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Objectives: This study explores whether textural features from initial non-contrast CT scans of infarcted brain tissue are linked to hemorrhagic transformation susceptibility. Materials and methods: Stroke patients undergoing thrombolysis or thrombectomy from Jan 2012 to Jan 2022 were analyzed retrospectively. Hemorrhagic transformation was defined using follow-up magnetic resonance imaging. A total of 94 radiomic features were extracted from the infarcted tissue on initial NCCT scans. Patients were divided into training and test sets (7:3 ratio). Two models were developed with fivefold cross-validation: one incorporating first-order and textural radiomic features, and another using only textural radiomic features. A clinical model was also constructed using logistic regression with clinical variables, and test set validation was performed. Results: Among 362 patients, 218 had hemorrhagic transformations. The LightGBM model with all radiomics features had the best performance, with an area under the receiver operating characteristic curve (AUROC) of 0.986 (95% confidence interval [CI], 0.971–1.000) on the test dataset. The ExtraTrees model performed best when textural features were employed, with an AUROC of 0.845 (95% CI, 0.774–0.916). Minimum, maximum, and ten percentile values were significant predictors of hemorrhagic transformation. The clinical model showed an AUROC of 0.544 (95% CI, 0.431–0.658). The performance of the radiomics models was significantly better than that of the clinical model on the test dataset (p < 0.001). Conclusions: The radiomics model can predict hemorrhagic transformation using NCCT in stroke patients. Low Hounsfield unit was a strong predictor of hemorrhagic transformation, while textural features alone can predict hemorrhagic transformation. Clinical relevance statement: Using radiomic features extracted from initial non-contrast computed tomography, early prediction of hemorrhagic transformation has the potential to improve patient care and outcomes by aiding in personalized treatment decision-making and early identification of at-risk patients. Key Points: • Predicting hemorrhagic transformation following thrombolysis in stroke is challenging since multiple factors are associated. • Radiomics features of infarcted tissue on initial non-contrast CT are associated with hemorrhagic transformation. • Textural features on non-contrast CT are associated with the frailty of the infarcted tissue. [ABSTRACT FROM AUTHOR]

Background: We analyzed the impact of social distancing (SD) on vitamin D status and associated morbidity in neonates during the coronavirus disease (COVID-19) pandemic. Methods: Serum levels of 25-hydroxy vitamin D (25OHD) and clinical characteristics of newborn infants before (2019) and during SD (2021) were compared. Results: A total of 526 neonates (263 in 2019 and 263 in 2021) were included. The rate of vitamin D deficiency in neonates (47.1% vs. 35.4 %, p = 0.008) decreased and the rate of maternal vitamin D intake increased (6.8% vs. 37.6%, p < 0.001), respectively, during SD compared to those in 2019. The rates of hypocalcemia (12.5% vs. 3.8%, p < 0.001) and respiratory illness (57.0% vs. 43.0%, p = 0.002) decreased during SD. Neonatal vitamin D deficiency during SD was associated with maternal vitamin D supplementation (odds ratio [OR] = 0.463, p = 0.003) but was not associated with SD (OR = 0.772, p = 0.189). The mediation effect of SD on neonatal morbidity by neonatal vitamin D status was statistically insignificant. Conclusions: SD might affect the increased maternal vitamin D intake and decreased neonatal vitamin D deficiency. However, neonatal morbidity was not affected by SD, even with neonatal vitamin D status changes. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a deep learning model for predicting hemorrhagic transformation after endovascular thrombectomy using dual-energy computed tomography (CT). Materials and methods: This was a retrospective study from a prospective registry of acute ischemic stroke. Patients admitted between May 2019 and February 2023 who underwent endovascular thrombectomy for acute anterior circulation occlusions were enrolled. Hemorrhagic transformation was defined using follow-up magnetic resonance imaging or CT. The deep learning model was developed using post-thrombectomy dual-energy CT to predict hemorrhagic transformation within 72 h. Temporal validation was performed with patients who were admitted after July 2022. The deep learning model's performance was compared with a logistic regression model developed from clinical variables using the area under the receiver operating characteristic curve (AUC). Results: Total of 202 patients (mean age 71.4 years ± 14.5 [standard deviation], 92 men) were included, with 109 (54.0%) patients having hemorrhagic transformation. The deep learning model performed consistently well, showing an average AUC of 0.867 (95% confidence interval [CI], 0.815–0.902) upon five-fold cross validation and AUC of 0.911 (95% CI, 0.774–1.000) with the test dataset. The clinical variable model showed an AUC of 0.775 (95% CI, 0.709–0.842) on the training dataset (p < 0.01) and AUC of 0.634 (95% CI, 0.385–0.883) on the test dataset (p = 0.06). Conclusion: A deep learning model was developed and validated for prediction of hemorrhagic transformation after endovascular thrombectomy in patients with acute stroke using dual-energy computed tomography. Clinical relevance statement: This study demonstrates that a convolutional neural network (CNN) can be utilized on dual-energy computed tomography (DECT) for the accurate prediction of hemorrhagic transformation after thrombectomy. The CNN achieves high performance without the need for region of interest drawing. Key Points: • Iodine leakage on dual-energy CT after thrombectomy may be from blood-brain barrier disruption. • A convolutional neural network on post-thrombectomy dual-energy CT enables individualized prediction of hemorrhagic transformation. • Iodine leakage is an important predictor of hemorrhagic transformation following thrombectomy for ischemic stroke. [ABSTRACT FROM AUTHOR]

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia–Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections. [ABSTRACT FROM AUTHOR]

This document, published in the Journal of Translational Medicine, discusses the potential therapeutic benefits of Salinosporamides (SSAs) in treating cancer. The study aims to identify the key SSAs and their mechanisms of action using systems biology concepts. Through database-driven analysis and computer screening tools, the researchers identified 11 SSAs with drug-like properties and common targets. The study highlights the importance of the NOD-like receptor signaling pathway and specific targets, such as STAT3, MAPK1, TBK1, and P2RX7, in the anti-cancer effects of SSAs. The research suggests that incorporating biological data can help uncover the potential of marine organic molecules in cancer medicine. [Extracted from the article]

