver disease.

Eur J Gastroenterol Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Hyogo Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Women's Medical University Medical Center East, Tokyo Liver Center, Saga University Hospital, Saga Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima Department of General Internal Medicine2, Kawasaki Medical School, Okayama Faculty of Nursing, Gifu Kyoritsu University, Gifu Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa Department of Gastroenterology and Hepatology, Center for Digestive and Liver Diseases, Nara City Hospital, Nara Department of Diagnostic Pathology, Nara City Hospital, Nara Shiroishi Clinic of Internal Medicine, Hokkaido Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga Center for Innovative Cancer Therapy, Kurume University Research, Kurume Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan.

Objective: Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH.

Results: The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of <2.67, the AUROC value of the CK18-F level for predicting NASH was 0.77 and a CK18-F cutoff level of 260 U/L resulted in a sensitivity and specificity of 82.4 and 56.9%.

Conclusions: The CK18-F level had a good predictive ability for diagnosing NASH in patients with NAFLD. Additionally, the combination of the CK18-F level and FIB-4 index accurately and noninvasively predicted NASH, even those with a low FIB-4 index.
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http://dx.doi.org/10.1097/MEG.0000000000002176DOI Listing
July 2021

Short-term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain-derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety-like behaviors.

FASEB J 2021 08;35(8):e21767

The Fukuoka University Institute for Physical Activity, Fukuoka University, Fukuoka, Japan.

Running exercise has beneficial effects on brain health. However, the effects of relatively short-term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. C57BL/6J male mice were divided into sedentary (SED, n = 12) and STEx (EX, n = 15) groups; STEx was conducted with the mice for a duration of 11 days. STEx reduced anxiety-like behaviors, and STEx reduced Nos1α and increased Bdnf exon I and IV mRNA levels in the hippocampus. Interestingly, behavioral parameters were associated with Bdnf exon I and IV and Nos1α mRNA levels in the ventral, but not dorsal, hippocampal region. However, STEx had no effect on peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α) or fibronectin type III domain-containing 5 (Fndc5) mRNA levels, which are relatively long-term exercise-induced upstream regulators of BDNF. In parallel with gene expression changes, we found, for the first time, that STEx downregulated Bdnf promoter IV and upregulated Nos1 DNA methylation levels in the hippocampus, and these patterns were partially different between the dorsal and ventral regions. These findings suggest that the beneficial effects of running exercise on mood regulation may be controlled by alterations in epigenetic mechanisms, especially in the ventral hippocampus. These effects occur even after a relatively short-term period of exercise.
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http://dx.doi.org/10.1096/fj.202100630RDOI Listing
August 2021

Encouraging participation in colorectal cancer screening for people with schizophrenia: A randomized controlled trial.

Acta Psychiatr Scand 2021 Jul 9. Epub 2021 Jul 9.

Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, 693-8501, Japan.

Objective: We examined the efficacy of a case management approach to improve participation in colorectal cancer screening among people with schizophrenia.

Methods: This was a randomized, parallel group trial. We recruited outpatients with schizophrenia aged 40 years or over from two psychiatric hospitals in Japan. Participants were randomly assigned (1:1) to treatment as usual or case management intervention plus treatment as usual using a web-based system. Attending clinicians and participants were unmasked to the allocation. Case management included education and patient navigation for colorectal cancer screening using a fecal occult blood test. Treatment as usual included direct mail government recommendations. The primary endpoint was participation in colorectal cancer screening assessed using municipal records. We also assessed the secondary endpoint of participation in other cancer screenings (lung, gastric, breast, and cervical).

Results: Between June 3 and September 9, 2019, 172 eligible participants were randomly assigned to the case management plus treatment as usual group (n=86) or treatment as usual group (n=86). One participant was ineligible and another withdrew consent; both were excluded from analysis. A significantly higher proportion of participants received colorectal cancer screening in the case management plus treatment as usual group than in the treatment as usual group (40 [47.1%] of 85 participants vs. 10 [11.8%] of 85 participants, P<0.0001). The proportion of lung cancer screening also increased. No serious adverse events associated with the study intervention occurred.

