Modified multi-Rayleigh model-based statistical analysis of ultrasound envelope for quantification of liver steatosis and fibrosis.

PURPOSE: Quantitative diagnosis of the degree of fibrosis progression is currently a focus of attention for fatty liver in nonalcoholic steatohepatitis (NASH). However, previous studies have focused on either lipid droplets or fibrotic tissue, and few have reported the evaluation of both in patients whose livers contain adipose and fibrous features. Our aim was to evaluate fibrosis tissue and lipid droplets in the liver. METHODS: We used an analytical method combining the multi-Rayleigh (MRA) model and a healthy liver structure filter (HLSF) as a technique for statistical analysis of the amplitude envelope to estimate fat and fibrotic volumes in clinical datasets with different degrees of fat and fibrosis progression. RESULTS: Fat mass was estimated based on the non-MRA fraction corresponding to the signal characteristics of aggregated lipid droplets. Non-MRA fraction has a positive correlation with fat mass and is effective for detecting moderate and severe fatty livers. Progression of fibrosis was estimated using MRA parameters in combination with the HLSF. The proposed method was used to extract non-healthy areas with characteristics of fibrotic tissue. Fibrosis in early fatty liver suggested the possibility of evaluation. On the other hand, fat was identified as a factor that reduced the accuracy of estimating fibrosis progression in moderate and severe fatty livers. CONCLUSION: The proposed method was used to simultaneously evaluate fat mass and fibrosis progression in early fatty liver, suggesting the possibility of quantitative evaluation for discriminating between lipid droplets and fibrous tissue in the early fatty liver.

Use of albumin infusion for cirrhosis-related complications: An international position statement.

Background & Aims: Numerous studies have evaluated the role of human albumin (HA) in managing various liver cirrhosis-related complications. However, their conclusions remain partially controversial, probably because HA was evaluated in different settings, including indications, patient characteristics, and dosage and duration of therapy. Methods: Thirty-three investigators from 19 countries with expertise in the management of liver cirrhosis-related complications were invited to organise an International Special Interest Group. A three-round Delphi consensus process was conducted to complete the international position statement on the use of HA for treatment of liver cirrhosis-related complications. Results: Twelve clinically significant position statements were proposed. Short-term infusion of HA should be recommended for the management of hepatorenal syndrome, large volume paracentesis, and spontaneous bacterial peritonitis in liver cirrhosis. Its effects on the prevention or treatment of other liver cirrhosis-related complications should be further elucidated. Long-term HA administration can be considered in specific settings. Pulmonary oedema should be closely monitored as a potential adverse effect in cirrhotic patients receiving HA infusion. Conclusions: Based on the currently available evidence, the international position statement suggests the potential benefits of HA for the management of multiple liver cirrhosis-related complications and summarises its safety profile. However, its optimal timing and infusion strategy remain to be further elucidated. Impact and implications: Thirty-three investigators from 19 countries proposed 12 position statements on the use of human albumin (HA) infusion in liver cirrhosis-related complications. Based on current evidence, short-term HA infusion should be recommended for the management of HRS, LVP, and SBP; whereas, long-term HA administration can be considered in the setting where budget and logistical issues can be resolved. However, pulmonary oedema should be closely monitored in cirrhotic patients who receive HA infusion.

Effects of Diamond Steps Exercises on Balance Improvement in Healthy Young and Older Adults: A Protocol Proposal.

Diamond step (DS) exercises are associated with multiple components of postural control and, thus, have the potential to efficiently improve balance ability. This study aimed to verify whether DS exercises contribute to improving balance ability. This study included 35 healthy young people and 29 older adults. DS exercises were performed continuously for 3 min, four times a week, for 1 month. Balance ability was assessed at baseline and after 1 and 2 months; eight items in total were examined: 30 s chair stand test, functional reach test, standing on one leg with eyes closed, time required for five rounds of DS, left-right DS, Y balance test, open-close stepping test, and finger-to-floor distance. The difficulty, achievement, and lightness/enjoyment of DS exercises were measured after the first practice and 1 month after beginning the exercises as subjective evaluations. Older adults showed improvement in seven of the eight items, with the exception being the one-legged stance with closed eyes. The subjective evaluation showed a decrease in the level of difficulty of DS exercises for older adults. DS exercises may improve balance by effectively utilizing various postural control strategies. These exercises can be effective and easy to implement, given their moderate difficulty level and self-efficacy.

