Search

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

Background/aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients., Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted., Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching., Conclusions: Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes.

While steroid therapy is the preferred treatment for severe alcohol-associated hepatitis, the role of effector regulatory T (eTreg) cells and their association with steroid response and clinical outcomes in these patients remains to be elucidated. We prospectively enrolled 47 consecutive patients with alcohol-associated hepatitis, consisting of severe alcohol-associated hepatitis treated with steroids (n=18; steroid-treated group) and mild alcohol-associated hepatitis (n=29; nontreated group). After isolating peripheral blood mononuclear cells from the patients at enrollment and again 7 days later, the frequency of eTreg cells was examined using flow cytometry. Single-cell RNA sequencing analysis was conducted using paired peripheral blood mononuclear cells. In vitro experiments were also performed to assess phenotype changes and the suppressive function of Treg cells following steroid treatment. The steroid-treated group exhibited significantly higher Model for End-Stage Liver Disease scores than the nontreated group ( p < 0.01). Within the steroid-treated group, the proportion of eTreg cells significantly expanded in the steroid responders (n=13; p = 0.01). Furthermore, a significant positive correlation was observed between the decrease in the Model for End-Stage Liver Disease score and the increase in eTreg cells ( p < 0.05). Single-cell RNA sequencing using paired peripheral blood mononuclear cells (pre-steroid and post-steroid therapy) from a steroid responder revealed gene expression changes in T cells and monocytes, suggesting enhancement of Treg cell function. In vitro results showed an elevation in the proportion of eTreg cells after steroid therapy. In conclusion, our findings suggest that the efficacy of steroid therapy in patients with severe alcohol-associated hepatitis is mediated by an increase in the number of eTreg cells., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aim: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD)., Methods: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021., Results: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m 2 ; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m 2 ), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m 2 ; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively., Conclusion: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Nutritional status and sarcopenia affects the prognosis of head and neck cancers including hypopharyngeal cancer. Hypopharyngeal cancer patients tend to exhibit sarcopenia, which is associated with poor treatment outcomes. This study aims to determine the correlation between nutritional status and sarcopenia, and their prognostic role in surgically treated hypopharyngeal cancer., Materials and Methods: Patients who had been diagnosed with squamous cell carcinoma originating from the hypopharynx and underwent surgery between January 2009 and December 2019 were enrolled in this study. The median neutrophil-to-lymphocyte ratio and prognostic nutritional index (PNI) of the cohort were considered the cut-off values. Sarcopenia was evaluated by measuring skeletal muscle index (SMI) at the third lumbar vertebra. Clinical and serological factors predictive of survival outcomes were evaluated., Results: Patients with high PNI showed better 5-year Overall survival (OS) (52.8% vs. 27.2%, p = 0.001) and disease-free survival (DFS) (59.6% vs. 44.6%, p = 0.033) than those with low PNI. Likewise, patients with low SMI showed worse 5-year OS (25.0% vs. 60.9%, p = 0.002) and DFS (42.4% vs. 68.7%, p = 0.034) than patients with high SMI. Among the patients with high PNI, those with sarcopenia displayed significantly worse OS than those with high SMI (78.0% vs. 34.4%, p = 0.049). High PNI with high SMI presented better overall (p = 0.010) and DFS (p = 0.055) than any other group., Conclusions: Both sarcopenia and PNI were associated with the prognosis of hypopharyngeal cancer. Considering that PNI and sarcopenia indicate the nutritional status, nutritional status may be a significant risk factor. Therefore, nutritional support that ameliorates sarcopenia may improve survival outcomes in surgically treated patients with hypopharyngeal cancer., (© 2024 The Author(s). World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Objectives: Injection laryngoplasty (IL) has been widely used as an initial treatment option for unilateral vocal fold paralysis (UVFP). An additional (second) IL is considered a salvage treatment for unsatisfactory outcomes of initial IL resulting from inadequate injection or early resorption of the injection material. This study aims to evaluate the efficacy of additional IL, distinguishing between "salvage" (within 4 months) and "repeated" injections (beyond 4 months), and to analyze prognostic factors for successful outcomes., Methods: This retrospective study involved patients who received IL at Asan Medical Center from January 2014 to December 2020. Voice parameters were collected after each procedure, and those who conducted the statistical analysis were blinded to the study subjects. Among the 65 patients who underwent additional IL, 51 patients were enrolled in this study. Postinjection grade, roughness, breathiness, asthenia, strain (GRBAS) scales were used to determine satisfactory treatment outcomes. Success of the additional IL was defined as a postinjection grade of dysphonia score of 0 or 1, with a reduction in grade compared with the preinjection grade., Results: The mean age of the patients was 61.6 years. Out of a total of 51 patients, 37 were men participating in the study. The odds ratio represents the likelihood of success in the second IL. Improved voice outcome after the additional IL was maintained in 23 (45%) patients. Compared with the failure group, the success group had a longer injection time interval between the initial and additional injection (9.1 vs. 7.4 months, respectively, p = 0.010). The success group had a higher proportion of patients with injection intervals >6 months (73.9% vs. 42.9%, p = 0.026). Logistic regression analysis revealed an injection interval >6 months had an odds ratio of 0.265 (confidence interval: 0.080-0.874, p = 0.029)., Conclusions: Additional injections would benefit the patients whose voice outcomes are maintained for a longer period (>6 months) after the first injection., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Given its heterogeneity and diverse clinical outcomes, precise subclassification of Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment., Experimental Design: We recruited 2,626 patients with BCLC-C HCC from multiple centers, comprising training/test (n = 1,693) and validation cohorts (n = 933). The XGBoost model was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-, intermediate-, high-, and very high-risk subgroups 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-, and 24-month survival of patients with BCLC-C were 0.800, 0.831, and 0.715, respectively-significantly higher than those of the conventional models, which were 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 (TKI) 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., (©2024 American Association for Cancer Research.)

