Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia.

The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations.

An Early Increase in IL-10 and TNF-α Levels Following Atezolizumab Plus Bevacizumab Treatment Predicts Survival in Advanced Hepatocellular Carcinoma Patients: A Prospective Cohort Study.

Background/Objectives: Reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev) are still lacking. Cytokines, which play a crucial role in immune regulation and HCC progression, have potential as predictive markers, but data supporting their use are limited. This study aimed to evaluate the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. Methods: We prospectively enrolled 32 advanced HCC patients, collecting blood samples before the first and second Ate/Bev treatments. These samples were analyzed for IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels to assess changes post-treatment. The primary outcome was overall survival, with a secondary focus on progression-free survival (PFS) at 6 months. Results: The mean age of the participants was 64.2 years, with the majority being male (93.8%). Patients showing increased IL-10, IL-17, and TNF-α levels had significantly better survival (p < 0.05) and marginally improved PFS compared to those with decreased cytokine levels. Interestingly, a positive correlation was noted between changes in IL-10 and TNF-α levels (p = 0.009). Furthermore, a multivariable analysis revealed that increased levels of IL-10 and TNF-α were significant predictors of enhanced survival (hazard ratio, 0.07; 95% confidence interval, 0.01-0.46; p = 0.005). Conclusions: An early increases in IL-10 and TNF-α after Ate/Bev treatment may serve as effective biomarkers for clinical outcomes in advanced HCC patients.

Genome-wide association study of subfoveal choroidal thickness in a longitudinal cohort of older adults.

To identify genetic influences on subfoveal choroidal thickness of older adults using a genome-wide association study (GWAS). We recruited 300 participants from the population-based Korean Longitudinal Study on Health and Aging (KLoSHA) and Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort studies and 500 participants from the Bundang age-related macular degeneration (AMD) cohort study dataset. We conducted a GWAS on older adult populations in the KLoSHA and KLOSCAD cohorts. Single nucleotide polymorphisms (SNPs) associated with choroidal thickness were identified with P values < 1.0 × 10-4 in both the right and left eyes, followed by validation using the Bundang AMD cohort dataset. This association was further confirmed by a functional in vitro study using human umbilical vein endothelial cells (HUVECs). The ages of the cohort participants in the discovery and validation datasets were 73.5 ± 3.3 and 71.3 ± 7.9 years, respectively. In the discovery dataset, three SNPs (rs1916762, rs7587019, and rs13320098) were significantly associated with choroidal thickness in both eyes. This association was confirmed for rs1916762 (genotypes GG, GA, and AA) and rs7587019 (genotypes GG, GA, and AA), but not for rs13320098. The mean choroidal thickness decreased by 56.7 µm (AA, 73.8%) and 31.1 µm (GA, 85.6%) compared with that of the GG genotype of rs1916762, and by 55.4 µm (AA, 74.2%) and 28.2 µm (GA, 86.7%) compared with that of the GG genotype of rs7587019. The SNPs rs1916762 and rs7587019 were located close to the FAM124B gene near its cis-regulatory region. Moreover, FAM124B was highly expressed in vascular endothelial cells. In vitro HUVEC experiments showed that the inhibition of FAM124B was associated with decreased vascular endothelial proliferation, suggesting a potential mechanism of choroidal thinning. FAM124B was identified as a susceptibility gene affecting subfoveal choroidal thickness in older adults. This gene may be involved in mechanisms underlying retinal diseases associated with altered choroidal thickness, such as age-related macular degeneration.

Masticatory Function, Sex, and Risk of Dementia Among Older Adults: A Population-Based Cohort Study.