Background: The effectiveness of endovascular treatment for in-hospital stroke remains debatable. We aimed to compare the outcomes between patients with in-hospital stroke and community-onset stroke who received endovascular treatment. Methods: This prospective registry-based cohort study included consecutive patients who underwent endovascular treatment from January 2013 to December 2022 and were registered in the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy study and Yonsei Stroke Cohort. Functional outcomes at day 90, radiological outcomes, and safety outcomes were compared between the in-hospital and community-onset groups using logistic regression and propensity score-matched analysis. Results: Of 1,219 patients who underwent endovascular treatment, 117 (9.6%) had in-hospital stroke. Patients with in-hospital onset were more likely to have a pre-stroke disability and active cancer than those with community-onset. The interval from the last known well to puncture was shorter in the in-hospital group than in the community-onset group (155 vs. 355 min, p<0.001). No significant differences in successful recanalization or safety outcomes were observed between the groups; however, the in-hospital group exhibited worse functional outcomes and higher mortality at day 90 than the community-onset group (all p<0.05). After propensity score matching including baseline characteristics, functional outcomes after endovascular treatment did not differ between the groups (OR: 1.19, 95% CI 0.78–1.83, p=0.4). Safety outcomes did not significantly differ between the groups. Conclusion: Endovascular treatment is a safe and effective treatment for eligible patients with in-hospital stroke. Our results will help physicians in making decisions when planning treatment and counseling caregivers or patients. [ABSTRACT FROM AUTHOR]

Background and aim: The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients. Methods: This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight–mass spectrometry (LC–TOF–MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages. Results: The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism. Conclusions: This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression. Clinical trial: Clinicaltrials.gov, number NCT04339725. [ABSTRACT FROM AUTHOR]

This document, published in the Journal of Translational Medicine, discusses the potential use of short positively charged peptides (SPCPs) as a therapy for hepatocellular carcinoma (HCC). SPCPs have been identified as having anti-cancer properties and the ability to penetrate cancer cell membranes. The study identifies specific SPCPs that have stable physicochemical properties and can target key proteins and signaling pathways associated with HCC. The two key SPCPs identified, KFAH and HFAK, show strong affinity for the targets and have the potential to be developed into a localized injection therapy for HCC. [Extracted from the article]

This document explores the potential of Cephalotaxus alkaloids (CAs) as anti-cancer agents. Through data analysis using various tools and software, the study identifies heat shock protein 90 alpha family class A member 1 (HSP90AA1) as a potential target for inhibiting cancer progression and the NOD-like receptor (NLR) signaling pathway as a promising pathway for cancer treatment. The compound Nordeoxyharringtonine is identified as a potential anti-cancer mediator, and its toxicity is found to be manageable. The study suggests that Nordeoxyharringtonine can be used to validate its anti-pan-cancer effects by targeting multiple pathways. The research was supported by multiple funding sources and has been approved by all authors. [Extracted from the article]

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Further information is necessary regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). When we compared the HCC incidence in non-cirrhotic CHB patients receiving BSV with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model, the standardized incidence ratio (SIR) was significantly reduced to 0.128 at 7 years. The incidence of HCC in patients with cirrhosis was compared using the GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, and the SIR was significantly decreased to 0.371 at 7.5 years. HCC prediction was available for BSV-treated patients using existing models. We concluded that BSV decreases the risk of HCC in patients with CHB, and HCC risk prediction models are applicable. No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806. [ABSTRACT FROM AUTHOR]

Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation, as they relieve metabolic disorders, including obesity (OB). In another aspect, this study was focused on the anti‐OB efficacy of the non‐fatty acids (NFAs) in PAF through network pharmacology (NP). Natural product activity & species source (NPASS), SwissADME, similarity ensemble approach (SEA), Swiss target prediction (STP), DisGeNET, and online Mendelian inheritance in man (OMIM) were utilized to gather significant molecules and its targets. The crucial targets were adopted to construct certain networks: protein–protein interaction (PPI), PAF‐signaling pathways‐targets‐compounds (PSTC) networks, a bubble chart, molecular docking assay (MDA), and density function theory (DFT). Finally, the toxicities of the key compounds were validated by ADMETlab 2.0 platform. All 41 compounds in PAF conformed to Lipinski's rule, and the key 31 targets were identified between OB and PAF. On the bubble chart, PPAR signaling pathway had the highest rich factor, suggesting that the pathway might be an agonism for anti‐OB. Conversely, estrogen signaling pathway had the lowest rich factor, indicating that the mechanism might be antagonism against OB. Likewise, the PSTC network represented that AKT1 had the greatest degree value. The MDA results showed that AKT1‐gamma‐tocopherol, PPARA‐fucosterol, PPARD‐stigmasterol, (PPARG)‐fucosterol, (NR1H3)‐campesterol, and ILK‐alpha‐tocopherol formed the most stable conformers. The DFT represented that the five molecules might be promising agents via multicomponent targeting. Overall, this study suggests that the NFAs in PAF might play important roles against OB. [ABSTRACT FROM AUTHOR]