Lithium metal anode (LMA) emerges as a promising candidate for lithium (Li)-based battery chemistries with high-energy-density. However, inhomogeneous charge distribution from the unbalanced ion/electron transport causes dendritic Li deposition, leading to "dead Li" and parasitic reactions, particularly at high Li utilization ratios (low negative/positive ratios in full cells). Herein, an innovative LMA structural model deploying a hyperporous/hybrid conductive architecture is proposed on single-walled carbon nanotube film (HCA/C), fabricated through a nonsolvent induced phase separation process. This design integrates ionic polymers with conductive carbon, offering a substantial improvement over traditional metal current collectors by reducing the weight of LMA and enabling high-energy-density batteries. The HCA/C promotes uniform lithium deposition even under rapid charging (up to 5 mA cm -2 ) owing to its efficient mixed ion/electron conduction pathways. Thus, the HCA/C demonstrates stable cycling for 200 cycles with a low negative/positive ratio of 1.0 when paired with a LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathode (areal capacity of 5.0 mAh cm -2 ). Furthermore, a stacked pouch-type full cell using HCA/C realizes a high energy density of 344 Wh kg -1 cell /951 Wh L -1 cell based on the total mass of the cell, exceeding previously reported pouch-type full cells. This work paves the way for LMA development in high-energy-density Li metal batteries., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3β pS9 (GSK3β activity inhibition through serine 9 phosphorylation at GSK3β), p53 wild-type (p53 WT ), and p53 mutant (p53 MT ) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53 WT , and p53 MT and increase in GSK3β pS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3β pS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53 WT , p53 MT , and GSK3β pS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3β pS9 , for older patients at elevated risk of CRC., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Considering practical viability, Li-metal battery electrolytes should be formulated by tuning solvent composition similar to electrolyte systems for Li-ion batteries to enable the facile salt-dissociation, ion-conduction, and introduction of sacrificial additives for building stable electrode-electrolyte interfaces. Although 1,2-dimethoxyethane with a high-donor number enables the implementation of ionic compounds as effective interface modifiers, its ubiquitous usage is limited by its low-oxidation durability and high-volatility. Regulation of the solvation structure and construction of well-structured interfacial layers ensure the potential strength of electrolytes in both Li-metal and LiNi 0.8 Co 0.1 Mn 0.1 O 2 (NCM811). This study reports the build-up of multilayer solid-electrolyte interphase by utilizing different electron-accepting tendencies of lithium difluoro(bisoxalato) phosphate (LiDFBP), lithium nitrate, and synthetic 1-((trifluoromethyl)sulfonyl)piperidine. Furthermore, a well-structured cathode-electrolyte interface from LiDFBP effectively addresses the issues with NCM811. The developed electrolyte based on a framework of highly- and weakly-solvating solvents with interface modifiers enables the operation of Li|NCM811 cells with a high areal capacity cathode (4.3 mAh cm -2 ) at 4.4 V versus Li/Li + ., (© 2024 Wiley‐VCH GmbH.)

Electrolyte additives with multiple functions enable the interfacial engineering of Li-metal batteries (LMBs). Owing to their unique reduction behavior, additives exhibit a high potential for electrode surface modification that increases the reversibility of Li-metal anodes by enabling the development of a hierarchical solid electrolyte interphase (SEI). This study confirms that an adequately designed SEI facilitates the homogeneous supply of Li + , nonlocalized Li deposition, and low electrolyte degradation in LMBs while enduring the volume fluctuation of Li-metal anodes on cycling. An in-depth analysis of interfacial engineering mechanisms reveals that multilayered SEI structures comprising mechanically robust LiF-rich species, electron-rich P-O species, and elastic polymeric species enabled the stable charge and discharge of LMBs. The polymeric outer SEI layer in the as-fabricated multilayered SEI could accommodate the volume fluctuation of Li-metal anodes, significantly enhancing the cycling stability Li||LiNi 0.8 Co 0.1 Mn 0.1 O 2 full cells with an electrolyte amount of 3.6 g Ah -1 and an areal capacity of 3.2 mAh cm -2 . Therefore, this study confirms the ability of interfacial layers formed by electrolyte additives and fluorinated solvents to advance the performance of LMBs and can open new frontiers in the fabrication of high-performance LMBs through electrolyte-formulation engineering., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objectives: We primarily aimed to evaluate whether parotid incidental lesion (PIL) in 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) for staging evaluation of patients with hepatocellular carcinoma (HCC) would represent a possibility of extrahepatic metastasis or second primary malignancy (SPM). Additionally, we explored the incidence of PIL in HCC patients and examined any associated risk factors., Methods: We retrospectively analyzed patients with HCC who underwent 18 F-FDG PET/CT at our institution from 2010 to 2022. The pathological findings of PILs in HCC patients were investigated for confirmatory identification of the risk of HCC metastasis or SPM in parotid gland. Healthy controls received 18 F-FDG PET/CT for health screening were also enrolled to compare the incidence of PILs with HCC patients. Various parameters associated with patient demographics and characteristics of HCC were analyzed to find the related factors of PILs., Results: A total of 17,674 patients with HCC and 2,090 healthy individuals who had undergone 18 F-FDG PET/CT scans were enrolled in the analyses. Among the 54 HCC patients who underwent pathological confirmation for PILs, benign primary parotid tumor was most commonly observed (n = 43 [79.6%]); however, no malignant lesions were detected, including HCC metastasis. The incidence of PILs was higher in patients diagnosed with HCC compared with the control group (485 [2.7%] vs. 23 [1.1%], p = 0.002). Analysis for the risk factors for PILs revealed that patient age, sex, and positive viral markers were significantly associated with the incidence of PILs in patients with HCC (all p < 0.001)., Conclusions: Our study demonstrates that PILs are more frequently identified in patients with HCC on 18 F-FDG PET/CT. However, no malignant PIL, including extrahepatic metastasis of HCC, was identified. Therefore, the presence of PIL should not impede or delay the treatment process for patients with HCC. Additionally, we suggested that for future swift and straightforward differential diagnoses of PIL, the development of additional protocols within the PET/CT imaging could be beneficial., (© 2024. The Author(s).)