BACKGROUND: A decline in masticatory function may indicate brain dysfunction related to dementia, but the relationship between masticatory function and dementia risk remains unclear. This study aimed to investigate whether masticatory function is associated with the risk of cognitive decline and dementia. METHODS: Data were obtained from the nationwide prospective cohort study of randomly sampled community-dwelling Koreans aged ≥ 60 years. The 5,064 non-demented participants, whose number of chewing cycles per bite was assessed by clinical interview, were followed for 8 years with biennial assessments of cognitive performance and clinical diagnoses of all-cause dementia and Alzheimer's disease (AD). Structural brain magnetic resonance imaging was collected from a subset of cohort participants and their spouses for imaging analyses. RESULTS: Males who chewed ≥ 30 cycles/bite had faster decline in global cognition and memory function and were at higher risk for incident all-cause dementia (hazard ratio [HR], 2.91; 95% confidence interval [CI], 1.18-7.18) and AD (HR, 3.22; 95% CI, 1.14-9.11) compared to males with less than 10 cycles/bite. Additionally, increased chewing cycles in males were associated with reduced brain volume, particularly in regions involved in compensatory cognitive control of mastication. There was no significant association between chewing cycles and the risk of dementia or brain volume in females. CONCLUSION: Older men who frequently chew their meals could be considered a notable population at risk for dementia who should be carefully assessed for their cognitive trajectories.

Association of Compensatory Mechanisms in Prefrontal Cortex and Impaired Anatomical Correlates in Semantic Verbal Fluency: A Functional Near-Infrared Spectroscopy Study.

OBJECTIVE: Semantic verbal fluency (SVF) engages cognitive functions such as executive function, mental flexibility, and semantic memory. Left frontal and temporal lobes, particularly the left inferior frontal gyrus (IFG), are crucial for SVF. This study investigates SVF and associated neural processing in older adults with mild SVF impairment and the relationship between structural abnormalities in the left IFG and functional activation during SVF in those individuals. METHODS: Fifty-four elderly individuals with modest level of mild cognitive impairment whose global cognition were preserved to normal but exhibited mild SVF impairment were participated. Prefrontal oxyhemoglobin (HbO2) activation and frontal cortical thickness were collected from the participants using functional near-infrared spectroscopy (fNIRS) and brain MRI, respectively. We calculated the ß coefficient of HbO2 activation induced by tasks, and performed correlation analysis between SVF induced HbO2 activation and cortical thickness in frontal areas. RESULTS: We observed increased prefrontal activation during SVF task compared to the resting and control task. The activation distinct to SVF was identified in the midline superior and left superior prefrontal regions (p<0.05). Correlation analysis revealed an inverse relationship between SVF-specific activation and cortical thickness in the left IFG, particularly in pars triangularis (r(54)=-0.304, p=0.025). CONCLUSION: The study contributes to understanding the relationship between reduced cortical thickness in left IFG and increased functional activity in cognitively normal individuals with mild SVF impairment, providing implications on potential compensatory mechanisms for cognitive preservation.

Non-invasive prediction of post-sustained virological response hepatocellular carcinoma in hepatitis C virus: A systematic review and meta-analysis.

BACKGROUNDS/AIMS: Despite advances in antiviral therapy for hepatitis C virus (HCV) infection, hepatocellular carcinoma (HCC) still develops even after sustained viral response (SVR) in patients with advanced liver fibrosis or cirrhosis. This meta-analysis investigated the predictive performance of vibration-controlled transient elastography (VCTE) and fibrosis 4-index (FIB-4) for the development of HCC after SVR. METHODS: We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library for studies examining the predictive performance of these tests in adult patients with HCV. Two authors independently screened the studies' methodological quality and extracted data. Pooled estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for HCC development using random-effects bivariate logit normal and linear-mixed effect models. RESULTS: We included 27 studies (169,911 patients). Meta-analysis of HCC after SVR was possible in nine VCTE and 15 FIB-4 studies. Regarding the prediction of HCC development after SVR, the pooled AUCs of pre-treatment VCTE >9.2-13 kPa and FIB-4 >3.25 were 0.79 and 0.73, respectively. VCTE >8.4-11 kPa and FIB-4 >3.25 measured after SVR maintained good predictive performance, albeit slightly reduced (pooled AUCs: 0.77 and 0.70, respectively). The identified optimal cut-off value for HCC development after SVR was 12.6 kPa for pre-treatment VCTE. That of VCTE measured after the SVR was 11.2 kPa. CONCLUSION: VCTE and FIB-4 showed acceptable predictive performance for HCC development in patients with HCV who achieved SVR, underscoring their utility in clinical practice for guiding surveillance strategies. Future studies are needed to validate these findings prospectively and validate their clinical impact.

