Optic nerve head factors associated with initial central visual field defect in primary open-angle glaucoma.

We investigated optic nerve head factors associated with initial parafoveal scotoma (IPFS) in primary open-angle glaucoma. Eighty (80) patients with an IPFS and 84 patients with an initial nasal step (INS) were compared. Central retinal vascular trunk (CRVT) deviation from the Bruch's membrane opening (BMO) center was measured as a surrogate of lamina cribrosa (LC)/BMO offset, and its obliqueness was defined as the absolute value of angular deviation from the fovea-BMO axis. Proximity of retinal nerve fiber layer defect (RNFLD) was defined as the angular deviation of the inner RNFLD margin from the fovea-BMO axis. Microvasculature dropout (MvD) was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, as compared with INS, were assessed using logistic regression analyses and conditional inference tree analysis. The IPFS group had more oblique CRVT offset (P < 0.001), RNFLD closer to the fovea (P < 0.001), more MvD (P < 0.001), and more LC defects (P < 0.001) compared to the INS group. In logistic regression analyses, obliqueness of CRVT offset (P = 0.002), RNFLD proximity (P < 0.001), and MvD (P = 0.001) were significant factors influencing the presence of IPFS. Conditional inference tree analysis showed that RNFLD closer to the fovea (P < 0.001) in the upper level, more oblique CRVT offset (P = 0.013) and presence of MvD (P = 0.001) in the lower level were associated with the probability of having IPFS. IPFS was associated with closer RNFLD location to the fovea when assessed from the BMO. Oblique LC/BMO offset may not only mask RNFLD proximity to the fovea due to a deviated funduscopic disc appearance, but also potentiate IPFS via focal LC defect and MvD.

A refined prediction model for survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.

Background/Aims: Transarterial chemoembolization (TACE) is widely performed as a major treatment for hepatocellular carcinoma (HCC) patients, and there is a need to stratify patients for whom the most benefit from the treatment. This study aimed to develop a refined prediction model for overall survival (OS) in patients undergoing TACE as a first-line treatment in a large cohort and validate its performance. Methods: A total of 2,632 patients with HCC of Barcelona Clinic Liver Cancer stage A or B who underwent TACE between 2008 and 2017 were enrolled. The patients were randomly assigned to a training cohort (n = 1,304) or a validation cohort (n = 1,328). Independent predictors of OS were used to develop a prediction model. Results: The median age of patients in the entire cohort was 63 years, with the majority having hepatitis B virus (56.6%) and being classified as Child-Pugh class A (82.4%). We developed a new prognostic model, called the TACE-prognostic (TP) score, based on tumor burden (sum of the largest tumor diameter and tumor number), alpha-fetoprotein, and Albumin-Bilirubin grade. Patients were classified into five risk groups according to TP scores, with median survival significantly differentiated in both training and validation cohorts (P < 0.001). The new model consistently outperformed other currently available models in both the training and validation cohorts. Conclusion: This newly developed TP scoring system has the potential to be a useful tool in identifying ideal candidates of TACE and predicting OS with favorable performance and discrimination. However, further external validation is needed to confirm its effectiveness.

A Machine Learning Algorithm Facilitates Prognosis Prediction and Treatment Selection for Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma.

BACKGROUND: Given its heterogeneity and diverse clinical outcomes, precise subclassification of BCLC-C hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment. METHODS: We recruited 2,626 patients with BCLC-C stage HCC from multiple centers, comprising training/test (n=1,693) and validation cohorts (n=933). The XGBoost was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-/intermediate-/high-/very high-risk subgroups which were based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C). RESULTS: The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-/12-/24-month survival of patients with BCLC-C were 0.800/0.831/0.715, respectively-significantly higher than those of the conventional models, which was consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKIs) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high-to-very high-risk subgroup. CONCLUSIONS: ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.

Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea.

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Clostridium ventriculi in a cynomolgus monkey with acute gastric dilatation and rupture: A case report.

Acute gastric dilatation (AGD) is one of the most prevalent and life-threatening diseases in nonhuman primates worldwide. However, the etiology of this syndrome has not been determined. Recently, sudden death occurred in a 7-year-old female cynomolgus monkey with a history of fecal microbiota transplantation using diarrheic stools. The monkey had undergone surgery previously. On necropsy, gastric dilatation and rupture demonstrated a tetrad arrangement on histopathologic examination. On 16S rRNA sequencing, a high population of Clostridium ventriculi was identified in the duodenum adjacent to stomach but not in the colon. This paper is the first report of Clostridium ventriculi infection in a cynomolgus macaque with acute gastric dilatation and rupture.

