Characteristics of Gastric Mucosa-Associated Microbiota in Patients with Early Gastric Cancer After Successful Helicobacter pylori Eradication.

BACKGROUND: Helicobacter pylori (H. pylori) is widely recognized as a definite carcinogen in gastric cancer (GC). Although H. pylori eradication reduces the risk of GC, GC recurrence has been detected even after successful H. pylori eradication. Recently, the analysis of gut microbiota was reported. AIMS: This study aimed to evaluate the correlation between gastric mucosa-associated microbiota (G-MAM) and early gastric cancer (EGC) after successful H. pylori eradication. METHODS: In this pilot study, G-MAM were collected during the esophagogastroduodenoscopy of 17 patients, receiving H. pylori eradication therapy at least 5 years ago. The patients were divided into those with EGC (the EGC group, 8 patients) and those without EGC (the NGC group, 9 patients). Microbial samples in the greater curvature of the pyloric site were obtained using an endoscopic cytology brush, and the G-MAM profiles of each sample were analyzed using 16S rRNA V3-V4 gene sequencing. RESULTS: Between the two groups, there was no significant difference in the median age, sex, median period after successful eradication of H. pylori, the α diversity, and the average abundance at the phylum level. At the genus level, the average abundance of Unclassified Oxalobacteraceae, Capnocytophaga, and Haemophilus was significantly lower in the EGC group than in the NGC group (0.89 vs. 0.14%, P < 0.01, 0.28 vs. 0.00%, P < 0.01 and 5.84 vs. 2.16%, P = 0.034, respectively). CONCLUSIONS: We demonstrated alternations in the profiles of G-MAM between the two groups. Our results suggest that G-MAM may influence carcinogenesis after successful H. pylori eradication.

Risk and prognostic factors of invasive gastric cancer detection during surveillance endoscopy: Multi-institutional cross-sectional study.

OBJECTIVES: Esophagogastroduodenoscopy (EGD) is important for the detection of curable gastric cancer (GC). However, there are no appropriate surveillance data during routine endoscopic inspections. This study aimed to clarify the risk factors of pT1b or deeper GC detection during surveillance endoscopy. METHODS: This was a retrospective, multicenter, cross-sectional study conducted in 15 Japanese hospitals. We retrospectively analyzed patients with GC who had previously undergone surveillance endoscopy at each institution from January 2014 to March 2020. Patients who had undergone gastrectomy, non-infection of Helicobacter pylori (Hp), and those with intervals <3 months or >10 years from a previous endoscopy were excluded. RESULTS: In total, 1085 patients with GCs detected during surveillance endoscopy were enrolled. The multivariate logistic analysis revealed that current Hp infection (odds ratio [OR] 2.18; 95% confidence interval [CI] 1.50-3.16) and a surveillance interval of >1.5 years (OR 1.96; 95% CI 1.35-2.84) were independent risk factors for pT1b or deeper GC. The 5-year disease-specific survival (5y-DSS) rate of GC was significantly lower in patients with surveillance interval of >1.5 years than in those with surveillance interval of ≤1.5 years (93.7% vs. 98.3%, P < 0.001). Similarly, the 5y-DSS rate of GC was significantly lower in patients with active Hp infection than in those without (93.7% vs. 99.4%, P < 0.001). CONCLUSION: In this study, a surveillance interval of >1.5 years and current Hp infection were independent risk factors for detecting pT1b or deeper GC. Additionally, these factors were poor prognostic factors of the detected GC during surveillance endoscopy.