The Impact of Partial Splenic Embolization on Portal Hypertensive Gastropathy in Cirrhotic Patients with Portal Hypertension.

This study investigated the impact of partial splenic embolization (PSE) on portal hypertensive gastropathy (PHG). We retrospectively analyzed endoscopic findings and the portal venous system of 31 cirrhotic patients with PHG. The improved group was defined as the amelioration of PHG findings using the McCormack classification. Child-Pugh scores of the improved group (18 of 31 patients) were significantly lower compared with those of the non-improved group (p = 0.018). The changes in the diameters of the portal trunk and those of the spleno-portal junction and spleen hilum in the splenic vein of the improved group were significantly larger than those of the non-improved group (p = 0.007, p = 0.025, and p = 0.003, respectively). The changes in the diameters of the portal vein and splenic hilum of the splenic vein showed significant correlations with Child-Pugh score (r = 0.386, p = 0.039; r = 0.510, p = 0.004). In a multivariate analysis of baseline factors related to the improved group, Child-Pugh grade A was significantly associated with the improvement of PHG (odds ratio 6.875, p = 0.033). PSE could be useful for PHG, especially in patients with Child-Pugh grade A, at least in the short term.

Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors.

BACKGROUND/AIM: MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed. MATERIALS AND METHODS: To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells. RESULTS: CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells. CONCLUSION: CCL347 has potential as a novel therapeutic drug for HCC.

Body mass index combined with (waist + hip)/height accurately screened for normal-weight obesity in Chinese young adults.

OBJECTIVES: Only a few studies have explored the prevalence of normal-weight obesity in young adults or the development of a simple evaluation index for body fat percentage. Therefore, this study aimed to examine the prevalence of normal-weight obesity in young Chinese adults and use anthropometric measurements to develop an evaluation index. METHODS: In total, 1322 college students participated in the study and were divided into the normal-weight lean, normal-weight obese, and overweight and obese groups based on their body mass index and body fat percentage. The differences in body composition, circumference, and circumference ratio among these three groups were examined. RESULTS: When exploring the correlation between the circumference ratio and body fat percentage, the circumference ratio was suitable for early screening of abnormal body fat percentage, and the cutoff value was calculated. Body composition and circumference were significantly different among the three groups: (waist + hip)-to-height, hip-to-height, and waist-to-height ratios were strongly correlated with body fat percentage. CONCLUSIONS: (Waist + hip)-to-height ratio can be used as a simple evaluation index for indicating abnormal body fat percentage when higher than 1.032 in male and 1.047 in female individuals. Downregulating the normal upper limit for body mass index to 24.4 and 23.8 kg/m2 in male and female individuals, respectively, is recommended. Body mass index combined with (waist + hip)-to-height ratio allowed for more accurate screening of normal-weight obesity as an easy and cost-free evaluation measure for abnormal body fat percentage.

Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-ß/Smad pathway suppression in hepatic stellate cells.

Transforming growth factor (TGF)-ß/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-ß/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-ß/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-ß and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-ß-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-ß/Smad pathway.

Ablation for Benign Liver Tumors: Current Concepts and Limitations.

Percutaneous ablation under imaging guidance is a curative treatment that can induce complete tumor necrosis with advantages of minimal invasiveness and a low risk of complications. Thermal ablation, which includes radiofrequency ablation and microwave ablation, is a representative technique that has sufficient antitumor effects in cases of hepatocellular carcinoma with ≤3 lesions measuring ≤3 cm and preserved liver function. The short- and long-term outcomes of patients are comparable with those achieved with surgical resection. Despite their nonmalignant nature, some benign liver tumors require treatment for symptoms caused by the presence of the tumor and/or continuous enlargement. Ablation may be the treatment of choice because it has lower burden on patients than surgical treatment. This review describes the recent concepts, progress, and limitations of ablation-based treatment for benign liver tumors.

The RNA-Binding Protein ELAVL1 Regulates Hepatitis B Virus Replication and Growth of Hepatocellular Carcinoma Cells.

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.

Diagnostic accuracy of transient elastography in diagnosing clinically significant portal hypertension in patients with chronic liver disease: a systematic review and meta-analysis.