Diagnostic accuracy of vibration-controlled transient elastography for staging liver fibrosis in autoimmune liver diseases: A systematic review and meta-analysis.

BACKGROUND/AIMS: The assessment of liver fibrosis is crucial for managing autoimmune liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). However, data on the efficacy of noninvasive tests for these diseases are limited. This meta-analysis evaluated the diagnostic accuracy of vibration-controlled transient elastography (VCTE) for staging fibrosis in patients with autoimmune liver disease. METHODS: Searches were conducted in PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases to assess the diagnostic accuracy of VCTE against histology as the reference standard in adult patients with autoimmune liver disease. The summary area under the curve (sAUC) and diagnostic odds ratio were calculated for significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis, according to liver biopsy. RESULTS: Fourteen articles were included, comprising 559 PBC patients from six studies, 388 AIH patients from five studies, and 151 PSC patients from three studies. VCTE demonstrated good performance for fibrosis staging in PBC, AIH, and PSC. In PBC, sAUCs of VCTE were 0.87, 0.89, and 0.99 for staging SF, AF, and cirrhosis, respectively. In AIH, the sAUCs were 0.88, 0.88, and 0.92, respectively, while in PSC, they were 0.88, 0.95, and 0.92, respectively. The cutoff values for AF were 7.5-17.9 kPa in PBC, 8.18-12.1 kPa in AIH, and 9.6 kPa in PSC. CONCLUSION: VCTE shows high diagnostic accuracy for staging liver fibrosis in patients with autoimmune liver diseases. This non-invasive method serves as a valuable tool for the evaluation and monitoring of fibrosis in these lifelong diseases.

Evolving trends in treatment patterns for hepatocellular carcinoma in Korea from 2008 to 2022: a nationwide population-based study.

BACKGROUNDS/AIMS: The treatment landscape for hepatocellular carcinoma (HCC) has significantly evolved over the past decade. We aimed to analyze trends in treatment patterns for HCC using a nationwide claims database from the Korean Health Insurance Review and Assessment Service. METHODS: This retrospective population-based cohort study analyzed 171,002 newly diagnosed HCC patients between 2008 and 2022. Etiologies and treatment modalities were categorized based on the ICD-10 codes and insurance data. RESULTS: The annual incidence decreased from 11,814 in 2008 to 10,443 in 2022. However, patients aged ≥70 increased noticeably, with those aged ≥80 rising from 3.8% in 2008 to 13.1% in 2022. From 2008 to 2022, the predominant cause of hepatitis B virus decreased from 68.9% to 59.7%, whereas nonalcoholic fatty liver disease increased from 8.9% to 15.8%. The initial treatment trends shifted: surgical resection and systemic therapy increased from 12.2% to 21.3% and from 0.2% to 9.6%, whereas transarterial therapy decreased from 49.9% to 36.6%. Best supportive care decreased from 31.7% to 21.3%. In the subgroup analysis, laparoscopic resection rate increased from 10.6% to 60.6% among the surgical resections. Sorafenib initially accounted for 100%, lenvatinib peaked at 36.5% in 2021, and atezolizumab-bevacizumab became the most widely used (63.1%) by 2022 among the systemic therapies. CONCLUSIONS: This study demonstrates the temporal changes in the treatment patterns of Korean HCC patients. Surgical resection, particularly laparoscopic liver resection, and systemic therapy has increased significantly. These changes may have been influenced by reimbursement policies and advances in clinical research.