Effects of Guidelines for Gastroenterological Endoscopy in Patients Undergoing Antithrombotic Treatment on Postoperative Bleeding after Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: Management of antithrombotic agents during endoscopic treatment changed after the publishing of -Japan Gastroenterological Endoscopy Society guidelines for gastroenterological endoscopy in antithrombotic drug users (GL-2012). OBJECTIVES: We aimed to evaluate the effect of implementing antithrombotic agent management guidelines (GL-2012) on postoperative bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and on the prevention of thromboembolic events. METHODS: A total of 1,264 patients who underwent ESD for EGC at Kyoto Prefectural University Hospital between June 2002 and March 2017 were enrolled and divided into 2 groups: 621 patients before the publication of GL-2012 (Pre-GL group) and 643 patients after (Post-GL group). Relationships between postoperative bleeding and various clinicopathological factors in each group were investigated through propensity score-matching analysis. RESULTS: In the Pre-GL group, antihypertensive agent use (p < 0.01) and upper third of the stomach (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 4.6, 95% CI 1.6-12.8) and upper third of the stomach (OR 4.9, 95% CI 1.8-13.4) were significantly related to postoperative bleeding in multivariate analysis. In the Post-GL group, antihypertensive agent use (p < 0.01), dual antiplatelet agents use (p < 0.01), anticoagulant agents use (p < 0.01), and heparin replacement therapy (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 3.4, 95% CI 1.1-9.6), dual antiplatelet agents (OR 12.3, 95% CI 2.4-63.0), and heparin replacement therapy (OR 10.2, 95% CI 2.5-41.5) were significantly related to postoperative bleeding in multivariate analysis. CONCLUSIONS: The adherence to GL-2012 might reduce risk of thromboembolic events. On the other hand, dual antiplatelet agents therapy and heparin replacement therapy were the new independent risk factors for ESD postoperative bleeding in EGC after GL-2012. Especially as for heparin replacement therapy, uninterrupted warfarin or a temporary short interruption of direct oral anticoagulants without heparin replacement therapy might be recommended rather than heparin replacement therapy.

Diagnostic Ability of Magnifying Blue Light Imaging with a Light Emitting Diode Light Source for Early Gastric Cancer: A Prospective Comparative Study.

INTRODUCTION: An innovative endoscopic system using 4-color light-emitting diodes (LED) was released between 2016 and 2017 in locations that had not approved laser endoscopes for use, including the United States and Europe. OBJECTIVE: This study compared the diagnostic efficacy between magnifying blue light imaging with an LED light source (LED-BLI) and magnifying blue laser imaging with a laser light source (Laser-BLI) for early gastric cancer (EGC). METHODS: In this prospective, single-center, noninferiority study, 80 gastric lesions were evaluated between January 2017 and July 2017. The magnifying findings of gastric lesions - including the demarcation line (DL), microvascular pattern (MVP), and microsurface pattern (MSP) - were evaluated using Laser-BLI and LED-BLI according to the vessel plus surface classification system (VSCS). The primary end point was to determine whether the diagnostic accuracy of LED-BLI for EGC was noninferior to that of conventional Laser-BLI. RESULTS: Overall, we evaluated 79 gastric lesions histopathologically diagnosed as adenocarcinomas from the specimens obtained via endoscopic submucosal dissection. A DL was observed by Laser-BLI and LED-BLI in 98.7% (78/79) and 96.2% (76/79) of EGCs, respectively. The MVP observed using Laser-BLI and LED-BLI was irregular in 92.4% (73/79) and 89.9% (71/79), respectively. The MSP observed using Laser-BLI and LED-BLI was irregular in 83.5% (66/79) and 82.2% (65/79), respectively. According to the VSCS, diagnosable cancers were found in 94.9% (75/79) and 93.7% (74/79) of cases when using Laser-BLI and LED-BLI, respectively (p = 0.73; difference ratio, 1.2%; 95% CI -8.5 to 6.0%). CONCLUSIONS: LED-BLI could accurately visualize the DL, MVP, and MSP of EGCs and was not inferior to Laser-BLI. Therefore, LED-BLI can be used to diagnose EGC accurately according to the VSCS-based diagnosis criteria.

Diagnostic performance of magnifying blue laser imaging versus magnifying narrow-band imaging for identifying the depth of invasion of superficial esophageal squamous cell carcinoma.