PURPOSE: Liver stiffness measurement using transient elastography (TE-LSM) is a promising noninvasive alternative to hepatic venous pressure gradient (HVPG) for diagnosing clinically significant portal hypertension (CSPH). However, previous studies have yielded conflicting results. We evaluated the correlation between TE-LSM and HVPG and the performance of TE-LSM in diagnosing CSPH (HVPG ≥ 10 mmHg). METHODS: We conducted a systematic review and meta-analysis by searching PubMed and Scopus databases for relevant literature evaluating the clinical usefulness of TE for diagnosing CSPH in patients with chronic liver disease. RESULTS: Twenty-six studies (4337 patients with valid TE and HVPG) met our inclusion criteria. The median correlation coefficient of TE with HVPG was 0.70 (range 0.36-0.86). The weighted mean of optimal cut-off of liver stiffness value for diagnosing CSPH was 22.8 kPa (95% CI 22.7-23.0 kPa). The summary sensitivity and specificity were 79% (95% CI 74-84%) and 88% (95% CI 84-91%), respectively. The area under the hierarchical summary receiver operating characteristic (HSROC) curve was 0.91 (95% CI 0.88-0.93) according to the bivariate model. One limitation of the study was significant heterogeneity in the results of summary sensitivity and specificity (I2 83 and 74%, respectively). The heterogeneity could be explained by the variable liver stiffness cut-offs used in studies. The meta-regression plot revealed that as the optimal cut-off increased, the sensitivity decreased, the specificity increased, and vice versa. CONCLUSIONS: Liver stiffness measurement using TE correlates well with HVPG, and a liver stiffness cut-off value of 22.8 kPa shows a high accuracy for diagnosing CSPH. Thus, use of TE should be integrated into clinical practice for noninvasive diagnosis of CSPH.

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring CTNNB1 Mutation in Early Clinical Experience.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1. These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

The Efficacy of Expiratory Muscle Training during Inspiratory Load in Healthy Adult Males: A Randomized Controlled Trial.

This study aimed to evaluate the effects of expiratory muscle training (EMT) on respiratory muscle strength and respiratory distress during inspiratory load. Thirty-one healthy adult males were randomly divided into an EMT group who underwent EMT (n = 15) and a control group who did not undergo EMT (n = 16). The EMT group underwent EMT with a 50% load of maximum expiratory mouth pressure (PEmax) for 15 min, twice a day, every day, for 4 weeks. The parameter of respiratory muscle fatigue was a decrease in maximum inspiratory mouth pressure (PImax) and PEmax during 20 min of inspiratory load; thus, PImax and PEmax during inspiratory load were measured. Respiratory distress during inspiratory load was assessed using the Borg scale. These assessments were performed on the same subjects in each group before and after the 4 week study. In the EMT group, the PEmax values after the study were significantly higher than those before the study (p < 0.01). Furthermore, before the study, the PImax and PEmax values for the EMT group during inspiratory load were significantly lower than those before inspiratory load (p < 0.01). However, after the study, there was no difference in these values between during and before inspiratory load. In the EMT group, the Borg scale value during inspiratory load from 6 to 20 min was significantly lower after the study than before the study (p < 0.05). EMT increases expiratory muscle strength, thereby attenuating decreased respiratory muscle strength (PImax and PEmax) and respiratory distress during inspiratory load in healthy subjects.

Body Fat Percentage and Normal-Weight Obesity in the Chinese Population: Development of a Simple Evaluation Indicator Using Anthropometric Measurements.

Few studies explore the associations between body fat percentage (BFP) prediction and evaluation indicators for Chinese with normal-weight obesity. We aimed to explore convenient and cost-free BFP evaluation indicators to routinely monitor BFP status in Chinese patients with normal-weight obesity. Participants (N = 164) were divided into three groups according to body mass index (BMI) and BFP: normal-weight lean, normal-weight obese, and overweight and obese. Differences in body composition and circumference were compared to examine the relationship between BFP and circumference, determine a simple evaluation indicator reflecting BFP, and identify cutoff values for normal-weight obesity circumference. Significant differences in body composition and circumference were observed among the three groups. The correlation between thigh/height, hip/height, (hip + waist)/height, and BFP was stronger than that with BMI. The (hip + waist)/height ratio was the indicator most reflective of BFP (95% confidence interval: 3.004−9.018, p = 0.013), and a ratio above 1.115 (95% confidence interval: 0.936−0.992, p < 0.001) was predictive of normal-weight obesity. Furthermore, we suggest that the upper value for a normal BMI in Chinese individuals be lowered to 23.4 kg/m2 (95% confidence interval: 0.984−0.999, p < 0.001). The (hip + waist)/height ratio can be used with body mass index for a more accurate evaluations of BFP abnormalities and health risks.