Assessment of the postoperative prognosis in patients with hepatocellular carcinoma using vibration-controlled transient elastography: A systemic review and meta-analysis.

BACKGROUNDS/AIMS: This meta-analysis examined whether preoperative vibration-controlled transient elastography (VCTE) can predict postoperative complications and recurrence in patients undergoing hepatic resection for hepatocellular carcinoma (HCC). METHODS: A systematic literature search was conducted using Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases. Out of 431 individual studies, thirteen published between 2008 and 2022 were included. Five studies focused on HCC recurrence, while eight examined postoperative complications. RESULTS: The meta-analysis of five studies on HCC recurrence showed that the high-risk group with a high VCTE score had a significantly increased recurrence rate after hepatic resection (hazard ratio 2.14). The cutoff value of VCTE in the high-risk group of HCC recurrence was 7.4-13.4 kPa, the sensitivity was 0.60 (95% confidence interval [CI] 0.47-0.72), and the specificity was 0.60 (95% CI 0.46-0.72). The area under the receiver operating characteristic curve (AUC) of the liver stiffness measured by VCTE to predict the HCC recurrence was 0.63 (95% CI 0.59-0.67). The meta-analysis on the postoperative complications revealed a significantly increased risk of postoperative complications in the high-risk group (12-25.6 kPa) with a high VCTE value (odds ratio [OR], 8.32). The AUC of the liver stiffness measured by VCTE to predict the postoperative complications was 0.87 (95% CI 0.84-0.90), the sensitivity was 0.76 (95% CI 0.55-0.89) and the specificity was 0.85 (95% CI 0.73-0.92). CONCLUSION: This meta-analysis suggests that preoperative VCTE in patients undergoing hepatic resection for HCC is useful in identifying individuals at a high risk of postoperative complications and HCC recurrence.

Optimal cut-offs of vibration-controlled transient elastography and magnetic resonance elastography in diagnosing advanced liver fibrosis in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND/AIMS: Opinions differ regarding vibration-controlled transient elastography and magnetic resonance elastography (VCTE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of VCTE and MRE for diagnosing AF. METHODS: Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating VCTE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for VCTE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated. RESULTS: A total of 19,199 patients from 63 studies using VCTE showed diagnostic AUC of 0.83 (95% confidence interval: 0.80-0.86), 0.83 (0.80-0.86), 0.87 (0.84-0.90), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89 (0.86-0.92), 0.92 (0.89-0.94), 0.89 (0.86-0.92), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. The diagnostic AUC for AF using VCTE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa. CONCLUSION: VCTE (7.1-7.9 kPa) and MRE (3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

LONGITUDINAL CHANGE OF RETINAL LAYER THICKNESS IN COGNITIVELY NORMAL ELDERLY SUBJECTS: Population-Based Cohort Study.

PURPOSE: To identify longitudinal retinal layer thickness changes in normal eyes of cognitively healthy elderly people. METHODS: Post hoc analysis was performed on 57 cognitively healthy elderly participants from the population-based Korean Longitudinal Study on Health and Aging and Korean Longitudinal Study on Cognitive Aging and Dementia cohort studies who underwent baseline and final optical coherence tomography scans. The peripapillary retinal nerve fiber layer, subfoveal choroid, and average retinal layer thickness at four quadrant (nasal, temporal, superior, and inferior) points 1 mm, 2 mm, and 3 mm from the center of the fovea were measured. RESULTS: The mean age of subjects was 75.1 years and the mean follow-up period was 55.9 months. Among the analyzed retinal layers, both the ganglion cell-inner plexiform layer and the outer nuclear layer at all 1 mm, 2 mm, and 3 mm points showed a statistically significant decrease in thickness at the final visit compared with baseline. The annual decrease rates were -1.2 µm/year at 1 mm (total -6.6%), -1.3 µm/year at 2 mm (total -8.4%), and -1.1 µm/year at 3 mm (total -9.7%) for ganglion cell-inner plexiform layer and -0.6 µm/year at 1 mm (total -4.2%), -0.5 µm/year at 2 mm (total -3.9%), and -0.4 µm/year at 3 mm (total -4.1%) for outer nuclear layer. CONCLUSION: Aging plays a significant role in the reduction of ganglion cell-inner plexiform layer and outer nuclear layer thicknesses in cognitively healthy elderly individuals.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study.