The rapidly increasing prevalence of obesity and overweight, especially in children and adolescents, has become a serious societal issue. Although various genetic and environmental risk factors for pediatric obesity and overweight have been identified, the problem has not been solved. In this study, we examined whether environmental nanoplastic (NP) pollutants can act as environmental obesogens using mouse models exposed to NPs derived from polystyrene and polypropylene, which are abundant in the environment. We found abnormal weight gain in the progeny until 6 weeks of age following the oral administration of NPs to the mother during gestation and lactation. Through a series of experiments involving multi-omic analyses, we have demonstrated that NP-induced weight gain is caused by alterations in the lipid composition (lysophosphatidylcholine/phosphatidylcholine ratio) of maternal breast milk and he gut microbiota distribution of the progeny. These data indicate that environmental NPs can act as obesogens in childhood., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The long-term kinetics of quantitative HBsAg levels in HBV-infected patients treated with entecavir or tenofovir, as well as the role of quantitative HBsAg in predicting functional cure (HBsAg loss) and low HBsAg levels (<2 log IU/mL) remain unclear. Of some 1661 consecutively enrolled patients newly treated with entecavir or tenofovir, we analyzed 852 patients who underwent serial HBsAg level checks every 6-12 months. The primary outcomes included long-term kinetics in HBsAg levels and the rate of functional cure and achieving low HBsAg levels. Over a mean 6.3-year follow-up, the functional cure rate was 2.28% (n = 19), and 12.9% (n = 108) achieved low HBsAg levels. A significant HBsAg level reduction was seen in the first treatment year ( p < 0.05), with another stepwise decrease between year 6-7. These trends were pronounced in patients with chronic hepatitis and HBeAg-positivity compared to those with cirrhosis and HBeAg-negativity, respectively. Baseline HBsAg of ≤3 log IU/mL and the first-year HBsAg reduction were key predictors for both functional cure and low HBsAg levels ( p < 0.05). In conclusion, our findings elucidate the stepwise reduction in quantitative HBsAg dynamics during high-potency NA therapy (entecavir or tenofovir) along with variations based on different conditions. We also underscore the significance of quantitative HBsAg titer in predicting functional cure and low-HBsAg levels.

Background: Cervical lymph node metastasis (CLNM) from remote primary sites is rare in head and neck cancer. The efficacy of neck dissection is still being investigated for therapeutic benefits of local management in oligometastasis from non-head and neck cancer., Objectives: To evaluate the clinical efficacy of neck dissection (ND) in CLNM from distant primary cancers and identify factors contributing to improved survival., Materials and Methods: This retrospective case-control study enrolled patients who underwent ND for CLNM from distant primary cancer at Asan Medical Centre between January 2010 and December 2020. We analysed overall survival and association between clinical covariate and survival., Results: The study included 31 (14 males, 17 females) among 114 patients. Ovarian cancer was the most common primary malignancy (32.3%). Patients with fewer than three metastatic lymph nodes, without extranodal extension and with adjuvant therapy after surgery had better survival rates., Conclusion and Significance: In patients with CLNM from a distant primary cancer, ND is beneficial as local treatment. And adequate selection of patients for ND is pivotal to improve prognosis.

ARL6IP1 is implicated in hereditary spastic paraplegia (HSP), but the specific pathogenic mechanism leading to neurodegeneration has not been elucidated. Here, we clarified the molecular mechanism of ARL6IP1 in HSP using in vitro and in vivo models. The Arl6ip1 knockout (KO) mouse model was generated to represent the clinically involved frameshift mutations and mimicked the HSP phenotypes. Notably, in vivo brain histopathological analysis revealed demyelination of the axon and neuroinflammation in the white matter, including the corticospinal tract. In in vitro experiments, ARL6IP1 silencing caused cell death during neuronal differentiation and mitochondrial dysfunction by dysregulated autophagy. ARL6IP1 localized on mitochondria-associated membranes (MAMs) to maintain endoplasmic reticulum and mitochondrial homeostasis via direct interaction with LC3B and BCl2L13. ARL6IP1 played a crucial role in connecting the endoplasmic reticulum and mitochondria as a member of MAMs. ARL6IP1 gene therapy reduced HSP phenotypes and restored pathophysiological changes in the Arl6ip1 KO model. Our results established that ARL6IP1 could be a potential target for HSP gene therapy., (© 2023 Lim et al.)

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment., Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs., Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 ( n = 84) had no irAEs, group 2 ( n = 37) had mild irAEs (grade 1-2), and group 3 ( n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months ( p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 ( p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS., Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis., Competing Interests: None to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. This study was designed to identify valuable prognosticator in MEC., Methods: Histopathologic analysis, immunohistochemistry, and in situ hybridization were performed on 128 carcinomas diagnosed as MEC of the head and neck., Results: Expression of p16 was found in 96 cases (76%) of MEC. Lymphoid stroma was identified in 63 cases (49%). There was a significant correlation between loss of p16 expression and absence of lymphoid stroma. Expression of p16 was significantly associated with better clinicopathologic features. Lymphoid stroma was significantly associated with lower histologic grade. Overall survival (OS) was significantly longer in cases expressing p16 (P = 0.00096) and lymphoid stroma cases (P = 0.0023). Multivariate analysis revealed loss of p16 expression as negative prognosticators for OS., Conclusion: Our data showed p16 expression and the presence of lymphoid stroma were significantly associated with good clinical outcomes. Testing for these factors could lead to better prognostication and treatment of patients with MEC., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer pathogenicity for hereditary spastic paraplegia (HSP) type SPG8, a rare neurodegenerative gait disorder. WASH complex activates actin-related protein-2/3-mediated actin polymerization and plays a pivotal role in intracellular membrane trafficking in endosomes. In this study, we examined the role of strumpellin in the regulation of structural plasticity of cortical neurons involved in gait coordination. Administration of a lentivirus containing a strumpellin-targeting short hairpin RNA (shRNA) to cortical motor neurons lead to abnormal motor coordination in mice. Strumpellin knockdown using shRNA attenuated dendritic arborization and synapse formation in cultured cortical neurons, and this effect was rescued by wild-type strumpellin expression. Compared with the wild-type, strumpellin mutants N471D or V626F identified in patients with SPG8 exhibited no differences in rescuing the defects. Moreover, the number of F-actin clusters in neuronal dendrites was decreased by strumpellin knockdown and rescued by strumpellin expression. In conclusion, our results indicate that strumpellin regulates the structural plasticity of cortical neurons via actin polymerization., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Next-generation battery development necessitates the coevolution of liquid electrolyte and electrode chemistries, as their erroneous combinations lead to battery failure. In this regard, priority should be given to the alleviation of the volumetric stress experienced by silicon and lithium-metal anodes during cycling and the mitigation of other problems hindering their commercialization. This review summarizes the advances in sacrificial compound-based volumetric stress-adaptable interfacial engineering, which has primarily driven the development of liquid electrolytes for high-performance lithium batteries. Besides, we discuss how the regulation of lithium-ion solvation structures helps expand the range of electrolyte formulations and thus enhance the quality of solid electrolyte interphases (SEIs), improve lithium-ion desolvation kinetics, and realize longer-lasting SEIs on high-capacity anodes. The presented insights are expected to inspire the design and synthesis of next-generation electrolyte materials and accelerate the development of advanced electrode materials for industrial battery applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ni-rich layered oxides are regarded as key components for realizing post Li-ion batteries (LIBs). However, high-valence Ni, which acts as an oxidant in deeply delithiated states, aggravates the oxidation of the electrolyte at the cathode, causing cell impedance to increase. Additionally, the leaching of transition metal (TM) ions from Ni-rich cathodes by acidic compounds such as Brønsted-acidic HF produced through LiPF 6 hydrolysis aggravates the structural instability of the cathode and renders the electrode-electrolyte interface unstable. Herein, we present a multifunctional electrolyte additive, bis(trimethylsilyl) phosphorofluoridate (BTSPFA), to attain enhanced interfacial stability of graphite anodes and Ni-rich cathodes in Li-ion cells. BTSPFA eliminates the corrosive HF molecules by cleaving silyl ether bonds and enables the formation of a polar P-O- and P-F-enriched cathode electrolyte interface (CEI) on the Ni-rich cathode. It also promotes the creation of a solid electrolyte interphase composed of inorganic-rich species, which suppresses the reduction of the electrolyte during battery operation. The synergistic effect of the HF scavenging ability of BTSPFA and the stable BTSPFA-promoted CEI effectively suppresses the TM leaching from the Ni-rich cathode while also preventing unwanted TM deposition on the anode. LiNi 0.8 Co 0.1 Mn 0.1 O 2 /graphite full cells with 1 wt % BTSPFA exhibited an enhanced discharge capacity retention of 79.8% after 500 cycles at 1C and 45 °C. These unique features of BTSPFA are useful for resolving the interfacial deterioration issue of high-capacity Ni-rich cathodes paired with graphite anodes.