Clinical benefit can be time-dependent even after first-pass recanalization (FPR) in endovascular treatment of acute stroke. This study aimed to evaluate the association between favorable outcome and FPR under a specific time frame. Patients who underwent mechanical thrombectomy were retrospectively reviewed. Recanalization status was categorized into four groups based on FPR and dichotomized time from groin puncture to recanalization (P-to-R time). Favorable outcomes were compared between groups. A total of 458 patients were included. As the cutoff of P-to-R time for favorable outcome was 30 min, recanalization status was categorized into FPR (+) with a P-to-R time ≤ 30 min (Group 1), FPR (–) with a P-to-R time ≤ 30 min (Group 2), FPR (+) with a P-to-R time > 30 min (Group 3), and FPR (–) with a P-to-R time > 30 min (Group 4). Favorable outcomes in Group 3 (37.5%) were significantly less frequent than those in Group 1 (60.4%, p = 0.029) and Group 2 (59.5%, p = 0.033) but were not significantly different from those in Group 4 (35.7%, p = 0.903). Compared to Group 1, Group 3 (adjusted odds ratio, 0.30 [95% confidence interval, 0.12–0.76]; p = 0.011) and Group 4 (0.25 [0.14–0.48]; p < 0.001) were adversely associated with favorable outcomes. FPR was associated with functional outcome in a time-dependent manner. Even for patients who have achieved FPR, their functional outcome might not be favorable if the P-to-R time is >30 min. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the association between preprocedural D-dimer levels and endovascular and clinical outcomes. We retrospectively reviewed patients with acute intracranial large-vessel occlusion who underwent mechanical thrombectomy. Plasma D-dimer levels were measured immediately before the endovascular procedure. Endovascular outcomes included successful recanalization, first-pass recanalization (first-pass effect (FPE) and modified FPE (mFPE)), thrombus fragmentation, and the number of passes of the thrombectomy device. Clinical outcomes were assessed at 3 months using the modified Rankin Scale. A total of 215 patients were included. Preprocedural D-dimer levels were lower in patients with FPE (606.0 ng/mL [interquartile range, 268.0–1062.0]) than in those without (879.0 ng/mL [437.0–2748.0]; p = 0.002). Preprocedural D-dimer level was the only factor affecting FPE (odds ratio, 0.92 [95% confidence interval, 0.85–0.98] per 500 ng/mL; p = 0.022). D-dimer levels did not differ significantly based on successful recanalization and thrombus fragmentation. The number of passes of the thrombectomy device was higher (p = 0.002 for trend) and the puncture-to-recanalization time was longer (p = 0.044 for trend) as the D-dimer levels increased. Patients with favorable outcome had significantly lower D-dimer levels (495.0 ng/mL [290.0–856.0]) than those without (1189.0 ng/mL [526.0–3208.0]; p < 0.001). Preprocedural D-dimer level was an independent factor for favorable outcome (adjusted odds ratio, 0.88 [0.81–0.97] per 500 ng/mL; p = 0.008). In conclusion, higher preprocedural D-dimer levels were significantly associated with poor endovascular and unfavorable functional outcomes. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does early intensive blood pressure management improve outcomes after successful reperfusion with endovascular thrombectomy in acute ischemic stroke? Findings: In this randomized clinical trial that included 306 patients, 39.4% of patients with intensive blood pressure management (systolic blood pressure target <140 mm Hg) and 54.4% of those with conventional blood pressure management (systolic blood pressure target 140-180 mm Hg) achieved functional independence (modified Rankin Scale score ≤2) at 3 months; this represented a significant difference. Meaning: Intensive blood pressure lowering during the first 24 hours after successful reperfusion may be harmful in patients with acute ischemic stroke who have undergone endovascular thrombectomy. Importance: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective: To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants: Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions: Participants were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures: The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results: The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (−15.1% [95% CI, −26.2% to −3.9%]) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P =.03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, −5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53]; P =.82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, −3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92]; P =.31). Conclusions and Relevance: Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT04205305 This randomized trial assesses the effect of intensive blood pressure management vs conventional management on functional independence at 3 months among patients with large vessel occlusion acute ischemic stroke treated with endovascular thrombectomy. [ABSTRACT FROM AUTHOR]

Simple Summary: Beta-transducin repeat-containing proteins (β-TrCPs) are a component of the E3 ubiquitin ligase complex and function in many cellular processes to maintain protein homeostasis. Mounting evidence suggests that β-TrCPs are aberrantly upregulated in cancer tissues and are potential targets for cancer treatment. Although extensive studies have been performed to understand the mode of regulation of their substrates and its biological consequences, little attention has been paid to the mechanisms of the regulation of β-TrCPs themselves. The current review is focused on the modulation of β-TrCPs' activities and the implications for cancer treatment. Beta-transducin repeat-containing proteins (β-TrCPs) are E3-ubiquitin-ligase-recognizing substrates and regulate proteasomal degradation. The degradation of β-TrCPs' substrates is tightly controlled by various external and internal signaling and confers diverse cellular processes, including cell cycle progression, apoptosis, and DNA damage response. In addition, β-TrCPs function to regulate transcriptional activity and stabilize a set of substrates by distinct mechanisms. Despite the association of β-TrCPs with tumorigenesis and tumor progression, studies on the mechanisms of the regulation of β-TrCPs' activity have been limited. In this review, we studied publications on the regulation of β-TrCPs themselves and analyzed the knowledge gaps to understand and modulate β-TrCPs' activity in the future. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress induced growth inhibitor 1 (OSGIN1) regulates cell death. The role and underlying molecular mechanism of OSGIN1 in non-small cell lung cancer (NSCLC) are uncharacterized. Methods: OSGIN1 expression in NSCLC samples was detected using immunohistochemistry and Western blotting. Growth of NSCLC cells and gefitinib-resistant cells expressing OSGIN1 or TUBB3 knockdown was determined by MTT, soft agar, and foci formation assays. The effect of OSGIN1 knockdown on in vivo tumor growth was assessed using NSCLC patient-derived xenograft models and gefitinib-resistant patient-derived xenograft models. Potentially interacting protein partners of OSGIN1 were identified using IP-MS/MS, immunoprecipitation, PLA, and Western blotting assays. Microtubule dynamics were explored by tubulin polymerization assay and immunofluorescence. Differential expression of signaling molecules in OSGIN1 knockdown cells was investigated using phospho-proteomics, KEGG analysis, and Western blotting. Results: We found that OSGIN1 is highly expressed in NSCLC tissues and is positively correlated with low survival rates and tumor size in lung cancer patients. OSGIN1 knockdown inhibited NSCLC cell growth and patient-derived NSCLC tumor growth in vivo. Knockdown of OSGIN1 strongly increased tubulin polymerization and re-established gefitinib sensitivity in vitro and in vivo. Additionally, knockdown of TUBB3 strongly inhibited NSCLC cell proliferation. Mechanistically, we found that OSGIN1 enhances DYRK1A-mediated TUBB3 phosphorylation, which is critical for inducing tubulin depolymerization. The results of phospho-proteomics and ontology analysis indicated that knockdown of OSGIN1 led to reduced propagation of the MKK3/6-p38 signaling axis. Conclusions: We propose that OSGIN1 modulates microtubule dynamics by enhancing DYRK1A-mediated phosphorylation of TUBB3 at serine 172. Moreover, elevated OSGIN1 expression promotes NSCLC tumor growth and gefitinib resistance through the MKK3/6-p38 signaling pathway. Our findings unveil a new mechanism of OSGIN1 and provide a promising therapeutic target for NSCLC treatment in the clinic. [ABSTRACT FROM AUTHOR]