Identifying the depth of invasion (DOI) of superficial esophageal squamous cell carcinoma (SESCC) is crucial to determine the indication for endoscopic resection. This retrospective, single-center study aimed to evaluate the diagnostic efficacy of magnifying blue laser imaging (M-BLI) compared with white-light imaging (WLI) or magnifying narrow-band imaging (M-NBI) for identifying the DOI of SESCC. A total of 160 consecutive patients with SESCCs who underwent endoscopic submucosal dissection were enrolled in this study. Still images of the lesion were obtained using WLI, M-BLI and M-NBI prior to endoscopic submucosal dissection. Three endoscopists retrospectively evaluated the DOI using WLI according to non-magnifying findings and using M-BLI and M-NBI images according to the magnifying endoscopic classification of the Japan Esophageal Society. The diagnostic accuracy of each modality was compared using the chi-square test. The DOIs in 160 SESCCs evaluated pathologically were as follows: invasion to the epithelium or lamina propria mucosa in 130, invasion to the lamina muscularis mucosa or submucosa to a depth ≤ 200 µm in 18, and invasion to the submucosa to a depth > 200 µm in 12. The overall diagnostic accuracy rates of WLI, M-BLI, M-NBI, WLI with M-BLI (WLI + M-BLI), and WLI with M-NBI (WLI + M-NBI) were 86.9, 91.2, 90.6, 95.6 and 94.4%, respectively. Significant differences were found between WLI and WLI + M-BLI or WLI + M-NBI (P = 0.006 and P = 0.021, respectively). The concordance of intrapapillary capillary loops between M-BLI and M-NBI was 91.2%. The kappa coefficients for interobserver variability of the three endoscopists for M-BLI and M-NBI were 0.728/0.649/0.792 and 0.729/0.666/0.791, respectively, while those for intraobserver variability were 0.919/0.746/0.778 and 0.736/0.720/0.745, respectively. Similar to M-NBI, M-BLI was useful in predicting the DOI of SESCCs.

Can image-enhanced endoscopy improve the diagnosis of Kyoto classification of gastritis in the clinical setting?

Endoscopic diagnosis of Helicobacter pylori (H. pylori) infection, the most common cause of gastric cancer, is very important to clarify high-risk patients of gastric cancer for reducing morbidity and mortality of gastric cancer. Recently, the Kyoto classification of gastritis was developed based on the endoscopic characteristics of H. pylori infection-associated gastritis for clarifying H. pylori infection status and evaluating risk factors of gastric cancer. Recently, magnifying endoscopy with narrow-band imaging (NBI) has reported benefits of the accuracy and reproducibility of endoscopic diagnosis for H. pylori-related premalignant lesions. In addition to NBI, various types of image-enhanced endoscopies (IEEs) are available including autofluorescence imaging, blue laser imaging, and linked color imaging. This review focuses on understanding the clinical applications and the corresponding evidences shown to improve the diagnosis of gastritis based on Kyoto classification using currently available advanced technologies of IEEs.

Efficacy and safety of endoscopic submucosal dissection using a scissors-type knife with prophylactic over-the-scope clip closure for superficial non-ampullary duodenal epithelial tumors.

BACKGROUND AND STUDY AIM: This study aimed to assess the safety and feasibility of endoscopic submucosal dissection (ESD) using a scissors-type knife with prophylactic closure using over-the-scope clip (OTSC) for superficial non-ampullary duodenal epithelial tumors (SNADETs). PATIENTS AND METHODS: Consecutive patients who underwent ESD for SNADETs >10 mm between January 2009 and July 2019 were retrospectively enrolled. We performed ESD using either a needle-type knife (Flush Knife-ESD) or a scissors-type knife (Clutch Cutter-ESD). Mucosal defects were prophylactically closed using three methods: conventional clip, laparoscopic closure, or OTSC. RESULTS: A total of 84 lesions were resected using the Flush Knife-ESD and the Clutch Cutter-ESD (37 and 47 patients, respectively), and conventional clip, laparoscopic closure, and OTSC for mucosal defect closure after ESD were applied in 13, 13, and 56 lesions, respectively. The R0 resection rate was significantly higher in the Clutch Cutter-ESD than that in the Flush Knife-ESD (97.9% vs 83.8%, respectively, P = 0.040). The intraoperative perforation rate was significantly lower in the Clutch Cutter-ESD than in the Flush Knife-ESD (0% vs 13.5%, respectively, P = 0.014). Complete closure rates of conventional clip, laparoscopic closure, and OTSC were 76.9%, 92.3%, and 98.2%, respectively (P = 0.021); and delayed perforation rates were 15.4%, 7.7%, and 1.8%, respectively (P = 0.092). CONCLUSIONS: Endoscopic submucosal dissection using a scissors-type knife with prophylactic OTSC closure is safe and feasible for the low-invasive treatment of SNADETs.