Conclusion: The case management intervention to encourage participation in colorectal cancer screening was effective for patients with schizophrenia.
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http://dx.doi.org/10.1111/acps.13348DOI Listing
July 2021

A Global Survey of Physicians Knowledge About Non-alcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2021 Jul 3. Epub 2021 Jul 3.

Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, Virginia; Inova Medicine, Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia.

Background & Aims: Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers' knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally.

Methods: NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America).

Results: Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60-300) vs 100 (interquartile range, 35-200) for GEs, 100 (interquartile range, 30-200) for ENDOs, and 10 (interquartile range, 4-50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%-26%) and practice guidelines for others (39%-44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05).

Conclusions: Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.
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http://dx.doi.org/10.1016/j.cgh.2021.06.048DOI Listing
July 2021

Gemcitabine plus nab-paclitaxel in older patients with metastatic pancreatic cancer: A post-hoc analysis of the real-world data of a multicenter study (the NAPOLEON study).

J Geriatr Oncol 2021 Jun 29. Epub 2021 Jun 29.

Department of Medical Oncology, Hamanomachi Hospital, 3-3-1 Nagahama, Chuo-ku, Fukuoka-shi, Fukuoka, 810-8539, Japan.

Objectives: This study aimed to examine the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) in older patients with metastatic pancreatic cancer (MPC), especially those ≥75 years old.

Materials And Methods: This study retrospectively enrolled 153 patients with MPC who received GnP as first-line chemotherapy. Patients ≥75 years old were allocated to the older group, and those <75 years old were assigned to the non-older group. We compared safety, antitumor efficacy, and survival between the two groups. In the older group, prognostic indicators of survival were also assessed.

Results: The pretreatment characteristics of the two groups were not significantly different excluding age, history of malignancy, and C-reactive protein levels. The initial dose and relative dose intensities of GnP were significantly lower in the older group. There were no significant differences in the adverse event and antitumor response rates between the two groups. Median progression-free survival and overall survival were 5.5 and 12.0 months, respectively, in the older group, versus 6.0 and 11.1 months, respectively, in the non-older group. In the older group, a Geriatric Nutrition Risk Index (GNRI) of less than 86 was associated with poor prognosis.

Conclusion: GnP exhibited acceptable efficacy and safety in patients ≥75 years old with MPC. GNRI might be helpful for identifying older individuals at higher risk of unfavorable outcomes.
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http://dx.doi.org/10.1016/j.jgo.2021.06.011DOI Listing
June 2021

Visualization of Gene Reciprocity among Lactic Acid Bacteria in Yogurt by RNase H-Assisted Rolling Circle Amplification-Fluorescence Hybridization.

Microorganisms 2021 Jun 3;9(6). Epub 2021 Jun 3.

Graduate School of Integrated Sciences for Life, Hiroshima University, Higashihiroshima 739-8530, Japan.

Recently, we developed an mRNA detection method termed RNase H-assisted rolling circle amplification-fluorescence hybridization (RHa-RCA-FISH), which can detect even short mRNA in a bacterial cell. However, because this FISH method is sensitive to the sample condition, it is necessary to find a suitable cell permeabilization and collection protocol. Here, we demonstrate its further applicability for detecting intrinsic mRNA expression using lactic acid bacteria (LAB) as a model consortium. Our results show that this method can visualize functional gene expression in LAB cells and can be used for monitoring the temporal transition of gene expression. In addition, we also confirmed that data obtained from bulk analyses such as RNA-seq or microarray do not always correspond to gene expression in individual cells. RHa-RCA-FISH will be a powerful tool to compensate for insufficient data from metatranscriptome analyses while clarifying the carriers of function in microbial consortia. By extending this technique to capture spatiotemporal microbial gene expression at the single-cell level, it will be able to characterize microbial interactions in phytoplankton-bacteria interactions.
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http://dx.doi.org/10.3390/microorganisms9061208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228470PMC
June 2021

Case Report: Metreleptin and SGLT2 Inhibitor Combination Therapy Is Effective for Acquired Incomplete Lipodystrophy.