Background and aim: Acute-on-chronic liver failure (ACLF) is a severe form of alcoholic hepatitis (SAH). We aimed to study the natural course, response to corticosteroids (CS), and the role of the Asian Pacific Association for the Study of Liver (APASL) research consortium (AARC) score in determining clinical outcomes in AH patients. Methods: Prospectively collected data from the AARC database were analyzed. Results: Of the 1249 AH patients, (aged 43.8 ± 10.6 years, 96.9% male, AARC score 9.2 ± 1.9), 38.8% died on a 90 day follow-up. Of these, 150 (12.0%) had mild–moderate AH (MAH), 65 (5.2%) had SAH and 1034 (82.8%) had ACLF. Two hundred and eleven (16.9%) patients received CS, of which 101 (47.87%) were steroid responders by day 7 of Lille's model, which was associated with improved survival [Hazard ratio (HR) 0.15, 95% CI 0.12–0.19]. AARC-ACLF grade 3 [OR 0.28, 0.14–0.55] was an independent predictor of steroid non-response and mortality [HR 3.29, 2.63–4.11]. Complications increased with degree of liver failure [AARC grade III vs. II vs I], bacterial infections [48.6% vs. 37% vs. 34.7%; p < 0.001); extrahepatic organ failure [66.9% vs. 41.8% vs. 35.4%; p < 0.001] respectively. The AARC score better discriminated 90-day mortality. Harrell's C-index was 0.72 compared to other scores. Conclusion: Nearly 4 of 5 patients with AH present with ACLF. Such patients have a higher risk of infections, organ failures, lower response to CS, and higher mortality. Patients with AH and ACLF with AARC grade 3 should be considered for an early liver transplant. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue globally, currently, the treatment of NAFLD lies still in the labyrinth. In the inchoate stage, the combinatorial application of food regimen and favorable gut microbiota (GM) are considered as an alternative therapeutic. Accordingly, we integrated secondary metabolites (SMs) from GM and Avena sativa (AS) known as potent dietary grain to identify the combinatorial efficacy through network pharmacology. Methods: We browsed the SMs of AS via Natural Product Activity & Species Source (NPASS) database and SMs of GM were retrieved by gutMGene database. Then, specific intersecting targets were identified from targets related to SMs of AS and GM. The final targets were selected on NAFLD-related targets, which was considered as crucial targets. The protein–protein interaction (PPI) networks and bubble chart analysis to identify a hub target and a key signaling pathway were conducted, respectively. In parallel, we analyzed the relationship of GM or AS─a key signaling pathway─targets─SMs (GASTM) by merging the five components via RPackage. We identified key SMs on a key signaling pathway via molecular docking assay (MDA). Finally, the identified key SMs were verified the physicochemical properties and toxicity in silico platform. Results: The final 16 targets were regarded as critical proteins against NAFLD, and Vascular Endothelial Growth Factor A (VEGFA) was a key target in PPI network analysis. The PI3K-Akt signaling pathway was the uppermost mechanism associated with VEGFA as an antagonistic mode. GASTM networks represented 122 nodes (60 GM, AS, PI3K-Akt signaling pathway, 4 targets, and 56 SMs) and 154 edges. The VEGFA-myricetin, or quercetin, GSK3B-myricetin, IL2-diosgenin complexes formed the most stable conformation, the three ligands were derived from GM. Conversely, NR4A1-vestitol formed stable conformation with the highest affinity, and the vestitol was obtained from AS. The given four SMs were no hurdles to develop into drugs devoid of its toxicity. Conclusion: In conclusion, we show that combinatorial application of AS and GM might be exerted to the potent synergistic effects against NAFLD, dampening PI3K-Akt signaling pathway. This work provides the importance of dietary strategy and beneficial GM on NAFLD, a data mining basis for further explicating the SMs and pharmacological mechanisms of combinatorial application (AS and GM) against NAFLD. [ABSTRACT FROM AUTHOR]

We demonstrated a narrow-linewidth high-power Yb-doped polarization-maintaining (PM) fiber laser with near-diffraction-limited beam. The laser system consisted of a phase-modulated single-frequency seed source and four-stage amplifiers in the master oscillator power amplifier configuration. A quasi-flat-top pseudo random binary sequence (PRBS) phase-modulated single-frequency laser with a linewidth of 8 GHz was injected into the amplifiers for suppressing stimulated Brillouin scattering. The quasi-flat-top PRBS signal was readily generated from the conventional PRBS signal. The maximum output power was 2.01 kW with polarization extinction ratio (PER) of ~15 dB. The beam quality (M2) was less than 1.3 over the power scaling range. [ABSTRACT FROM AUTHOR]

The skin protects our body; however, it is directly exposed to the environment and is stimulated by various external factors. Among the various environmental factors that can threaten skin health, the effects of ultraviolet (UV) and particulate matter (PM) are considered the most notable. Repetitive exposure to ultraviolet and particulate matter can cause chronic skin diseases such as skin inflammation, photoaging, and skin cancer. The abnormal activation of the Src family of protein tyrosine kinases (SFKs) and the aryl hydrocarbon receptor (AhR) in response to UV and/or PM exposure are involved in the development and aggravation of skin diseases. Phytochemicals, chemical compounds of natural plants, exert preventive effects on skin diseases through the regulation of various signaling pathways. Therefore, this review aims to highlight the efficacy of phytochemicals as potential nutraceuticals and pharmaceutical materials for the treatment of skin diseases, primarily by targeting SFK and AhR, and to explore the underlying mechanisms of action. Future studies are essential to validate the clinical potential for the prevention and treatment of skin diseases. [ABSTRACT FROM AUTHOR]