Clinical and pathological features of sarcopenia-related indices in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sarcopenia is diagnosed with the skeletal muscle index (SMI) or the sarcopenia index (SI). We previously reported that the ratio of skeletal muscle mass to body fat mass (SF ratio) was a novel index of sarcopenia in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to evaluate sarcopenia with these indices in patients with NAFLD. METHODS: One hundred and fifty-six consecutive patients with biopsy-proven NAFLD and alanine aminotransferase (ALT) >40 IU/L were enrolled. Liver function and body composition were evaluated in 121 patients after 12 months. We evaluated the relationship between histological findings, changes in liver function, and the SMI, SI, and SF ratio. RESULTS: Of the 156 patients enrolled, 13.5% and 26.3% were diagnosed with sarcopenia with the SMI and SI. In patients with hepatic fibrosis stage <2, the SI and the SF ratio were significantly greater than in patients with fibrosis stage ≥2. There was no difference in SMI between groups. In the cohort assessed at baseline and 12 months later, transaminase activity and SMI decreased significantly, and the SF ratio increased over time. A multivariate analysis revealed the presence of the PNPLA3 G allele and an increase in SF ratio (odds ratio, 7.406) as predictive factors of ALT reduction >30% from baseline. CONCLUSIONS: Due to the high prevalence of obesity, we should consider both skeletal muscle mass and body fat mass in the diagnosis and treatment of NAFLD. The SF ratio could be a useful index in sarcopenic NAFLD.

Efficacy of Clutch Cutter for Standardizing Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matched Analysis.

BACKGROUND/AIMS: The purpose of this study was to evaluate the safety and efficacy of gastric endoscopic submucosal dissection (ESD) using the Clutch Cutter (CC), a scissor-type knife, compared with those of procedures using conventional devices. METHODS: This single-center retrospective study evaluated 237 patients with early gastric cancer: 83 who underwent ESD using the CC group and 154 who underwent ESD using the insulated-tip knife 2 (IT2 group). Clinicopathological features and technical outcomes were compared between the 2 groups using a propensity score-matched analysis. RESULTS: In 61 pairs of matched patients, there was no significant difference in R0 resection, perforation, or postoperative bleeding between the CC and IT2 groups. Comparisons between the 2 groups showed similar treatment outcomes for an expert endoscopist. Nevertheless, there were significant differences between the 2 groups for nonexperts in terms of self-completion (61.7 and 24.5%, respectively, p < 0.001), mean procedure times (45 and 61 min, respectively, p = 0.002), and mean numbers of intraoperative bleeding points and bleeding points requiring hemostatic forceps (3 and 0 vs. 8 and 3, respectively, p < 0.001). CONCLUSION: Better self-completion rates and shorter procedure times were noted for gastric ESD using the CC by nonexperts than for that using IT2, probably due to hemostatic efficacy.

FIB-4 Index and Diabetes Mellitus Are Associated with Chronic Kidney Disease in Japanese Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). The aim of this retrospective study was to determine the risk factors for progression of CKD in patients with biopsy-proven NAFLD including patatin-like phospholipase domain containing 3 (PNPLA3) polymorphism. A total of 344 patients with biopsy-proven NAFLD were enrolled consecutively in this study. Multivariate analysis identified males (odds ratio (OR) 5.46), age (per 1 year, OR 1.07), and FIB-4 index (≥1.30, OR 3.85) as factors associated with CKD. Of the 154 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min, 30 had a deterioration in CKD stage and 15 developed CKD after 3 years. Multivariate analysis identified diabetes mellitus (OR 2.44) as a risk factor for deterioration in CKD stage, while diabetes mellitus (OR 21.54) and baseline eGFR (per 1 mL/min OR 0.88) were risk factors for development of CKD. PNPLA3 did not affect the change in eGFR. In NAFLD patients, a high FIB-4 index was associated with CKD to increases in the index linked to reductions in eGFR. In order to prevent development of CKD, an appropriate therapy focusing on renal function is needed for NAFLD patients, especially those with diabetes.