Front Endocrinol (Lausanne) 2021 31;12:690996. Epub 2021 May 31.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.
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http://dx.doi.org/10.3389/fendo.2021.690996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201990PMC
May 2021

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

Hepatol Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.

Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.

Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235).

Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
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http://dx.doi.org/10.1111/hepr.13685DOI Listing
June 2021

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Department of Internal Medicine, Saga University Hospital, Saga, Japan.

Background & Aims: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines.

Methods: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years.

Results: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria.

Conclusion: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.
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http://dx.doi.org/10.1016/j.cgh.2021.05.062DOI Listing
June 2021

Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir.

Am J Gastroenterol 2021 06;116(6):1264-1273

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.

Introduction: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch.

Methods: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL).

Results: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR.

Discussion: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.
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http://dx.doi.org/10.14309/ajg.0000000000001157DOI Listing
June 2021

Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan.

Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.
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http://dx.doi.org/10.3390/ijms22073728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038294PMC
April 2021

Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

Hepatol Commun 2021 Apr 16;5(4):559-572. Epub 2020 Nov 16.

Department of Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Kyoto Japan.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.
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http://dx.doi.org/10.1002/hep4.1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034577PMC
April 2021

Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients.

Genes (Basel) 2021 03 11;12(3). Epub 2021 Mar 11.

Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.

Accumulating evidence has suggested that viral infection causes type 1 diabetes due to direct β-cell damage and the triggering of autoimmune reactivity to β cells. Here, we elucidated that the tyrosine kinase 2 ) gene, encoding an interferon receptor signaling molecule, is responsible for virus-induced diabetes in mice, and its promoter variant confers a risk of type 1 diabetes in humans. This study investigated the relationship between a promoter variant and insulin secretion in type 2 diabetes patients. status was determined using direct DNA sequencing and its associations with fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated in type 2 diabetes patients without sulfonylurea or insulin medication. Of the 172 patients assessed, 18 (10.5%) showed -positivity. Their body mass index (BMI) was significantly lower than in those without the variant (23.4 vs. 25.4 kg/m, = 0.025). Fasting insulin (3.9 vs. 6.2 μIU/mL, = 0.007), C-peptide (1.37 vs. 1.76 ng/mL, = 0.008), and HOMA-IR (1.39 vs. 2.05, = 0.006) were lower in those with than in those without the variant. Multivariable analysis identified that was associated with fasting insulin ≤ 5 μIU/mL (odds ratio (OR) 3.63, = 0.025) and C-peptide ≤ 1.0 ng/mL (OR 3.61, = 0.028), and also lower insulin resistance (HOMA-IR ≤ 2.5; OR 8.60, = 0.042). is associated with impaired insulin secretion and low insulin resistance in type 2 diabetes. Type 2 diabetes patients with should be carefully followed in order to receive the appropriate treatment including insulin injections.
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http://dx.doi.org/10.3390/genes12030400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999758PMC
March 2021

Entecavir administration to pregnant Japanese woman with chronic hepatitis B and hepatocellular carcinoma: A case report.

Clin Case Rep 2021 Mar 16;9(3):1752-1758. Epub 2021 Feb 16.

Department of Pediatrics, Faculty of Medicine Saga University Saga Japan.

Women taking entecavir hydrate (ETV) may not need to consider abortion in the event of an unexpected pregnancy. If a woman with renal dysfunction and taking ETV for chronic hepatitis B becomes pregnant, continuous use of ETV may also be tolerated.
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http://dx.doi.org/10.1002/ccr3.3896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981745PMC
March 2021

Root phenotyping: important and minimum information required for root modeling in crop plants.