The pulverization of lithium metal electrodes during cycling recently has been suppressed through various techniques, but the issue of irreversible consumption of the electrolyte remains a critical challenge, hindering the progress of energy-dense lithium metal batteries. Here, we design a single-ion-conductor-based composite layer on the lithium metal electrode, which significantly reduces the liquid electrolyte loss via adjusting the solvation environment of moving Li + in the layer. A Li||Ni 0.5 Mn 0.3 Co 0.2 O 2 pouch cell with a thin lithium metal (N/P of 2.15), high loading cathode (21.5 mg cm -2 ), and carbonate electrolyte achieves 400 cycles at the electrolyte to capacity ratio of 2.15 g Ah -1 (2.44 g Ah -1 including mass of composite layer) or 100 cycles at 1.28 g Ah -1 (1.57 g Ah -1 including mass of composite layer) under a stack pressure of 280 kPa (0.2 C charge with a constant voltage charge at 4.3 V to 0.05 C and 1.0 C discharge within a voltage window of 4.3 V to 3.0 V). The rational design of the single-ion-conductor-based composite layer demonstrated in this work provides a way forward for constructing energy-dense rechargeable lithium metal batteries with minimal electrolyte content., (© 2023. The Author(s).)

In view of their high theoretical capacities, nickel-rich layered oxides are promising cathode materials for high-energy Li-ion batteries. However, the practical applications of these oxides are hindered by transition metal dissolution, microcracking, and gas/reactive compound formation due to the undesired reactions of residual lithium species. Herein, we show that the interfacial degradation of the LiNi 0.9 Co x Mn y Al z O 2 (NCMA, x + y + z = 0.1) cathode and the graphite (Gr) anode of a representative Li-ion battery by HF can be hindered by supplementing the electrolyte with tert -butyldimethylsilyl glycidyl ether (tBS-GE). The silyl ether moiety of tBS-GE scavenges HF and PF 5 , thus stabilizing the interfacial layers on both electrodes, while the epoxide moiety reacts with CO 2 released by the parasitic reaction between HF and Li 2 CO 3 on the NCMA surface to afford cyclic carbonates and thus suppresses battery swelling. NCMA/Gr full cells fabricated by supplementing the baseline electrolyte with 0.1 wt % tBS-GE feature an increased capacity retention of 85.5% and deliver a high discharge capacity of 162.9 mAh/g after 500 cycles at 1 C and 25 °C. Thus, our results reveal that the molecular aspect-based design of electrolyte additives can be efficiently used to eliminate reactive species and gas components from Li-ion batteries and increase their performance.

Background: The most common type of carcinoma ex pleomorphic adenoma (CPA) is histologically equivalent to salivary duct carcinoma, which has an apocrine phenotype. Invasive CPA is often accompanied by non-invasive or in situ carcinoma, an observation that suggests the presence of precursor lesions. The aim of this study was to identify candidate precursor lesions of CPA within pleomorphic adenoma (PA)., Methods: Eleven resected cases of CPA with residual PA and 17 cases of PA with atypical changes were subjected to immunohistochemistry (IHC) for p53, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), pleomorphic adenoma gene 1, gross cystic disease fluid protein-15 (GCDFP-15), and anti-mitochondrial antibody., Results: Invasive or in situ carcinoma cells in all CPAs were positive for AR, GCDFP-15, and HER2. Atypical foci in PAs corresponded to either apocrine or oncocytic changes on the basis of their reactivity to AR, GCDFP-15, and anti-mitochondrial antibody. Atypical cells in PAs surrounding CPAs had an apocrine phenotype without HER2 expression., Conclusions: Our study identified frequent apocrine changes in residual PAs in CPA cases, suggesting a possible precursor role of apocrine changes. We recommend the use of HER2 IHC in atypical PAs, and that clinicians take HER2 positivity into serious consideration.