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

The Impact of Histologic Portal T-Cell Density on the Clinical Outcomes in Hepatic Graft-versus-Host Disease and Autoimmune Liver Diseases.

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8-12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3+ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20+, CD38+, or CD68+ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

Blood Pressure, Antihypertensive Use, and Late-Life Alzheimer and Non-Alzheimer Dementia Risk: An Individual Participant Data Meta-Analysis.

BACKGROUND AND OBJECTIVES: Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies. METHODS: This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age2, sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group. RESULTS: There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship (p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk. DISCUSSION: Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using vibration-controlled transient elastography: Systematic review and meta-analysis.

BACKGROUNDS/AIMS: Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using VCTE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. METHODS: A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used VCTE were finally registered. Hazard ratios (HRs) and the 95% confidence intervals (CIs) were considered summary estimates of treatment effect sizes of ≥11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model. RESULTS: Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45-4.54) in CHB patients with a baseline LSM of ≥11 kPa compared to patients who did not. In ten studies included, LSM of ≥11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50-71%) and 78% (95% CI, 66-86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70-0.77). CONCLUSION: The risk of HCC development was elevated in CHB patients with VCTE-determined LSM of ≥11 kPa. This finding suggests that VCTE-determined LSM values may aid the risk prediction of HCC development in CHB patients.

Vibration-controlled transient elastography for significant fibrosis in treatment-naïve chronic hepatitis B patients: A systematic review and meta-analysis.

BACKGROUNDS/AIMS: Accurate diagnosis of significant liver fibrosis in patients with chronic hepatitis B (CHB) is crucial when determining whether to initiate antiviral treatment (AVT). We conduct a meta-analysis to assess the diagnostic performance of vibration-controlled transient elastography (VCTE) for significant liver fibrosis in AVT-naïve CHB patients with serum alanine transaminase (ALT) levels within 5-fold the upper limit of normal (ULN). METHODS: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched to identify studies that compared the performance of VCTE and liver biopsy (reference standard) when diagnosing significant liver fibrosis (≥F2) in AVT-naïve CHB patients with ALT within 5-fold the ULN. A hierarchical summary receiver operating characteristic curve (HSROC) and bivariate model were performed to evaluate the diagnostic performance of VCTE in the meta-analysis. RESULTS: Eight studies (2,003 patients) were included. The summary sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 (95% confidence interval [CI], 0.66-0.86) and 0.72 (95% CI, 0.60-0.82), respectively. The HSROC for the diagnosis of significant liver fibrosis was 0.81 (95% CI, 0.72-0.86). The optimal cutoff value of VCTE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 (95% CI, 0.50-0.76) and specificity of 0.83 (95% CI, 0.72-0.90). CONCLUSION: Our study demonstrated that VCTE has an acceptable diagnostic performance for significant liver fibrosis in AVT-naïve CHB patients with ALT within 5-fold the ULN.

Prevalence of clinically significant liver fibrosis in the general population: A systematic review and meta-analysis.