Impact of Insufficient Response with an Increase in Tumor Number in Predicting Transcatheter Arterial Chemoembolization Refractoriness for Hepatocellular Carcinoma.

AIM: In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after ≥2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of > 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness. METHODS: Patients who underwent TACE for hepatocellular carcinomas > 3 cm in size or with > 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the "either" group, evaluated as either "ineffective" or "progressive," and the "both" group, that is, both "ineffective" and "progressive." RESULTS: The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (n = 23) and both (n = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (p = 0.0295). CONCLUSIONS: Patients with both "ineffective" and "progressive" lesions are extremely likely to be TACE -refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered.

A trans-species missense SNP in Amhr2 is associated with sex determination in the tiger pufferfish, Takifugu rubripes (fugu).

Heterogametic sex chromosomes have evolved independently in various lineages of vertebrates. Such sex chromosome pairs often contain nonrecombining regions, with one of the chromosomes harboring a master sex-determining (SD) gene. It is hypothesized that these sex chromosomes evolved from a pair of autosomes that diverged after acquiring the SD gene. By linkage and association mapping of the SD locus in fugu (Takifugu rubripes), we show that a SNP (C/G) in the anti-Müllerian hormone receptor type II (Amhr2) gene is the only polymorphism associated with phenotypic sex. This SNP changes an amino acid (His/Asp384) in the kinase domain. While females are homozygous (His/His384), males are heterozygous. Sex in fugu is most likely determined by a combination of the two alleles of Amhr2. Consistent with this model, the medaka hotei mutant carrying a substitution in the kinase domain of Amhr2 causes a female phenotype. The association of the Amhr2 SNP with phenotypic sex is conserved in two other species of Takifugu but not in Tetraodon. The fugu SD locus shows no sign of recombination suppression between X and Y chromosomes. Thus, fugu sex chromosomes represent an unusual example of proto-sex chromosomes. Such undifferentiated X-Y chromosomes may be more common in vertebrates than previously thought.

l-fucoside localization in the gills of the genus Takifugu and its possible implication in the parasitism of Heterobothrium okamotoi (Monogenea: Diclidophoridae).

BACKGROUND: The monogenean parasite Heterobothrium okamotoi only parasitizes the gills of Takifugu rubripes. In this study, we hypothesized that the carbohydrates contribute to high host specificity of H. okamotoi. METHODS: T. rubripes, T. niphobles, T. snyderi, and T. pardalis were used for UEA I staining of the gills and an in vivo challenge test against H. okamotoi. To examine the effect of l-fucose, an in vitro detachment test was conducted using the host's gills. Additionally, fucosylated proteins were isolated from the membrane proteins of T. niphobles gills. RESULTS: The location of l-fucoside and the infection dynamics in four species were correlated to some extent; H. okamotoi detached relatively quickly from T. niphobles possessing l-fucoside both on the surface of the gills and in certain types of cells, including mucus cells, but detached slowly from T. snyderi possessing l-fucoside in only certain types of cells, including mucus cells. Under the conditions examined, H. okamotoi exhibited minimal detachment from T. rubripes and T. pardalis, and l-fucoside was not detected. The significantly higher detachment rate of H. okamotoi from the host's gills incubated in l-fucose-containing medium compared with the controls suggests that l-fucose in the non-host gills induced detachment of H. okamotoi. Four fucosylated proteins, including mucin5AC-like, were identified as potential factors for the detachment of H. okamotoi. CONCLUSIONS: Fucosylated proteins covering the surface of non-host gills might contribute to H. okamotoi detachment. GENERAL SIGNIFICANCE: This research shows the possible involvement of oligosaccharides in the host specificity of monogenean parasites.