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis.

This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy.

Factors Associated with Refractive Prediction Error after Phacotrabeculectomy.

PURPOSE: To compare refractive prediction errors between phacotrabeculectomy and phacoemulsification. METHODS: Refractive prediction error was defined as the difference in spherical equivalent between the predicted value using the Barrett Universal II formula and the actual value obtained at postoperative one month. Forty-eight eyes that had undergone phacotrabeculectomy (19 eyes, open-angle glaucoma; 29 eyes, angle-closure glaucoma) were matched with 48 eyes that had undergone phacoemulsification by age, average keratometry value and axial length (AL), and their prediction errors were compared. The factors associated with prediction errors were analyzed by multivariable regression analyses. RESULTS: The phacotrabeculectomy group showed a larger absolute prediction error than the phacoemulsification group (0.51 ± 0.37 Diopters vs. 0.38 ± 0.22 Diopters, p = 0.033). Larger absolute prediction error was associated with longer AL (p = 0.010) and higher intraocular pressure (IOP) difference (p = 0.012). Hyperopic shift (prediction error > 0) was associated with shallower preoperative anterior chamber depth (ACD) (p = 0.024) and larger IOP difference (p = 0.031). In the phacotrabeculectomy group, the prediction error was inversely correlated with AL: long eyes showed myopic shift and short eyes hyperopic shift (p = 0.002). CONCLUSIONS: Surgeons should be aware of the possibility of worse refractive outcomes when planning phacotrabeculectomy, especially in eyes with high preoperative IOP, shallow ACD, and/or extreme AL.

GDF10 is related to obesity as an adipokine derived from subcutaneous adipose tissue.

Introduction: Adipokines are proteins that are secreted by the adipose tissue. Although they are associated with obesity-related metabolic disorders, most studies have focused on adipokines expressed by visceral adipose tissue (VAT). This study aimed to identify the adipokine potentially derived from subcutaneous adipose tissue (SAT) and its clinical significance. Methods: Samples of SAT and VAT were obtained from six adult male patients who underwent laparoscopic surgery for benign gall bladder disease. Differentially expressed genes were analyzed by subjecting the samples to RNA sequencing. The serum concentration of selected proteins according to body mass index (BMI) was analyzed in 58 individuals. Results: GDF10 showed significantly higher expression in the SAT, as per RNA sequencing (fold change = 5.8, adjusted P value = 0.009). Genes related to insulin response, glucose homeostasis, lipid homeostasis, and fatty acid metabolism were suppressed when GDF10 expression was high in SAT, as per genotype-tissue expression data. The serum GDF10 concentration was higher in participants with BMI ≥ 25 kg/m2 (n = 35, 2674 ± 441 pg/mL) than in those with BMI < 25 kg/m2 (n = 23, 2339 ± 639 pg/mL; P = 0.022). There was a positive correlation between BMI and serum GDF10 concentration (r = 0.308, P = 0.019). Conclusions: GDF10 expression was higher in SAT than in VAT. Serum GDF10 concentration was high in patients with obesity. Therefore, GDF10 could be a SAT-derived protein related to obesity.

Lower abdominal approach in laparoscopic cholecystectomy: A propensity score-matching analysis and prospective cohort study.

BACKGROUND: Classic laparoscopic cholecystectomy) using multiple ports is a widely used method with excellent surgical outcomes. However, the resulting wounds do not meet the cosmetic needs of patients. Therefore, this study aimed to find a new minimally invasive surgical method for invisible wounds while maintaining surgical safety through a new port site. METHODS: In this prospective cohort study, we used propensity score matching analysis to evaluate the perioperative outcomes of multiport laparoscopic cholecystectomy using articulating devices with the lower abdominal approach. We performed a propensity score matching analysis of prospectively maintained data from 228 patients who underwent classic laparoscopic cholecystectomy using straight instruments and laparoscopic cholecystectomy with a lower abdominal approach using articulating devices between January and October 2022. A single surgeon performed all operations included in the study. We evaluated several perioperative outcomes. RESULTS: No differences were found in potential confounding factors, such as sex, age, admission type, previous abdominal surgery, and medical comorbidities, between the 2 groups after propensity score matching. In the classic laparoscopic cholecystectomy group, the mean operation time was shorter (43.73 ± 23.71 vs 50.60 ± 9.75 min; P < .04). No significant difference was noted in the 2 groups' numerical rating scale scores for pain, body mass index, and incidence of postoperative complications. The mean length of hospital stay was longer for patients who underwent classic laparoscopic cholecystectomy (4.27 vs 2.07 days; P = .064). The lower abdominal laparoscopic cholecystectomy group had delayed defecation after surgery. CONCLUSION: Regarding surgical outcomes and minimal invasiveness, lower abdominal laparoscopic cholecystectomy is a feasible cholecystectomy method.

xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.