BACKGROUND/AIMS: Although important, clinically significant liver fibrosis is often overlooked in the general population. We aimed to examine the prevalence of clinically significant liver fibrosis using noninvasive tests (NITs) in the general population. METHODS: We collected data from four databases (MEDLINE, Embase, Cochrane Library, and KoreaMed) from inception to June 13, 2023. Original articles reporting the prevalence of clinically significant liver fibrosis in the general population were included. The Stata metaprop function was used to obtain the pooled prevalence of liver fibrosis with NITs in the general population. RESULTS: We screened 6,429 articles and included 45 eligible studies that reported the prevalence of clinically significant liver fibrosis in the general population. The prevalence of advanced liver fibrosis, using the high probability cutoff of the fibrosis-4 (FIB-4) index, was 2.3% (95% confidence interval [CI], 1.2-3.7%). The prevalence of significant liver fibrosis, advanced liver fibrosis, and liver cirrhosis, assessed using vibration-controlled transient elastography (VCTE) among the general population, was 7.3% (95% CI, 5.9-8.8%), 3.5% (95% CI, 2.7-4.5), and 1.2% (95% CI, 0.8-1.8%), respectively. Region-based subgroup analysis revealed that the highest prevalence of advanced fibrosis using the high probability cutoff of the FIB-4 index was observed in the American region. Furthermore, the American region exhibited the highest prevalence of significant liver fibrosis, advanced liver fibrosis, and liver cirrhosis, using VCTE. CONCLUSION: Previously undiagnosed clinically significant liver fibrosis is found in the general population through NITs. Future research is necessary to stratify the risk in the general population.

Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg.

BACKGROUND AND AIMS: Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. METHODS: This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. RESULTS: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. CONCLUSIONS: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.

RECIST 1.1, mRECIST, and Choi criteria for evaluating treatment response and survival outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab.

OBJECTIVES: We aimed to compare the early responder rates, defined as complete or partial responders, using response evaluation criteria in solid tumors (RECIST) 1.1, modified RECIST (mRECIST), and Choi criteria in advanced HCC patients treated with atezolizumab-bevacizumab (atezo-bev), and to correlate them with progression-free survival (PFS) and overall survival (OS). METHODS: This retrospective study included advanced HCC patients treated with ≥ 3 cycles of atezo-bev. Two reviewers assessed responses using RECIST 1.1, mRECIST, and Choi criteria at 1st follow-up imaging. Kaplan-Meier curves with log-rank tests evaluated and compared PFS and OS. Cox proportional hazard models identified survival outcome predictors. Kappa statistics assessed inter-reader agreement. RESULTS: We evaluated 77 patients (65 men; mean age, 62.8 ± 12.3 years). Choi's criteria revealed the highest early responders rate (53.2%), exceeding mRECIST (32.5-33.8%) and RECIST 1.1 (24.7-26.0%), with an excellent agreement in all criteria (κ, 0.85-0.95). Across criteria, a consistent number of patients progressed (23-26) and was associated with significantly poor OS (ps ≤ 0.049). Responders by any criteria showed longer PFS (ps ≤ 0.009), and 1-year OS (ps ≤ 0.01). Choi criteria linked to significantly better OS without landmark (p = 0.003), with 1-year OS rates at 76.9% for responders vs 38.1% for non-responders. Cox analysis identified responders by Choi criteria as a significant OS predictor. CONCLUSION: Choi criteria identified more early responders than RECIST 1.1 and mRECIST, significantly correlating with improved OS. Choi criteria could be considered as a formal response assessment criterion for the emerging atezo-bev systemic treatment. CLINICAL RELEVANCE STATEMENT: For atezo-bev treatment of advanced HCC, more comprehensive response criteria, such as Choi criteria, could be effective in identifying early responders and predicting survival outcomes along with RECIST 1.1 and mRECIST. KEY POINTS: Choi criteria identified a higher rate of early responders compared to mRECIST and RECIST1.1 following atezo-bev treatment. Responders by all criteria had longer PFS and 1-year OS, and only those by Choi criteria experienced longer OS without landmark time. Choi criteria, with RECIST 1.1 and mRECIST, is an effective response assessment tool for atezo-bev treatment.