Genomic selection for heterobothriosis resistance concurrent with body size in the tiger pufferfish, Takifugu rubripes.

Parasite resistance traits in aquaculture species often have moderate heritability, indicating the potential for genetic improvements by selective breeding. However, parasite resistance is often synonymous with an undesirable negative correlation with body size. In this study, we first tested the feasibility of genomic selection (GS) on resistance to heterobothriosis, caused by the monogenean parasite Heterobothrium okamotoi, which leads to huge economic losses in aquaculture of the tiger pufferfish Takifugu rubripes. Then, using a simulation study, we tested the possibility of simultaneous improvement of parasite resistance, assessed by parasite counts on host fish (HC), and standard length (SL). Each trait showed moderate heritability (square-root transformed HC: h2 = 0.308 ± 0.123, S.E.; SL: h2 = 0.405 ± 0.131). The predictive abilities of genomic prediction among 12 models, including genomic Best Linear Unbiased Predictor (GBLUP), Bayesian regressions, and machine learning procedures, were also moderate for both transformed HC (0.248‒0.344) and SL (0.340‒0.481). These results confirmed the feasibility of GS for this trait. Although an undesirable genetic correlation was suggested between transformed HC and SL (rg = 0.228), the simulation study suggested the desired gains index can help achieve simultaneous genetic improvements in both traits.

The Association between the Platelet Count and Liver Volume in Compensated Cirrhosis Patients after the Eradication of Hepatitis C virus by Direct-acting Antivirals.

Objective Although most patients who obtain a sustained virological response (SVR) show an improved liver function, some show decreased platelet counts after the eradication of hepatitis C virus (HCV). The aim of this retrospective study was to clarify the association of the liver and spleen volumes with the platelet count after SVR achieved by direct-acting antiviral (DAA) treatment. Methods This study enrolled 36 consecutive patients treated by DAAs who obtained an SVR between September 2014 and December 2018. The liver and spleen volumes were derived from computed tomography scans obtained at pretreatment, SVR, and 48 weeks after SVR. No patient developed hepatocellular carcinoma during this study. Results Compared with pretreatment, the median aspartate aminotransferase, alanine aminotransferase, albumin serum levels, and platelet counts were significantly improved at SVR and 48 weeks after SVR. The liver/spleen volumes per body weight had decreased significantly from 22.5/4.2 mL/kg at baseline to 21.1/3.6 mL/kg at 48 weeks after SVR. The change in the liver volume was associated with the change in the platelet count, and the change in the spleen volume was negatively associated with the change in the serum albumin level. A multivariate analysis identified the change in the liver volume (≥95%, odds ratio 76.9, p=0.005) as the factor associated with improvement in the platelet count at 48 weeks after SVR. The patients with an increased liver volume at 48 weeks after SVR showed an increased platelet count. Conclusion Both the liver and spleen volume decreased significantly after the eradication of HCV. The patients with a re-increased liver volume showed a rapid increase in the platelet count.

Effect of Sodium Glucose Cotransporter 2 Inhibitors on Renal Function in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Japan.

Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been reported to have renal-protective effects in patients with type 2 diabetes (T2DM). This a retrospective study aimed to evaluate the effect of SGLT2I on renal function in patients with nonalcoholic fatty liver disease (NAFLD) and T2DM. We analyzed 69 consecutive patients with a biopsy-proven NAFLD and T2DM with an estimated glomerular filtration rate (eGFR) >60 mL/min. Of these 69 patients, 22 received SGLT2I and 47 were treated without SGLT2I. Liver function and eGFR were analyzed at baseline and after three years. Body mass index, liver function and HbA1c improved significantly in both groups. In the total population, the median eGFR declined from 80.7 mL/min at the baseline to 74.9 mL/min at the end of follow-up. The median eGFR at the baseline/end of follow-up was 81.2/80.4 mL/min in patients treated with SGLT2I and 80.2/70.8 mL/min in patients treated without SGLT2I. Multivariate analysis identified an increased FIB-4 index with an odds ratio (OR) of 4.721, (p = 0.045) and SGLT2I treatment (OR 0.263, p = 0.033) as predictive factors for decreased eGFR. SGLT2I treatment has a protective effect on the renal function for NAFLD with T2DM. A long-term, randomized, controlled trial is warranted to confirm the renal protective effect of SGLT2I in NAFLD patients with T2DM.