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite‐duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI‐H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI‐H2158 (5–500 mg) or placebo; Part B, participants received multiple doses of ABI‐H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI‐H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety‐three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment‐emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI‐H2158; there were no deaths, SAEs or Grade 4 TEAEs. In Part A, median time to maximum ABI‐H2158 plasma concentration (Tmax) and mean terminal elimination half‐life (t½) were 1–4 and 9.8–20.7 h, and area under the plasma concentration‐time curve increased dose proportionally. In Part B, Day 10 Tmax was 2 h, mean t½ was 15.5–18.4 h, and exposure accumulated 1.7‐ to 3.1‐fold. In Part C, Day 14 Tmax was 1 h, exposure accumulated 1.4‐ to 1.8‐fold, and ABI‐H2158 was associated with >2 log10 declines in HBV nucleic acids. In conclusion, ABI‐H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing. [ABSTRACT FROM AUTHOR]

In this study, to enhance the stability of the cathode platinum (Pt) catalyst in polymer electrolyte membrane fuel cells, cerium oxide (CeOx) was deposited by plasma-enhanced atomic layer deposition (PEALD) process on the Pt catalyst sputtered on the cathode. A change in the peak power density loss after an accelerated stress test (AST) during I-V measurement of the membrane-electrode assembly according to the number of cycles was observed, which confirmed stability improvement. In polymer electrode membrane fuel cells (PEMFCs), free radicals lead to degradation of the performance and stability of catalysts; we used CeOx to prevent these problems. CeOx acts as a free radical scavenger through the redox reaction of Ce3+/4+ ions in the cell test and prevents oxidative hydroxyl and hydroperoxyl radical attack created in the reaction between hydrogen peroxide and released cations. By preventing oxidation, the stability was improved without decreasing the performance. Therefore, the improvement of stability through plasma-enhanced atomic layer deposition CeOx encapsulation can be considered a promising strategy for PEMFC catalysts. [ABSTRACT FROM AUTHOR]

Background and Aims: We hypothesized that artificial intelligence (AI) models are more precise than standard models for predicting outcomes in acute‐on‐chronic liver failure (ACLF). Methods: We recruited ACLF patients between 2009 and 2020 from APASL‐ACLF Research Consortium (AARC). Their clinical data, investigations and organ involvement were serially noted for 90‐days and utilized for AI modelling. Data were split randomly into train and validation sets. Multiple AI models, MELD and AARC‐Model, were created/optimized on train set. Outcome prediction abilities were evaluated on validation sets through area under the curve (AUC), accuracy, sensitivity, specificity and class precision. Results: Among 2481 ACLF patients, 1501 in train set and 980 in validation set, the extreme gradient boost‐cross‐validated model (XGB‐CV) demonstrated the highest AUC in train (0.999), validation (0.907) and overall sets (0.976) for predicting 30‐day outcomes. The AUC and accuracy of the XGB‐CV model (%Δ) were 7.0% and 6.9% higher than the standard day‐7 AARC model (p <.001) and 12.8% and 10.6% higher than the day 7 MELD for 30‐day predictions in validation set (p <.001). The XGB model had the highest AUC for 7‐ and 90‐day predictions as well (p <.001). Day‐7 creatinine, international normalized ratio (INR), circulatory failure, leucocyte count and day‐4 sepsis were top features determining the 30‐day outcomes. A simple decision tree incorporating creatinine, INR and circulatory failure was able to classify patients into high (~90%), intermediate (~60%) and low risk (~20%) of mortality. A web‐based AARC‐AI model was developed and validated twice with optimal performance for 30‐day predictions. Conclusions: The performance of the AARC‐AI model exceeds the standard models for outcome predictions in ACLF. An AI‐based decision tree can reliably undertake severity‐based stratification of patients for timely interventions. [ABSTRACT FROM AUTHOR]

The progression and exacerbation of liver fibrosis are closely related to the gut microbiome. It is hypothesized that some probiotics may slow the progression of liver fibrosis. In human stool analysis [healthy group (n = 44) and cirrhosis group (n = 18)], difference in Lactobacillus genus between healthy group and cirrhosis group was observed. Based on human data, preventive and therapeutic effect of probiotics Lactobacillus lactis and L. rhamnosus was evaluated by using four mice fibrosis models. L. lactis and L. rhamnosus were supplied to 3,5-diethoxycarbonyl-1,4-dihydrocollidine or carbon tetrachloride-induced liver fibrosis C57BL/6 mouse model. Serum biochemical measurements, tissue staining, and mRNA expression in the liver were evaluated. The microbiome was analyzed in mouse cecal contents. In the mouse model, the effects of Lactobacillus in preventing and treating liver fibrosis were different for each microbe species. In case of L. lactis, all models showed preventive and therapeutic effects against liver fibrosis. In microbiome analysis in mouse models administered Lactobacillus, migration and changes in the ratio and composition of the gut microbial community were confirmed. L. lactis and L. rhamnosus showed preventive and therapeutic effects on the progression of liver fibrosis, suggesting that Lactobacillus intake may be a useful strategy for prevention and treatment. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is one of the main complications of liver cirrhosis (LC) and is classified into minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy (overt HE). S100B is expressed mainly in astrocytes and other glial cells, and S100B has been reported to be associated with various neurological disorders. The present study aimed to investigate the diagnostic ability of serum S100B to discriminate the grade of HE and the parameters correlated with serum S100B levels. Additionally, we investigated whether serum S100B levels can be used to predict 1-year mortality in cirrhotic patients. In total, 95 cirrhotic patients were consecutively enrolled and divided into the following three groups: (i) without any types of HEs; (ii) with MHE; and (iii) with overt HE. The diagnosis of MHE was made by the Mini-Mental State Examination (MMSE) and Psychometric Hepatic Encephalopathy Score (PHES). Among the three groups, there were no significant differences in serum S100B levels regardless of HE severity. The clinical parameters correlated with serum S100B levels were age, serum bilirubin, and creatinine levels. The Model for End-Stage Liver Disease (MELD) score showed a significant positive correlation with serum S100B levels. The relationship between serum S100B levels and MELD score was maintained in 48 patients without any type of HE. Additionally, hyperammonemia, low cholesterol levels, and the combination of serum S100B levels ≥ 35 pg/mL with MELD score ≥ 13 were factors for predicting 1- year mortality. In conclusion, serum S100B level was not useful for differentiating the severity of HE. However, we found that serum S100B levels can be affected by age, serum bilirubin, and creatinine in cirrhotic patients and are associated with MELD scores. Additionally, serum S100B levels showed the possibility of predicting 1-year mortality in cirrhotic patients. These findings suggest that serum S100B levels may reflect liver dysfunction and prognosis in liver disease. [ABSTRACT FROM AUTHOR]