Outcomes of laparoscopic radiofrequency ablation versus percutaneous radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. METHODS: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. RESULTS: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. CONCLUSIONS: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.

Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease.

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the ß2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

Change of peripapillary retinal nerve fiber layer and choroidal thickness during 4-year myopic progress: Boramae Myopia Cohort Study Report 4.

AIMS: To investigate the longitudinal changes of peripapillary retinal nerve fibre layer (RNFL) and choroidal thickness during myopic axial elongation. METHODS: Peripapillary RNFL and choroidal thickness were prospectively evaluated by spectral-domain optical coherence tomography (SD-OCT) in 46 eyes of 23 myopic children over the course of 4 years. Using serial OCT images acquired based on a fixed scan circle in the glaucoma progression analysis mode, general and sectoral RNFL thicknesses were acquired at the same position and the angular location of the peak was measured. The peripapillary choroidal thickness likewise was measured at eight positions in serial OCT images. RESULTS: The mean age at the baseline was 9.6±1.7 years. The mean axial length increased from 24.80±1.28 mm to 25.64±1.35 mm. The global peripapillary RNFL thickness was 98.54±12.06 µm at baseline. The global and sectoral RNFL thicknesses did not change during the 4 years. The angular location of RNFL peaks was also stable and was located in the superotemporal (64.18±10.85°) and inferotemporal (293.98±11.62°) sectors. The global peripapillary choroidal thickness was 145.40±28.67 µm at the baseline. The global and sectoral choroidal thicknesses did not change during the 4 years. CONCLUSIONS: The peripapillary RNFL and choroidal thicknesses as well as the locations of the RNFL peaks had been preserved, during the 4-year follow-up on myopic children, when traced and measured from the same location.

Hemisphere opposite to central retinal vascular trunk deviation is earlier affected by glaucomatous damage in primary angle-closure glaucoma.

PURPOSE: The purpose of the study was to investigate whether the position of the central retinal vascular trunk (CRVT), as a surrogate for lamina cribrosa (LC) offset, is associated with the dominant hemisphere of visual field defect in primary angle-closure glaucoma (PACG) eyes. METHODS: Central retinal vascular trunk deviation was measured from Bruch's membrane opening (BMO) centre, which was delineated by OCT imaging, using the horizontal midline as a reference. The dominant hemisphere developing visual field defect was defined as three connected abnormal points (having a p-value < 5% probability of being normal) appearing in only one hemisphere or each point of the hemisphere having a statistically worse value compared with its mirrored point in the opposite hemisphere on pattern deviation plots. RESULTS: One hundred five (80%) of 132 eyes with PACG had dominant hemisphere of visual field defect initially: 70 eyes (67%) in the superior and 35 eyes (33%) in the inferior hemisphere. The CRVT was located superiorly in the dominant superior visual field defect group (p < 0.001). A logistic regression analysis revealed that superior deviation of the CRVT was the only factor associated with dominant superior visual field defect (p < 0.001). Externally oblique border (EOB) presence was associated with larger BMO (p = 0.005) and angular deviation of CRVT (p = 0.002). CONCLUSIONS: Central retinal vascular trunk deviation was associated with the dominant hemisphere of visual field defect in PACG eyes. This finding implies that the LC position relative to the BMO centre (LC/BMO offset) may incur structural vulnerability in the optic nerve head of PACG eyes.

Fractal Dimension of Peripapillary Vasculature in Primary Open-Angle Glaucoma.