Breed Sci 2021 Feb 10;71(1):109-116. Epub 2021 Feb 10.

UMR AGAP, CIRAD, F-34398 Montpellier, France.

As plants cannot relocate, they require effective root systems for water and nutrient uptake. Root development plasticity enables plants to adapt to different environmental conditions. Research on improvements in crop root systems is limited in comparison with that in shoots as the former are difficult to image. Breeding more effective root systems is proposed as the "second green revolution". There are several recent publications on root system architecture (RSA), but the methods used to analyze the RSA have not been standardized. Here, we introduce traditional and current root-imaging methods and discuss root structure phenotyping. Some important root structures have not been standardized as roots are easily affected by rhizosphere conditions and exhibit greater plasticity than shoots; moreover, root morphology significantly varies even in the same genotype. For these reasons, it is difficult to define the ideal root systems for breeding. In this review, we introduce several types of software to analyze roots and identify important root parameters by modeling to simplify the root system characterization. These parameters can be extracted from photographs captured in the field. This modeling approach is applicable to various legacy root data stored in old or unpublished formats. Standardization of RSA data could help estimate root ideotypes.
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http://dx.doi.org/10.1270/jsbbs.20126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973500PMC
February 2021

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

J Gastroenterol Hepatol 2021 Mar 11. Epub 2021 Mar 11.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background And Aim: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease.

Methods: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m ) who underwent pathological examination and 87 controls at five hospitals in Japan.

Results: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease.

Conclusions: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).
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http://dx.doi.org/10.1111/jgh.15487DOI Listing
March 2021

FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic.

Life (Basel) 2021 Feb 14;11(2). Epub 2021 Feb 14.

Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi 460-0011, Japan.

The prevalence of obesity or metabolic syndrome is increasing worldwide (globally metabodemic). Approximately 25% of the adult general population is suffering from nonalcoholic fatty liver disease (NAFLD), which has become a serious health problem. In 2020, global experts suggested that the nomenclature of NAFLD should be updated to metabolic-dysfunction-associated fatty liver disease (MAFLD). Hepatic fibrosis is the most significant determinant of all cause- and liver -related mortality in MAFLD. The non-invasive test (NIT) is urgently required to evaluate hepatic fibrosis in MAFLD. The fibrosis-4 (FIB-4) index is the first triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness, especially for general physicians or endocrinologists, although the FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration-controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the second step after triaging by the FIB-4 index. The leading cause of mortality in MAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. MAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation. The FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocellular carcinoma, but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, the FIB-4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of the FIB-4 index in the management of MAFLD.
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http://dx.doi.org/10.3390/life11020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917687PMC
February 2021

The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

Hepatol Int 2021 Apr 12;15(2):366-379. Epub 2021 Feb 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 780 Welch Road, CJ250K, Palo Alto, CA, 94304, USA.

Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD.

Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients.

Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD.

Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.
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http://dx.doi.org/10.1007/s12072-021-10143-4DOI Listing
April 2021

Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue.

Diabetes 2021 Jun 9;70(6):1250-1264. Epub 2021 Feb 9.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA

Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 () as a novel adipokine that is only secreted from male iWAT in response to exercise. expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.
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http://dx.doi.org/10.2337/db20-0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275891PMC
June 2021

The first-round results of a population-based cohort study of HPV testing in Japanese cervical cancer screening: baseline characteristics, screening results, and referral rate.

J Gynecol Oncol 2021 May 26;32(3):e29. Epub 2021 Jan 26.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Objective: In 2013, a cohort study aimed to clarify the positive and negative effects of introducing the human papillomavirus (HPV) testing for population-based cervical cancer screening has been launched in Japan. This study included four screenings during the subsequent 7-year follow-up period. We aim to describe the results of the first round of this study on cervical cancer screening here.