Game playing is an accessible leisure activity. Recently, the World Health Organization officially included gaming disorder in the ICD-11, and studies using several bio-signals were conducted to quantitatively determine this. However, most EEG studies regarding internet gaming disorder (IGD) were conducted in the resting state, and the outcomes appeared to be too inconsistent to identify a general trend. Therefore, this study aimed to use a series of statistical processes with all the existing EEG parameters until the most effective ones to identify the difference between IGD subjects IGD and healthy subjects was determined. Thirty subjects were grouped into IGD (n = 15) and healthy (n = 15) subjects by using the Young's internet addition test (IAT) and the compulsive internet use scale (CIUS). EEG data for 16 channels were collected while the subjects played League of Legends. For the exhaustive search of parameters, 240 parameters were tested in terms of t-test, factor analysis, Pearson correlation, and finally logistic regression analysis. After a series of statistical processes, the parameters from Alpha, sensory motor rhythm (SMR), and MidBeta ranging from the Fp1, C3, C4, and O1 channels were found to be best indicators of IGD symptoms. The accuracy of diagnosis was computed as 63.5–73.1% before cross-validation. The most interesting finding of the study was the dynamics of EEG relative power in the 10–20 Hz band. This EEG crossing phenomenon between IGD and healthy subjects may explain why previous research showed inconsistent outcomes. The outcome of this study could be the referential guide for further investigation to quantitatively assess IGD symptoms. [ABSTRACT FROM AUTHOR]

The metabolites of gut microbiota show favorable therapeutic effects on nonalcoholic fatty liver disease (NAFLD), but the active metabolites and mechanisms against NAFLD have not been documented. The aim of the study was to investigate the active metabolites and mechanisms of gut microbiota against NAFLD by network pharmacology. We obtained a total of 208 metabolites from the gutMgene database and retrieved 1256 targets from similarity ensemble approach (SEA) and 947 targets from the SwissTargetPrediction (STP) database. In the SEA and STP databases, we identified 668 overlapping targets and obtained 237 targets for NAFLD. Thirty-eight targets were identified out of those 237 and 223 targets retrieved from the gutMgene database, and were considered the final NAFLD targets of metabolites from the microbiome. The results of molecular docking tests suggest that, of the 38 targets, mitogen-activated protein kinase 8-compound K and glycogen synthase kinase-3 beta-myricetin complexes might inhibit the Wnt signaling pathway. The microbiota-signaling pathways-targets-metabolites network analysis reveals that Firmicutes, Fusobacteria, the Toll-like receptor signaling pathway, mitogen-activated protein kinase 1, and phenylacetylglutamine are notable components of NAFLD and therefore to understanding its processes and possible therapeutic approaches. The key components and potential mechanisms of metabolites from gut microbiota against NAFLD were explored utilizing network pharmacology analyses. This study provides scientific evidence to support the therapeutic efficacy of metabolites for NAFLD and suggests holistic insights on which to base further research. [ABSTRACT FROM AUTHOR]

Background/Aims: The management of hepatic hydrothorax (HH) remains a challenging clinical scenario with suboptimal options. We investigated the effect and safety of pigtail catheter drainage compared to intermittent thoracentesis. Methods: This multicenter, retrospective study included 164 cirrhotic patients with recurrent pleural effusion from March 2012 to June 2017. Patients with neoplasms, cardiopulmonary disease, and infectious conditions were excluded. We compared the clinical outcomes of pigtail catheter drainage versus thoracentesis for variables including complications related to procedures, overall survival, and re-admission rates. Results: A total of 164 patients were divided into pigtail catheter (n = 115) and thoracentesis (n = 49) groups. During the follow-up period of 6.93 months after discharge, 98 patients died (pigtail; n = 47 vs. thoracentesis; n = 51). The overall survival (p = 0.61) and 30-day mortality (p = 0.77) rates were similar between the pigtail catheter and thoracentesis groups. Only MELD scores were associated with overall survival (adjusted HR, 1.08; p < 0.01) in patients with HH. Spontaneous pleurodesis occurred in 59 patients (51.3%) in the pigtail catheter group. Re-admission rates did not differ between the pigtail catheter and thoracentesis groups (13.2% vs 19.6% p = 0.7). A total of five complications occurred, including four total cases of bleeding (one patient in the pigtail catheter group and three in the thoracentesis group) and one case of empyema in the pigtail catheter group. Conclusions: Pigtail catheter drainage is not inferior to that of intermittent thoracentesis for the management of HH, proving it may be an effective and safe clinical option. [ABSTRACT FROM AUTHOR]

Background: CHADS2, CHA2DS2-VASc, ATRIA, and Essen stroke risk scores are used to estimate thromboembolism risk. We aimed to investigate the association between unfavorable outcomes and stroke risk scores in patients who received endovascular thrombectomy (EVT). Methods: This study was performed using data from a nationwide, multicenter registry to explore the selection criteria for patients who would benefit from reperfusion therapies. We calculated pre-admission CHADS2, CHA2DS2-VASc, ATRIA, and Essen scores for each patient who received EVT and compared the relationship between these scores and 3-month modified Rankin Scale (mRS) records. Results: Among the 404 patients who received EVT, 213 (52.7%) patients had unfavorable outcomes (mRS 3–6). All scores were significantly higher in patients with unfavorable outcomes than in those with favorable outcomes. Multivariable logistic regression analysis indicated that CHADS2 and the ATRIA score were positively correlated with unfavorable outcomes after adjusting for body mass index and variables with p < 0.1 in the univariable analysis (CHADS2 score: odds ratio [OR], 1.484; 95% confidence interval [CI], 1.290–1.950; p = 0.005, ATRIA score, OR, 1.128; 95% CI, 1.041–1.223; p = 0.004). Conclusions: The CHADS2 and ATRIA scores were positively correlated with unfavorable outcomes and could be used to predict unfavorable outcomes in patients who receive EVT. [ABSTRACT FROM AUTHOR]