Increase in the skeletal muscle mass to body fat mass ratio predicts the decline in transaminase in patients with nonalcoholic fatty liver disease.

BACKGROUND: The aim of this retrospective study was to determine the effect of skeletal muscle and body fat on liver function in patients with nonalcoholic fatty liver disease (NAFLD) diagnosed by liver biopsy. METHODS: Among the 219 patients with NAFLD enrolled in this study was a cohort of 139 patients who had their body composition measured with Inbody720 at baseline and at ≥ 1 year postbaseline, to elucidate the relationship between liver function and changes in skeletal muscle and body fat mass. Multivariate analysis was used to identify factors influencing low skeletal muscle mass index (SMI, defined as 7 kg/m2 in men, and 5.7 kg/m2 in women) and the skeletal muscle mass to body fat mass ratio (SF ratio). RESULTS: Of the 219 patients enrolled, 27 (12.3%) had a low SMI. Patient age (> 70 years) and female gender were identified as risk factors for low SMI. Hepatic fibrosis was not associated with SMI. In the cohort followed up at baseline and 12 months later, transaminase activity, body fat mass, and SMI significantly decreased over time. Changes in the SF ratio were significantly associated with changes in liver function. An increase in the SF ratio [hazard ratio (HR) 10.99 in men, 6.849 in women] was a predictor of reduced ALT, independent of age and other backgrounds. CONCLUSIONS: In the patients with NAFLD, SMI was decreased, even in the early stages of NAFLD. Therapeutic strategies for NAFLD require a reduction in body fat mass and the maintenance of skeletal muscle is also needed.

A SNP in a Steroidogenic Enzyme Is Associated with Phenotypic Sex in Seriola Fishes.

Vertebrate sex development consists largely of two processes: "sex determination," the initial bifurcation of sexual identity, and "sex differentiation," which subsequently facilitates maleness or femaleness according to the sex determination signal. Steroid hormones promote multiple types of sexual dimorphism in eutherian mammals and avians [1-3], in which they are indispensable for proper sex differentiation. By contrast, in many poikilothermic vertebrates, steroid hormones have been proposed to be key players in sex determination as well as sex differentiation [4-8]. This hypothesis was introduced more than 50 years ago but has never been rigorously tested due to difficulties in discriminating the roles of steroids in sex determination and differentiation. We found that a missense SNP in the gene encoding the steroidogenic enzyme 17ß-hydroxysteroid dehydrogenase 1 (Hsd17b1) was perfectly associated with ZZ/ZW sex determination in Seriola fishes. Biochemical analyses revealed that a glutamate residue present specifically in Z-type HSD17B1 attenuated interconversion between 17-keto and 17ß-hydroxy steroids relative to the allelic product from the W chromosome, which harbors glycine at that position, by disrupting the hydrogen bond network between the steroid and the enzyme's catalytic residues. Hsd17b1 mRNA is constitutively expressed in undifferentiated and differentiating gonads of both genotypic sexes, whereas W-type mRNA is expressed only in genotypic females. Meanwhile, Cyp19a1 is predominantly expressed in differentiating ovary. We conclude that the combination of Hsd17b1 alleles determines sex by modulating endogenous estrogen levels in Seriola species. These findings strongly support the long-standing hypothesis on steroids in sex determination.

The sex-determining locus in the tiger pufferfish, Takifugu rubripes.

The tiger pufferfish (fugu), Takifugu rubripes, is a model fish that has had its genome entirely sequenced. By performing genomewide linkage analyses, we show that the sex of fugu is determined by a single chromosomal region on linkage group 19 in an XX-XY system.

Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease.

BACKGROUND: Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. METHODS: We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). RESULTS: The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis. CONCLUSIONS: In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.