Methods: This study began in September 2013 with recruitment completed in March 2016. Women aged 30-49 years were divided into 2 groups: those who received uterine cervical cytology alone in the first year (control group), or those who received a combination of cytology and HPV testing (intervention group), based on their age. After first screening, women with positive result of cytology or positive HPV test required referral. We summarized the results of the first round of cervical cancer screening.

Results: Of the 25,074 women who were eligible for the study, 13,845 women (55.2%) were screened with cytology alone; 11,229 women (44.8%) received a combination of cytology and HPV testing. After screening, 407 women (2.9%) in the control group and 1,003 women (8.9%) in the intervention group required referral, respectively. Adding HPV testing increased referral rate significantly (p<0.001).

Conclusion: After first screening, introduction of HPV testing appears to contribute to significantly higher referral rates, suggesting that the number of colposcopies as a detailed examination may increase. These preliminary findings suggest that if HPV testing is introduced into screening, medical institutions need to be prepared for an increasing number of follow-up examinations.
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http://dx.doi.org/10.3802/jgo.2021.32.e29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039178PMC
May 2021

Eradication of hepatitis C virus with direct-acting antivirals improves glycemic control in diabetes: A multicenter study.

JGH Open 2021 Feb 19;5(2):228-234. Epub 2020 Dec 19.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan.

Background And Aim: Hepatitis C virus (HCV) infection causes insulin resistance and diabetes as extrahepatic manifestations. We aimed to analyze the effect of HCV eradication by direct-acting antiviral (DAA) agents on glucose tolerance.

Methods: The hemoglobin A1c (HbA1c) of 272 patients with HCV infection who achieved a sustained virologic response (SVR) was analyzed at baseline before DAA treatment, at the end of DAA therapy (ETR), and 12 weeks after therapy (Post12W).

Results: There were no significant differences in HbA1c between baseline, ETR, and Post12W in the overall patients. When the data were stratified according to the presence or absence of diabetes, median HbA1c significantly decreased from baseline (7.2%) to ETR (6.8%) and Post12W (6.8%) in the 55 patients with diabetes, whereas there were no significant changes in the patients without diabetes. Basal HbA1c, fasting plasma glucose, and age were independently associated with the changes in HbA1c according to multivariate analysis, and the predictive formula for changes in HbA1c was found to be ΔHbA1c (%) = 1.449-0.4* HbA1c (%) + 0.012 × Age (year). There were no changes in body mass in diabetic or nondiabetic patients. In diabetic patients taking medication, 63.4% of patients needed less medication.

Conclusions: Eradication of HCV improves glycemic control, indicated by a 0.4% decrease in HbA1c in diabetes.
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http://dx.doi.org/10.1002/jgh3.12474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857302PMC
February 2021

Endotoxemia by Alters Endocrine Functions in Brown Adipose Tissue.

Front Cell Infect Microbiol 2020 19;10:580577. Epub 2021 Jan 19.

Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Improvement of obesity is important for increasing longevity. The characteristics, size, and function of adipocytes are altered in patients with obesity. Adipose tissue is not only an energy storage but also an endocrine organ. Alteration of endocrine activities in adipose tissue, among them the functional decline of brown adipose tissue (BAT), is associated with obesity. Periodontal disease is a risk factor for systemic diseases since endotoxemia is caused by periodontal bacteria. However, the effect of periodontal disease on obesity remains unclear. Thus, this study aimed to investigate the effect of endotoxemia due to , a prominent cause of periodontal disease, on the BAT. Herein, endotoxemia was induced in 12-week-old C57BL/6J mice through intravenous injection of sonicated 10 CFU of (Pg) or saline (control [Co]) once. Eighteen hours later, despite no inflammatory M1 macrophage infiltration, inflammation-related genes were upregulated exclusively in the BAT of Pg mice compared with Co mice. Although no marked histological changes were observed in adipose tissues, expressions of genes related to lipolysis, and were downregulated after injection in BAT. Furthermore, expression of and was downregulated only in the BAT but not in the white adipose tissues, along with downregulation of and expression, which are BAT-specific markers, in Pg mice. Microarray analysis of the BAT showed 106 differentially expressed genes between Co and Pg mice. Gene set enrichment analysis revealed that the cholesterol homeostasis gene set and PI3/Akt/mTOR signaling gene set in BAT were downregulated, whereas the TGF-β signaling gene set was enriched in Pg mice. Overall, intravenous injection of sonicated altered the endocrine functions of the BAT in mice. This study indicates that endotoxemia by potentially affects obesity by disrupting BAT function.
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http://dx.doi.org/10.3389/fcimb.2020.580577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850987PMC
June 2021