The platelet-to-white blood cell ratio (PWR) has been reported to predict the severity of patients with various diseases. However, no previous studies have assessed the use of the PWR as a prognostic marker for pyogenic liver abscesses (PLA). This observational retrospective study was performed between January 2008 and December 2017, including 833 patients with PLA from multiple centers. The enrolled patients, on average, had a PWR of 17.05, and 416 patients had a PWR lower than 17.05. A total of 260 patients (31.2%) with PLA showed complications of metastatic infection, pleural effusion and abscess rupture. A low PWR level was identified as a strong risk factor for metastatic infection and pleural effusion. The low PWR group also had a longer hospital stay. In the multivariate analysis, old age, anemia, albumin and CRP levels and unidentified pathogens were significant factors for low PWR levels. A low PWR, old age, male sex, abscess size, albumin, ALP and unidentified causative pathogens showed significant associations with a hospital stay longer than 28 days. As a result, PLA patients presenting with a low PWR were shown to have more complications and a poor prognosis. Considering its cost-effectiveness, PWR could be a novel biomarker used to predict a prognosis of PLA. [ABSTRACT FROM AUTHOR]

Rationale: Very early stage blood pressure (BP) levels may affect outcome in stroke patients who have successfully undergone recanalization following intra-arterial treatment, but the optimal target of BP management remains uncertain. Aim: We hypothesized that the clinical outcome after intensive BP-lowering is superior to conventional BP control after successful recanalization by intra-arterial treatment. Sample-size estimates: We aim to randomize 668 patients (334 per arm), 1:1. Methods and design: We initiated a multicenter, prospective, randomized, open-label trial with a blinded end-point assessment (PROBE) design. After successful recanalization (thrombolysis in cerebral infarction score ≥ 2 b), patients with elevated systolic BP level, defined as the mean of two readings ≥ 140 mmHg, will be randomly assigned to the intensive BP-lowering (systolic BP < 140 mm Hg) group or the conventional BP-lowering (systolic BP, 140−180 mm Hg) group. Study outcomes: The primary efficacy outcomes are from dichotomized analysis of modified Rankin Scale (mRS) scores at three months (mRS scores: 0–2 vs. 3–6). The primary safety outcomes are symptomatic intracerebral hemorrhage and death within three months. Discussion: The OPTIMAL-BP trial will provide evidence for the effectiveness of active BP control to achieve systolic BP < 140 mmHg during 24 h in patients with successful recanalization after intra-arterial treatment. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04205305. [ABSTRACT FROM AUTHOR]

Background and aims: Limited data exist regarding outcomes of acute variceal bleeding (AVB) in patients with acute-on-chronic liver failure (ACLF), especially in those with hepatic failure. We evaluated the outcomes of AVB in patients with ACLF in a multinational cohort of APASL ACLF Research Consortium (AARC). Methods: Prospectively maintained data from AARC database on patients with ACLF who developed AVB (ACLF-AVB) was analysed. This data included demographic profile, severity of liver disease, and rebleeding and mortality in 6 weeks. These outcomes were compared with a propensity score matched (PSM) cohort of ACLF matched for severity of liver disease (MELD, AARC score) without AVB (ACLF without AVB). Results: Of the 4434 ACLF patients, the outcomes in ACLF-AVB (n = 72) [mean age—46 ± 10.4 years, 93% males, 66% with alcoholic liver disease, 65% with alcoholic hepatitis, AARC score: 10.1 ± 2.2, MELD score: 34 (IQR: 27–40)] were compared with a PSM cohort selected in a ratio of 1:2 (n = 143) [mean age—44.9 ± 12.5 years, 82.5% males, 48% alcoholic liver disease, 55.7% alcoholic hepatitis, AARC score: 9.4 ± 1.5, MELD score: 32 (IQR: 24–40)] of ACLF-without AVB. Despite PSM, ACLF patients with AVB had a higher baseline HVPG than without AVB (25.00 [IQR: 23.00–28.00] vs. 17.00 [15.00–21.75] mmHg; p = 0.045). The 6-week mortality in ACLF patients with or without AVB was 70.8% and 53.8%, respectively (p = 0.025). The 6-week rebleeding rate was 23% in ACLF-AVB. Presence of ascites [hazard ratio (HR) 2.2 (95% CI 1.03–9.8), p = 0.026], AVB [HR 1.9 (95% CI 1.2–2.5, p = 0.03)], and MELD score [HR 1.7 (95% CI 1.1–2.1), p = 0.001] independently predicted mortality in the overall ACLF cohort. Conclusion: Development of AVB confers poor outcomes in patients with ACLF with a high 6-week mortality. Elevated HVPG at baseline represents a potential risk factor for future AVB in ACLF. [ABSTRACT FROM AUTHOR]

The metabolites produced by the gut microbiota have been reported as crucial agents against obesity; however, their key targets have not been revealed completely in complex microbiome systems. Hence, the aim of this study was to decipher promising prebiotics, probiotics, postbiotics, and more importantly, key target(s) via a network pharmacology approach. First, we retrieved the metabolites related to gut microbes from the gutMGene database. Then, we performed a meta-analysis to identify metabolite-related targets via the similarity ensemble approach (SEA) and SwissTargetPrediction (STP), and obesity-related targets were identified by DisGeNET and OMIM databases. After selecting the overlapping targets, we adopted topological analysis to identify core targets against obesity. Furthermore, we employed the integrated networks to microbiota–substrate–metabolite–target (MSMT) via R Package. Finally, we performed a molecular docking test (MDT) to verify the binding affinity between metabolite(s) and target(s) with the Autodock 1.5.6 tool. Based on holistic viewpoints, we performed a filtering step to discover the core targets through topological analysis. Then, we implemented protein–protein interaction (PPI) networks with 342 overlapping target, another subnetwork was constructed with the top 30% degree centrality (DC), and the final core networks were obtained after screening the top 30% betweenness centrality (BC). The final core targets were IL6, AKT1, and ALB. We showed that the three core targets interacted with three other components via the MSMT network in alleviating obesity, i.e., four microbiota, two substrates, and six metabolites. The MDT confirmed that equol (postbiotics) converted from isoflavone (prebiotics) via Lactobacillus paracasei JS1 (probiotics) can bind the most stably on IL6 (target) compared with the other four metabolites (3-indolepropionic acid, trimethylamine oxide, butyrate, and acetate). In this study, we demonstrated that the promising substate (prebiotics), microbe (probiotics), metabolite (postbiotics), and target are suitable for obsesity treatment, providing a microbiome basis for further research. [ABSTRACT FROM AUTHOR]