Background: Many previous studies evaluated a combination of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) for treating early hepatocellular carcinoma (HCC); however, studies evaluating combination therapy for beyond-the-Milan criteria HCC are scarce., Methods: A total of 120 patients with beyond-the-Milan criteria HCC who have viable tumour after first TACE will be enrolled in this multi-institutional, parallel, pragmatic, randomized controlled trial. Patients with metastasis, vascular invasion, or a sum of tumour diameter > 8 cm will be excluded. Eligible patients will be randomly assigned to combination TACE and RFA therapy or TACE monotherapy groups. Patients in the combination therapy group will receive a second TACE and subsequent RFA at the viable tumour. Patients in the TACE monotherapy group will receive only second TACE. Patients in both groups will undergo magnetic resonance imaging 4-6 weeks after second TACE. The primary endpoint is 1-month tumour response, and secondary endpoints are progression-free survival, overall response rate, number of treatments until CR, overall survival, and change in liver function., Discussion: Although TACE can be used to treat intermediate-stage HCC, it is difficult to achieve CR by first TACE in most intermediate-stage patients. Recent studies show a survival advantage of combination therapy over monotherapy. However, most studies evaluating combination therapy included patients with a single tumour sized < 5 cm, and no studies included patients with intermediate-stage but more advanced (i.e., beyond-the-Milan criteria) HCC. This study will evaluate the efficacy of combined TACE and RFA therapy for patients with advanced HCC within the intermediate stage., Trial Registration: Clinical Research Information Service (CRiS) KCT0006483., (© 2023. The Author(s).)

Objective: This study aimed to investigate the prevalence of burnout experiences and factors associated with burnout among Korean health care workers during the coronavirus disease 2019 (COVID-19) pandemic., Methods: A nationwide survey was conducted in 2021, and the sample comprised 1000 public health center employees. Multivariate linear regression was used to examine the factors associated with burnout among the participants during the COVID-19 pandemic. Perceived factors contributing to burnout were also analyzed using an open-ended question., Results: Personal (e.g., age, gender, and self-rated health) and work-related factors (e.g., type of job tasks and COVID-19-related discrimination experience) affected burnout among health care workers. However, organizational support, including emotional support and sufficient financial compensation, was associated with lower burnout., Conclusions: Ensuring sufficient support and rewards for health care workers is essential to guaranteeing their well-being during the current public health crisis., Competing Interests: Conflict of Interest: None declared., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Dysphagia and feeding tube dependency commonly occur in patients with laryngeal or hypopharyngeal cancer (LHC) during and after treatment, often leading to poor functional outcomes. Therefore, we examined the factors related to feeding tube dependency among advanced-stage LHC patients undergoing curative surgery. This study included 69 consecutive patients who underwent conservative surgery for previously untreated, advanced-stage LHC (squamous cell carcinoma) between 2006 and 2016. Persistent feeding tube dependency was defined as 1 year or more after treatment completion. Binary logistic regression analysis was used to determine the factors associated with reactive prolonged and persistent feeding tube dependency. Cox proportional hazard regression analysis was used to determine the association between feeding tube dependency and survival. None of the study patients had a prophylactic feeding tube, but 15 (21.7%) patients had reactive feeding tube placement for 3 months or more. A total of 9 (13.0%) patients had persistent feeding tube dependency. Univariate analysis showed that age, tracheostomy, and common terminology criteria for adverse events (CTCAE) ≥ 3 were significantly associated with reactive prolonged and persistent feeding tube dependency (all P < 0.05). In the multivariate analysis, advanced age and CTCAE ≥ 3 remained the independent factors of reactive prolonged and persistent feeding tube dependency (all P < 0.05). Feeding tube dependency was not associated with overall survival or disease-free survival (P > 0.1). Feeding tube dependency might be related to clinical factors, such as age and severe adverse events, in the patients undergoing function-preserving surgery for advanced-stage LHC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ni-rich cathodes are the most promising candidates for realizing high-energy-density Li-ion batteries. However, the high-valence Ni 4+ ions formed in highly delithiated states are prone to reduction to lower valence states, such as Ni 3+ and Ni 2+ , which may cause lattice oxygen loss, cation mixing, and Ni ion dissolution. Further, LiPF 6 , a key salt in commercialized electrolytes, undergoes hydrolysis to produce acidic compounds, which accelerate Ni-ion dissolution and the interfacial deterioration of the Ni-rich cathode. Dissolved Ni ions migrate and deposit on the surface of the graphite anode, causing continuous electrolyte decomposition and threatening battery safety by forming Li dendrites on the anode. Herein, 1,2-bis(diphenylphosphino)ethane (DPPE) chelates Ni ions dissolved from the Ni-rich cathode using bidentate phosphine moieties and alleviates LiPF 6 hydrolysis via complexation with PF 5 . Further, DPPE reduces the generation of corrosive HF and HPO 2 F 2 substantially compared to the amounts observed using trimethyl phosphite and tris(trimethylsilyl) phosphite, which are HF-scavenging additives. Li-ion cells with Ni-rich cathodes and graphite anodes containing DPPE exhibit remarkable discharge capacity retentions of 83.4%, with high Coulombic efficiencies of >99.99% after 300 cycles at 45 °C. The results of this study will promote the development of electrolyte additives., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The research, which was designed as a "pre- and post-single group" study, included patients with lower-limb amputation and aimed to evaluate the effectiveness of self-directed physical-strength training and cardiovascular exercise using a novel digital healthcare management service three times a week for 12 weeks. Muscle strength, thigh circumference, lipid profile and glycated hemoglobin levels, pulmonary function, quality of life, and physical activity level were evaluated before and after the intervention, while satisfaction was measured after the study. Among the 14 included patients, the proportion of adherence to the physical-strength training and physical-strengthening activity were 85.2% and 75.8%, respectively. The level of satisfaction with the digital healthcare management system was high. Significant changes were observed in the muscle-strength tests (dominant grip power and muscle strength of knee flexion and extension of the intact side), thigh circumference, and glycated hemoglobin levels. Further, the quality-of-life score showed improvement, although without significant differences. Individualized exercise management using the novel digital healthcare management system for lower-limb amputees could induce interest in self-care and promote physical activity and healthy behavior. Through this effect, we can expect a reduction in the incidence of cardiovascular diseases, diabetes mellitus, dyslipidemia, and severe injuries from falling.