FIB-4 index-based surveillance for advanced liver fibrosis in diabetes patients.

Diabetol Int 2021 Jan 9;12(1):118-125. Epub 2020 Jul 9.

Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan.

Liver fibrosis is associated with lifestyle-related diseases, including diabetes. The identification of diabetic patients with severe liver fibrosis is important, but a simple and reliable diagnostic procedure remains to be determined. We conducted an observational study to evaluate the performance of a FIB-4 index-based screening strategy for the diagnosis of advanced liver fibrosis in patients with diabetes or prediabetes. Two hundred and forty-two patients underwent abdominal imaging in our Study. According to the abdominal imaging findings, fatty liver, liver cirrhosis, and hepatocellular carcinoma were defined, and their association with FIB-4 index evaluated. The prevalences of liver cirrhosis and hepatocellular carcinoma in patients with a high (≥ 2.67; liver cirrhosis: 42.9%, hepatocellular carcinoma: 14.3%) FIB-4 index were significantly higher than in those with an intermediate (1.3 ≤ FIB-4 < 2.67; liver cirrhosis: 1.6%, hepatocellular carcinoma: 0.8%) or low FIB-4 index (< 1.3; liver cirrhosis: 1.2%, hepatocellular carcinoma: 0%). The diagnostic accuracy, specificity, and sensitivity of the FIB-4 index for the diagnosis of liver cirrhosis or hepatocellular carcinoma were 84.3%, 85.5%, and 89.3%, respectively, with an optimized cut-off value of 2.96 (sensitivity = 0.86, specificity = 0.98). Using an optimized cut-off value, FIB-4 index might be useful to identify liver cirrhosis or hepatocellular carcinoma in diabetes patients with high diagnostic accuracy.
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http://dx.doi.org/10.1007/s13340-020-00453-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790961PMC
January 2021

Prediction of Nonalcoholic Fatty Liver Disease Using Noninvasive and Non-Imaging Procedures in Japanese Health Checkup Examinees.

Diagnostics (Basel) 2021 Jan 16;11(1). Epub 2021 Jan 16.

Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.

Access to imaging is limited for diagnosing nonalcoholic fatty liver disease (NAFLD) in general populations. This study evaluated the diagnostic performance of noninvasive and nonimaging indexes to predict NAFLD in the general Japanese population. Health checkup examinees without hepatitis virus infection or habitual alcohol drinking were included. Fatty liver was diagnosed by ultrasonography. The hepatic steatosis index (HSI), Zhejiang University (ZJU) index, and fatty liver index (FLI) were determined, and risk of advanced liver fibrosis was evaluated by the fibrosis-4 index. NAFLD was diagnosed in 1935 (28.0%) of the 6927 subjects. The area under the receiver operating characteristic (AUROC) curve of the HSI, ZJU index, and FLI was 0.874, 0.886, and 0.884, respectively. The AUROC of the ZJU index ( < 0.001) and FLI ( = 0.002) was significantly greater than that for the HSI. In subjects with a high risk of advanced fibrosis, the sensitivity of the HSI, ZJU index, and FLI were 88.8%, 94.4%, and 83.3% with a low cut-off value and the specificity was 98.5%, 100%, and 100% with a high cut-off value. In conclusion, all indexes were useful to diagnose NAFLD in the general Japanese population and in subjects with potentially advanced liver fibrosis.
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http://dx.doi.org/10.3390/diagnostics11010132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830542PMC
January 2021

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

Hepatol Int 2021 Feb 4;15(1):71-81. Epub 2021 Jan 4.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Hepatitis Research Center, College of Medicine and Cohort Research Center and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.