Diet and lifestyle are crucial factors that influence the susceptibility of humans to nonalcoholic fatty liver disease (NAFLD). Personalized diet patterns chronically affect the composition and activity of microbiota in the human gut; consequently, nutrition-related dysbiosis exacerbates NAFLD via the gut–liver axis. Recent advances in diagnostic technology for gut microbes and microbiota-derived metabolites have led to advances in the diagnosis, treatment, and prognosis of NAFLD. Microbiota-derived metabolites, including tryptophan, short-chain fatty acid, fat, fructose, or bile acid, regulate the pathophysiology of NAFLD. The microbiota metabolize nutrients, and metabolites are closely related to the development of NAFLD. In this review, we discuss the influence of nutrients, gut microbes, their corresponding metabolites, and metabolism in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy. [ABSTRACT FROM AUTHOR]

Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD. [ABSTRACT FROM AUTHOR]

Purpose: The territorial involvement and the clinical benefit of endovascular therapy (EVT) of the posterior cerebral artery (PCA) occlusion may vary between patients. The purpose of this study was to investigate the feasibility of mechanical thrombectomy (MT) in isolated posterior cerebral artery occlusions (IPCAOs) and the prognostic factors of EVT. Methods: Forty-eight patients with acute PCA occlusion who underwent EVT between Mar 2008 and Apr 2021 from 2 tertiary centers were retrospectively analyzed. Clinical characteristics, imaging and perfusion abnormalities, and angiographic and clinical outcomes were analyzed. Ischemic changes were assessed with the posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS). Perfusion abnormalities were assessed using automated software for Tmax volume measurement and identification of Tmax involved in PCA eloquent areas. Results: The IPCAO sites were P1 (n = 17) and P2 (n = 31). Overall successful recanalization (mTICI 2b/3) was achieved in 68.8% (33/48) and excellent outcome (90-day mRS 0–1) in 52.1% (25/48) of the patients. Excellent/non-excellent outcome was associated with male sex (p = 0.036), admission NIHSS (p = 0.002), pc-ASPECTS (p = 0.035), Tmax > 6 s involvement of the midbrain-thalamus (p = 0.008), first-line stent-retriever thrombectomy (p = 0.036), complete recanalization (p = 0.009), and modified first pass effect (FPE, p = 0.047). Tmax>6 s involvement of the midbrain-thalamus was an independent predictor for non-excellent outcome on multivariable analysis. Conclusion: Acute stroke from IPCAO may be successfully treated with EVT. Tmax > 6 s involvement of the midbrain-thalamus on perfusion imaging may be a predictor for clinical outcome. [ABSTRACT FROM AUTHOR]

Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments. [ABSTRACT FROM AUTHOR]

Purpose: To report the long-term clinical and angiographic outcomes of the endovascular treatment of large/giant basilar tip aneurysms (BTAs) in our institutions. Methods: We retrospectively reviewed cases of BTA larger than 10 mm that received endovascular treatment between January 2009 and December 2019. Data on the demographic and clinical characteristics and radiologic severity were obtained from the patients' medical records. The collected clinical follow-up data included neurological evaluation. Magnetic resonance angiography (MRA) was performed 6 to 12 months after the procedure, followed by once every 1 to 2 years as needed. Results: A total of 12 patients with BTA were included in this study. The median age was 60.08 years (27–80 years), and the mean clinical follow-up was 66.78 months (19.00–142.87 months). Almost half of the patients presented with unruptured BTAs (58.33%, n = 7). The median maximum aneurysm diameter was 13.00 mm (10.46–20.90 mm) and the mean neck size was 8.34 mm (4.82–13.04 mm). A Modified Raymond Roy Classification (MRRC1) of 1 or 2 was observed in 66.67% of the patients (n = 8) immediately after the first procedure. Procedural morbidity and mortality were 33.33% and 8.33%, respectively. Major recanalization occurred in two patients, one of whom underwent additional coiling with the other being merely observed due to older age. Conclusion: It is very difficult to cure a large BTA completely at once and recanalization occurred often after endovascular treatment. Conducting long-term follow-up studies at short intervals is warranted, as well as improving existing treatment methods and developing new approaches. [ABSTRACT FROM AUTHOR]

Preoperative localisation studies are essential for parathyroidectomy in patients with primary hyperparathyroidism. If the location of abnormal parathyroid glands cannot be identified through non-invasive studies, parathyroid venous sampling (PVS) may be employed. In this study, we evaluated the utility of preoperative PVS in parathyroid surgery. Patients with primary hyperparathyroidism who underwent preoperative PVS at Severance Hospital between January 2015 and June 2020 were identified. Patients for whom the results of non-invasive imaging studies were inconsistent or negative underwent PVS. The results of PVS were compared with operative findings and pathologic results. For 14 patients, the results of preoperative ultrasonography and 99mTc-sestamibi single-photon emission computed tomography (SPECT) were negative; for 20 patients, either the result of only one test was positive, or the results of the two tests were inconsistent. With respect to the lateralisation of diseased adenoma, the results of PVS and pathological examination were inconsistent only for one patient in either group (total: 2/34 patients). This study showed that PVS could be used effectively for preoperative localisation in patients with primary hyperparathyroidism in whom the location of diseased parathyroid glands cannot be determined through non-invasive image studies. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut–liver axis. [ABSTRACT FROM AUTHOR]