Objectives: Obliteration with cauterization of the internal opening of pyriform sinus fistulas, with or without marsupialization, has been a mainstay for preventing recurrence. However, this procedure predisposes patients to recurrence caused by the reopening of the cauterized orifice. We applied suture ligation to secure the closure of the internal orifice following cauterization and evaluated treatment., Methods: A total of 42 patients were diagnosed with third or fourth branchial cleft anomaly with internal pyriform sinus fistula and treated either with cauterization or with cauterization and suture ligation, between January 2008 and December 2020. The medical records were reviewed to assess demographic characteristics, clinical presentations, diagnoses, surgical treatment, and outcomes. Treatment flow characteristics for intractable patients were analyzed., Results: The median age of onset was 9 years (range, 0-57 years). Neck swelling (n = 32, 76.2%) was commonly encountered symptom, and a history of neck infection was found in 27 patients (64.3%). After initial treatment, 11 cases (56.2%) recurred. Younger age (≤9 years) and thyroid involvement were associated with recurrence ( P  = .034 and P  = .046, respectively). Cauterization with suture ligation presented lower recurrence rate (19.2%) than cauterization only (37.5%, P  = .037). Cauterization with suture ligation for recurrent cases (n = 11) showed 81.8% (9/11) of cure rate. Intractable fistulas (n = 2) from both groups were also salvaged by suture ligation., Conclusions: Suture ligation with cauterization for an internal orifice of branchial anomaly showed lower recurrence rate than cauterization only. This method was beneficial for refractory cases.

Background/aims: To evaluate the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) therapy in hepatitis C virus (HCV)-infected Korean patients in a real clinical setting., Methods: A total of 273 patients who received LDV/SOF therapy between May 2016 and February 2021 were consecutively enrolled and analyzed. A per-protocol analysis was performed to evaluate the virologic response., Results: Seventy-five percent were infected with genotype 1, and 25% were infected with genotype 2. A hundred eightyone (66.3%) patients had chronic hepatitis, 74 (27.1%) had compensated cirrhosis, eight (2.9%) had decompensated cirrhosis, and 10 (3.7%) had undergone liver transplantation. Undetectable HCV RNA at week 4 was achieved in 90.2% (231/256) of patients, 99.2% (250/252) achieved the end of treatment response, and 98.1% (202/206) achieved sustained virologic response at 12 weeks post-treatment (SVR12). According to liver function, the SVR12 rates were 99.3% (135/136) in chronic hepatitis, 96.4% (53/55) in compensated cirrhosis, and 100% (6/6) in decompensated cirrhosis. The SVR12 rates according to the genotype were 98.2% (167/170) for genotype 1 and 97.2% (35/36) for genotype 2. An 8-week LDV/SOF treatment in treatment-naïve chronic hepatitis patients with HCV RNA &lt; 6,000,000 IU/mL at baseline resulted in 100% (23/23) SVR12 rates. Overall, LDV/SOF was tolerated well, with a 0.7% (2/273) discontinuation rate due to adverse events that were unrelated to LDV/SOF., Conclusion: LDV/SOF is effective and safe for treating HCV-infected Korean patients with high SVR12 rates.

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 &lt; 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.

Background & Aims: After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance., Methods: A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation., Results: Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis., Conclusions: The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients., Lay Summary: After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Spastin significantly influences microtubule regulation in neurons and is implicated in the pathogenesis of hereditary spastic paraplegia (HSP). However, post-translational regulation of the spastin protein remains nebulous. The association between E3 ubiquitin ligase and spastin provides a potential therapeutic strategy., Results: As evidenced by protein chip analysis, FBXL17 inversely correlated with SPAST-M1 at the protein level in vitro and, also in vivo during embryonic developmental stage. SPAST-M1 protein interacted with FBXL17 specifically via the BTB domain at the N-terminus of SPAST-M1. The SCF FBXL17 E3 ubiquitin ligase complex degraded SPAST-M1 protein in the nuclear fraction in a proteasome-dependent manner. SPAST phosphorylation occurred only in the cytoplasmic fraction by CK2 and was involved in poly-ubiquitination. Inhibition of SCF FBXL17 E3 ubiquitin ligase by small chemical and FBXL17 shRNA decreased proteasome-dependent degradation of SPAST-M1 and induced axonal extension. The SPAST Y52C mutant, harboring abnormality in BTB domain could not interact with FBXL17, thereby escaping protein regulation by the SCF FBXL17 E3 ubiquitin ligase complex, resulting in loss of functionality with aberrant quantity. Although this mutant showed shortening of axonal outgrowth, low rate proliferation, and poor differentiation capacity in a 3D model, this phenotype was rescued by inhibiting SCF FBXL17 E3 ubiquitin ligase., Conclusions: We discovered that a novel pathway, FBXL17-SPAST was involved in pathogenicity of HSP by the loss of function and the quantitative regulation. This result suggested that targeting FBXL17 could provide new insight into HSP therapeutics., (© 2022. The Author(s).)

Objective: Hypopharyngeal cancer is managed by either surgical resection or radiation therapy-based treatment. In choosing the treatment modality, the patient's swallowing function should be considered to achieve optimal treatment outcomes. This study aimed to stratify the risk factors predictive of postoperative dysphagia in hypopharyngeal cancer., Study Design: Retrospective study., Setting: Tertiary referral center., Methods: We enrolled 100 patients who were diagnosed with hypopharyngeal cancer and underwent curative surgery between January 2010 and December 2019, and retrospectively reviewed their medical records., Results: Postoperative dysphagia occurred in 29 patients (29%) who required a tracheostomy tube or percutaneous gastrostomy tube for feeding or preventing aspiration; additionally, the overall survival rate was lower in those patients than in those without dysphagia. The univariate analysis revealed that postoperative dysphagia was associated with clinical T stage ( p  = 0.016), N stage ( p  = 0.002), and surgical resection extent of the larynx and pharynx ( p  < 0.001). Patients who underwent total laryngectomy with total/partial pharyngectomy were more likely to have dysphagia than those in the larynx-preserving pharyngectomy groups (odds ratio [OR] = 3.208, 95% confidence interval [CI] 1.283-8.024, p  = 0.011). Concerning the posterior pharyngeal wall (PPW), which has an important role in swallowing, patients who underwent resection of ≥1/2 of the PPW were more likely to have dysphagia (OR = 7.467, 95% CI 1.799-30.994, p  = 0.003)., Conclusions: Surgical resection extent was proportionally associated with dysphagia in hypopharyngeal cancer patients. Patients with smaller lesions but no laryngeal invasion had better postoperative swallowing function than patients with larger lesions or laryngeal involved lesions. Preserving the larynx and hypopharyngeal mucosa (especially the PPW) as much as possible can help preserve postoperative swallowing function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Joo, Lee, Jung, Choi, Nam and Kim.)