Methods: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.

Results: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.

Conclusion: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.
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http://dx.doi.org/10.1007/s12072-020-10113-2DOI Listing
February 2021

Improvement of fatty acid productivity of thraustochytrid, Aurantiochytrium sp. by genome editing.

J Biosci Bioeng 2021 Apr 30;131(4):373-380. Epub 2020 Dec 30.

Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530, Japan. Electronic address:

Thraustochytrid strains belonging to the genus Aurantiochytrium accumulate significant amounts of lipids including polyunsaturated fatty acids and carotenoids and, therefore, are expected to be used for industrial production of various valuable materials. Although various efforts such as chemical mutagenesis and homologous gene recombination have been made to improve lipid productivity of Aurantiochytrium species, low specificity and efficiency in the conventional methods hinder the research progress. Here, we attempted to apply a genome editing technology, the CRISPR-Cas9 system as an alternative molecular breeding technique for Aurantiochytrium species to accelerate the metabolic engineering. The efficiency of specific gene knock-in by the homologous recombination increased more than 10-folds by combining the CRISPR-Cas9 system. As a result of disrupting the genes associated with β-oxidation of fatty acids by the improved method, the genome edited strains with higher fatty acid productivity were isolated, demonstrating for the first time that the CRISPR-Cas9 system was effective for molecular breeding of the strains in the genus Aurantiochytrium to improve lipid productivity.
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http://dx.doi.org/10.1016/j.jbiosc.2020.11.013DOI Listing
April 2021

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

Clin Gastroenterol Hepatol 2020 Dec 17. Epub 2020 Dec 17.

Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address:

Background & Aims: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE).

Methods: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day.

Results: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE.

Conclusions: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.
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http://dx.doi.org/10.1016/j.cgh.2020.12.016DOI Listing
December 2020

HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort.

Hepatol Int 2020 Dec 4;14(6):1023-1033. Epub 2020 Dec 4.

Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Background: Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients.

Methods: To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups.

Results: In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p < 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p < 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005).

Conclusions: Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.
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http://dx.doi.org/10.1007/s12072-020-10105-2DOI Listing
December 2020

Diagnostic Accuracy of FibroScan and Factors Affecting Measurements.

Diagnostics (Basel) 2020 Nov 12;10(11). Epub 2020 Nov 12.

Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga 849-8501, Japan.

Evaluating liver steatosis and fibrosis is important for patients with non-alcoholic fatty liver disease. Although liver biopsy and pathological assessment is the gold standard for these conditions, this technique has several disadvantages. The evaluation of steatosis and fibrosis using ultrasound B-mode imaging is qualitative and subjective. The liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) determined using FibroScan are the evidence-based non-invasive measures of liver fibrosis and steatosis, respectively. The LSM and CAP measurements are carried out simultaneously, and the median values of more than ten valid measurements are used to quantify liver fibrosis and steatosis. Here, we demonstrate that the reliability of the LSM depends on the interquartile range to median ratio (IQR/Med), but CAP values do not depend on IQR/Med. In addition, the LSM is affected by inflammation, congestion, and cholestasis in addition to fibrosis, while CAP values are affected by the body mass index in addition to steatosis. We also show that the M probe provides higher LSM values but lower CAP values than the XL probe in the same population. However, there was no statistically significant difference between the diagnostic accuracies of the two probes. These findings are important to understand the reliability of FibroScan measurements and the factors influencing measurement values for all patients.
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http://dx.doi.org/10.3390/diagnostics10110940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696616PMC
November 2020
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