Immediate effects of neuromuscular joint-facilitation bridging exercises on walking ability and balance function in stroke patients.

[Purpose] This study aimed to examine the immediate effects of a pelvic neuromuscular joint-facilitation intervention on the walking and balance ability of patients with hemiplegia caused by cerebrovascular accidents. [Participants and Methods] A total of 15 patients with hemiplegia caused by cerebrovascular accidents underwent a neuromuscular joint-facilitation lumbar-pattern intervention (intervention group), a bridge exercise (bridge intervention group), or a neuromuscular joint-facilitation bridge intervention (neuromuscular joint-facilitation bridge group). Each intervention was randomly administered at 7-day intervals. Measurement items included the timed up-and-go test, functional reach test, 10-m maximum walking speed test, and load in the standing position. Measurements were taken before and after the intervention in each group. [Results] The timed up-and-go test result was significantly shorter in the neuromuscular joint-facilitation intervention group. Timed up-and-go test results, functional reach, 10-m walking time, and standing load (non-paralyzed side) significantly improved in the neuromuscular joint-facilitation bridge group. [Conclusion] The neuromuscular joint-facilitation bridge intervention was immediately effective in patients with hemiplegia caused by cerebrovascular accidents and improved their walking and balance ability.

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

The reliability and effectiveness of shoulder joint evaluation by ultrasonography in stroke patients: deltoid muscle thickness, acromion-humeral distance, acromion-lesser tuberosity distance.

[Purpose] This study aimed to evaluate the reliability of the intraclass correlation coefficient (ICC) in measuring deltoid muscle thickness (DMT) at different angles, acromion-humeral distance (AHD), and acromion nodule tuberosity (ALT) distance in a resting position in stroke patients using ultrasonography. [Participants and Methods] We included 40 stroke patients. During the measurement of parameters by ultrasonography, we measured the deltoid muscle thickness on both sides at three test angles (0°, 30°, and 60° abduction) and AHD and ALT on both sides at 0° angle. The ICC was used to assess intra- and interrater reliability. The relationship between the hemiplegic and non-hemiplegic sides and each angle were analyzed using a two-way repeated-measure analysis of variance (ANOVA). [Results] When the shoulders were at three testing angles (0°, 30°, and 60° abduction), the deltoid muscle thickness of the hemiplegic and non-hemiplegic sides showed good reliability; the AHD and ALT of the shoulder joint at 0° angle equally showed good reliability. There was a significant difference in each abduction angle of the shoulder joint between the thickness of the hemiplegic and non-hemiplegic deltoid. [Conclusion] Measuring deltoid muscle thickness by ultrasonography showed excellent reliability and can be used in stroke patients.

Evaluation of supraspinatus muscle changes in the shoulder joint of stroke patients with hemiplegic and shoulder subluxation using ultrasonography: comparison between affected and unaffected sides.

[Purpose] The shoulder joint has a very unstable structure yet a significantly wide range of motion. Weakness of the muscles around the shoulder joint may cause shoulder joint subluxation. This study aimed to determine changes in supraspinatus muscle thickness between different shoulder abduction angles using ultrasonography and to compare differences in supraspinatus muscle thickness changes between the affected and unaffected sides depending on shoulder joint subluxation. [Participants and Methods] Forty hemiplegic patients with stroke were recruited (20 patients with and 20 without shoulder subluxation). Using ultrasonography, we measured supraspinatus muscle thickness at three shoulder joint abduction angles and calculated the differences in supraspinatus muscle thickness. Depending on subluxation, we separately analyzed the thickness and variations in the supraspinatus muscle on both the affected and unaffected sides. [Results] In stroke patients with shoulder subluxation, the difference in supraspinatus muscle thickness was significantly less in the affected side than in the unaffected side. [Conclusion] The thickness and rate of supraspinatus muscle thickness change was significantly less in the affected side than in the unaffected side in stroke patients with shoulder subluxation.