PURPOSE: To compare the fractal dimensions of the peripapillary microvasculature as obtained by optical coherence tomography angiography (OCTA) between primary open-angle glaucoma (POAG) and controls. METHODS: Optic nerve head and peripapillary area images were taken using the 20° × 20°-scan of Spectralis OCTA (Heidelberg Engineering) in 97 subjects (64 POAG patients, 33 control patients). The optic nerve head microvasculature was evaluated according to predefined slabs: the superficial vascular complex (SVC) and the avascular complex (AVC). The en face image of each slab was processed by ImageJ software (National Institutes of Health) in order to calculate the vessel density and the fractal dimension using the box-counting method. For comparison, the peripapillary retinal nerve fiber layer (RNFL) thickness was obtained from Spectralis OCT circle scans. The utilities of the parameters for discriminating between the POAG and control groups were assessed using areas under the receiver operating characteristic curves (AUCs). RESULTS: The SVC fractal dimension was lower in the POAG than in the control group (p < 0.001), while AVC showed no intergroup difference (p = 0.563). The fractal dimension showed a good correlation with the vessel density in both SVC and AVC (both p < 0.001). In a multivariable regression analysis, the SVC fractal dimension was negatively correlated with age (p < 0.001) and axial length (p < 0.001) and positively correlated with average RNFL thickness (p < 0.001), while the AVC fractal dimension was positively correlated with the Bruch's membrane opening size (p = 0.013). In terms of diagnostic utility, the AUC was significantly larger for the average RNFL thickness (AUC, 0.889) than for the SVC fractal dimension (AUC, 0.772; p = 0.008). CONCLUSIONS: The fractal dimension of SVC was associated with the average RNFL thickness and was reduced in POAG patients. Fractal dimension analysis could be used in evaluating peripapillary vascularity by OCTA.

Effect of Strain on Rodent Glaucoma Models: Magnetic Bead Injection Versus Hydrogel Injection Versus Circumlimbal Suture.

Purpose: To compare the inter-strain differences of three rodent glaucoma models as induced by magnetic bead injection, hydrogel injection, and circumlimbal suture. Methods: In Brown Norway (BN) and Sprague Dawley (SD) rat strains, intraocular pressure (IOP) was elevated by injection of magnetic beads or hydrogel to obstruct the aqueous humor outflow or by external compression of circumlimbal suture. Maximum and average IOP values were compared according to both procedure and rat strain over 1 month postoperatively. Retinal ganglion cell (RGC) density loss was evaluated using confocal microscopic images of the flat-mounted retina obtained at postoperative days 14 and 30. Results: The maximum IOPs were higher in the hydrogel injection or circumlimbal injection models than in the magnetic bead injection model (P < 0.001), whereas average IOP showed no difference between the two strains (both P ≥ 0.05). A generalized estimating equation regression model showed that the IOP increase was maintained better in the BN rats than in the SD rats (P < 0.001). Such inter-strain difference was smaller in the circumlimbal suture model. A significant decrease in RGC density was observed in all of the models for the BN rats and in the circumlimbal suture model for the SD rats at postoperative day 30. Conclusions: BN rats were advantageous for the magnetic bead or hydrogel injection model, but either rat strain could be used for the circumlimbal suture model. Strains should be considered cautiously when establishing rodent glaucoma models with different IOP profiles. Translational Relevance: This comparison offers the best strain for each rodent glaucoma model for assessment of glaucoma-relevant therapeutics.

Safety and effectiveness of direct-acting antivirals in patients with chronic hepatitis C and chronic kidney disease.

BACKGROUND/AIMS: To evaluate the effectiveness and safety of direct acting antivirals (DAAs) available in chronic kidney disease (CKD) patients with hepatitis C virus (HCV) infection in Korea. METHODS: In a retrospective, multicenter cohort study, 362 patients were enrolled from 2015 to 2019. The effectiveness and safety of DAAs including glecaprevir/pibrentasvir, sofosubvir/ribavirin, ledipasvir/sofosbuvir, and daclatasvir/asunaprevir were analyzed for patients according to CKD stage. We evaluated sustained virologic response at week 12 after treatment (SVR12) as primary endpoint. The effectiveness and safety were also evaluated according to CKD stage. RESULTS: Among 362 patients, 307 patients completed DAAs treatment and follow-up period after end of treatment. The subjects comprised 87 patients (62 with CKD stage 3 and 25 with CKD stage (4-5), of whom 22 were undergoing hemodialysis). HCV patients with CKD stage 1 and 2 (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2) showed SVR12 of 97.2% and 95.4% respectively. SVR12 of CKD stage 3 and 4-5 (eGFR < 60 mL/min/1.73 m2) patients was 91.9% and 91.6% respectively. Patients undergoing hemodialysis achieved SVR12 (90.9%). Treatment failure of DAAs in stage 1, 2, 3, and 4-5 was 2.8%, 2.7%, 1.6%, and 4%. DAAs showed good safety profile and did not affect deterioration of renal function. CONCLUSION: DAAs shows comparable SVR12 and safety in CKD patients (stage 3, 4, and 5) with HCV compared with patients with stage 1 and 2. The effectiveness and safety of DAAs may be related to the treatment duration. Therefore, it is important to select adequate regimens of DAAs and to increase treatment adherence.

Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion.

BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer. METHODS: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively. RESULTS: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production. CONCLUSIONS: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.