Background and Purpose: Hereditary spastic paraplegia (HSP) progresses over time and is associated with locomotive dysfunction. Understanding the factors affecting disease severity and locomotive function is important in HSP. This study investigated the factors influencing disease severity and ambulation status of HSP., Methods: We consecutively enrolled 109 Korean patients (64 males, and 45 females)from 84 families with a clinical diagnosis of HSP. HSP was primarily diagnosed based on clinical criteria including clinical findings, family history, and supported by genetic studies. Epidemiological and clinical features of the patients were analyzed, and the Spastic Paraplegia Rating Scale (SPRS) score and ambulatory status were used to evaluate disease severity., Results: Ninety-two (84.4%) patients had pure HSP, and 55 (50.4%) had a dominant family history. Thirty-one (28.4%) patients required a mobility aid for locomotion. A Kaplan-Meier analysis showed that HSP patients lost their independent gait ability after a median disease duration of 34 years. Those with an age at onset of ≤18 years had a longer median independent walking time. Pure HSP is characterized by predominant bilateral lower extremity weakness and spasticity, whereas complicated HSP presents more complex neurological findings such as ocular and bulbar symptoms, ataxia, and cognitive impairment. Complicated HSP was significantly correlated with the SPRS mobility score (β=3.70, 95% confidence interval=0.45-6.94). The age at onset and disease duration were significantly correlated with disease severity, and they were significant predictors of the use of a mobility aid ( p <0.05)., Conclusions: These findings suggest that a later age at onset and longer disease duration are significant factors affecting the disease severity and ambulatory function in patients with HSP. These findings can help clinicians to identify subjects at risk of locomotive impairment., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 Korean Neurological Association.)

Objective: Postoperative delirium is known to have various adverse effects on head and neck surgery patients. This study was designed to identify possible risk factors of delirium following long periods of head and neck cancer surgery and to help prevent postoperative delirium., Methods: We enrolled 197 patients who underwent long-time (>6 h) head and neck surgery at the Asan Medical Center from January 2017 to December 2018 in this study. Clinical covariates that may be associated with delirium were analyzed retrospectively using univariate and multivariate analyses., Results: Delirium occurred in 18 patients (9.1%). Within the first 7 days, 16 patients (88.9%) experienced delirium. Upon univariate analysis, delirium was associated with old age (≥75, p  = 0.001), past neurological history ( p  = 0.019), time to ambulation ( p  = 0.014), and postoperative hospital day ( p  = 0.048). In multivariate analysis, old age (≥75, odds ratios (OR) 6.16, CI 2.00-19.00, p  = 0.002), time to ambulation (OR 1.04, CI 1.01-1.07, p  = 0.017), and past neurological history (OR 5.26, CI 1.09-25.37, p  = 0.039) were significant risk factors associated with postoperative delirium., Conclusions: Older patients or patients with neurologic history must be attended with care, especially early after surgery. Encouraging early ambulation might lower the incidence of postoperative delirium and, subsequently, reduce adverse effects. This result could benefit patients by helping them avoid undesirable outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Lee, Kim, Cho, Jung, Choi, Nam and Kim.)

As global plastic production continues to grow, microplastics released from a massive quantity of plastic wastes have become a critical environmental concern. These microplastic particles are found in a wide range of living organisms in a diverse array of ecosystems. In this study, we investigated the biological effects of polystyrene nanoplastic (PSNP) on development of the central nervous system using cultured neural stem cells (NSCs) and mice exposed to PSNP during developmental stages. Our study demonstrates that maternal administration of PSNP during gestation and lactating periods altered the functioning of NSCs, neural cell compositions, and brain histology in progeny. Similarly, PSNP-induced molecular and functional defects were also observed in cultured NSCs in vitro. Finally, we show that the abnormal brain development caused by exposure to high concentrations of PSNP results in neurophysiological and cognitive deficits in a gender-specific manner. Our data demonstrate the possibility that exposure to high amounts of PSNP may increase the risk of neurodevelopmental defects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Injection laryngoplasty (IL) is performed to reduce the gap between vocal folds induced by unilateral vocal fold paralysis (UVFP). Voice quality after IL may be different due to other factors that influence voice quality. Voice therapy has been reported to improve voice quality after IL in patients with UVFP. This study evaluated the efficacy of voice therapy combined with IL., Methods: Patients with UVFP who underwent IL as primary therapy from March 2017 to June 2019 were evaluated. The enrolled patients were divided into two groups, those who did and did not receive voice therapy after IL. Voice quality was evaluated using perceptual, acoustic, and aerodynamic parameters, and voice handicap index-30 scores one month after IL and after completing each treatment., Results: Of 261 patients who underwent IL during the study period, 40 were enrolled, including 21 who did and 19 who did not receive voice therapy. Voice parameters one month after IL did not differ between these two groups. Jitter, shimmer, noise-to-harmonic ratio, and mean flow rate decreased, while maximum phonation time increased after voice therapy (both P < 0.05). In the absence of voice therapy, improved voice parameters were maintained for six months after IL. Total voice handicap index-30 scores decreased, from 35.6 to 19.1 (P < 0.05), in patients who received voice therapy., Conclusion: Voice therapy following IL is beneficial to patients with UVFP. Combined treatment can help to maintain improved voice quality more than six months after IL., (Copyright © 2020 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca 2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP., (© 2021. The Author(s).)

(1) Background: Facial nerve resection with reconstruction helps achieve optimal outcomes in the treatment of facial nerve invasion (FNI) of parotid cancer. Preoperative imaging is crucial to predict facial nerve reconstruction. The radiological findings of CT or MRI may predict FNI in the parotid cancer even without facial paralysis. Methods: We retrospectively reviewed the records of 151 patients without facial nerve paralysis before surgery who had undergone tumor resection. Previously untreated parotid cancers were included. (2) Results: The median follow-up duration was 62 months (range: 24-120 months). The FNI (+) group ( n = 30) showed a significantly worse 5-year overall survival compared with the FNI (-) group (75.5 vs. 93.9%; hazard ratio = 4.19; 95% confidence interval: 1.74-10.08; p = 0.001). The tumor margin, tumor size, presence in the anterolateral parotid region (area 3), retromandibular vein involvement, distance from the stylomastoid foramen to the upper tumor margin, and a high tumor grade were significant factors related to FNI in the univariate analysis. A spiculated tumor margin, the tumor size (2.2 cm), and presence in area 3 were factors predicting FNI in the logistic regression model ( p = 0.020, 0.005, and 0.050, respectively; odds ratio: 4.02, 6.40, and 8.16, respectively). (3) Conclusions: The tumor size (≥2.2 cm), spiculated margin, and presence in area 3 as presented in CT and MRI may help clinicians preoperatively predict FNI in patients with parotid cancer and establish an appropriate surgical plan.

Background: Thyroid lobectomy is recommended as the primary treatment for low-risk thyroid cancer. However, recurrence and hypothyroidism may develop after lobectomy, necessitating thyroid hormone supplementation. The 2015 American Thyroid Association (ATA) guidelines recommended post-lobectomy thyroid-stimulating hormone (TSH) suppression. This study examined the need for TSH suppression and recurrence after lobectomy for unilateral papillary thyroid carcinoma (PTC)., Methods: This study involved 369 patients who underwent thyroid lobectomy and ipsilateral central neck dissection for PTC between 2007 and 2015. Thyroid function tests were performed before and regularly after lobectomy. Binary logistic regression analyses were used to find factors predictive of the post-lobectomy need for TSH suppression that was defined by the 2015 ATA guidelines., Results: Serum TSH concentrations gradually increased after lobectomy: proportions with TSH >2 mIU/L at post-lobectomy 1, 3-6, 12, and 24 months were found in 77.0%, 82.3%, 66.7%, and 59.9%, respectively. After lobectomy, 168 (45.5%) patients received levothyroxine (T4) supplementation. Multivariate logistic regression analyses showed that pre-TSH level >2 mIU/L was the sole independent variable predictive of the need for post-lobectomy TSH suppression (P = 0.003). During the median follow-up of 72 months, recurrence was found in 4 (1.1%) patients who never received T4 supplementation and had post-lobectomy TSH levels >2 mIU/L., Conclusions: Our data show that thyroid lobectomy for unilateral PTC is associated with a low recurrence rate, but a significant risk of hypothyroidism. Preoperative TSH level can predict the need for post-lobectomy TSH suppression compliant with the 2015 ATA guidelines., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The neural circuits of the infant brain are rapidly established near 6 months of age, but neurodevelopmental disorders can be diagnosed only at the age of 2-3 years using existing diagnostic methods. Early diagnosis is very important to alleviate life-long disability in patients through appropriate early intervention, and it is imperative to develop new diagnostic methods for early detection of neurodevelopmental disorders. We examined the serum level of secretogranin II (SCG2) in pediatric patients to evaluate its potential role as a biomarker for neurodevelopmental disorders. A plasmonic immunosensor performing an enzyme-linked immunosorbent assay (ELISA) on a gold nanodot array was developed to detect SCG2 in small volumes of serum. This nanoplasmonic immunosensor combined with tyramide signal amplification was highly sensitive to detect SCG2 in only 5 μL serum samples. The analysis using the nanoplasmonic immunosensor revealed higher serum SCG2 levels in pediatric patients with developmental delay than in the control group. Overexpression or knockdown of SCG2 in hippocampal neurons significantly attenuated dendritic arborization and synaptic formation. These results suggest that dysregulated SCG2 expression impairs neural development. In conclusion, we developed a highly sensitive nanoplasmonic immunosensor to detect serum SCG2, a candidate biomarker for the early diagnosis of neurodevelopmental disorders., (© 2021. The Author(s).)

Objectives/hypothesis: There may be an interobserver variation in the diagnosis of laryngeal disease based on laryngoscopic images according to clinical experience. Therefore, this study is aimed to perform computer-assisted diagnosis for common laryngeal diseases using deep learning-based disease classification models., Study Design: Experimental study with retrospective data METHODS: A total of 4106 images (cysts, nodules, polyps, leukoplakia, papillomas, Reinke's edema, granulomas, palsies, and normal cases) were analyzed. After equal distribution of diseases into ninefolds, stratified eightfold cross-validation was performed for training, validation process and remaining onefold was used as a test dataset. A trained model was applied to test sets, and model performance was assessed for precision (positive predictive value), recall (sensitivity), accuracy, F1 score, precision-recall (PR) curve, and PR-area under the receiver operating characteristic curve (PR-AUC). Outcomes were compared to those of visual assessments by four trainees., Results: The trained deep neural networks (DNNs) outperformed trainees' visual assessments in discriminating cysts, granulomas, nodules, normal cases, palsies, papillomas, and polyps according to the PR-AUC and F1 score. The lowest F1 score and PR-AUC of DNNs were estimated for Reinke's edema (0.720, 0.800) and nodules (0.730, 0.780) but were comparable to the mean of the two trainees' F1 score with the best performances (0.765 and 0.675, respectively). In discriminating papillomas, the F1 score was much higher for DNNs (0.870) than for trainees (0.685). Overall, DNNs outperformed all trainees (micro-average PR-AUC = 0.95; macro-average PR-AUC = 0.91)., Conclusions: DNN technology could be applied to laryngoscopy to supplement clinical assessment of examiners by providing additional diagnostic clues and having a role as a reference of diagnosis., Level of Evidence: 3 Laryngoscope, 131:2558-2566, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed. In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency. Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Currently, it is difficult to predict the reversibility of renal function and to discriminate renal parenchymal injury in cirrhotic patients with acute kidney injury (AKI). The aim of this study is to evaluate whether urine N -acetyl-β-d-Glucosaminidase (NAG) can predict the survival and response to terlipressin in cirrhotic patients with AKI., Methods: Two hundred sixty-two cirrhotic consecutive patients who developed AKI were prospectively enrolled from 11 tertiary medical centers in Korea between 2016 to 2019. AKI was defined as an increase in serum Cr (SCr) of 0.3 mg/dL or a 50% increase in baseline SCr. Patients diagnosed with hepatorenal syndrome (HRS-AKI) were treated with terlipressin plus albumin., Results: The patients were 58.8 ± 12.9 years old on average and were predominantly male (72.5%). The mean MELD score was 25.3 ± 9.1. When classified according to the AKI phenotype, there were 119 pre-renal, 52 acute tubular necrosis, 18 miscellaneous, and 73 HRS-AKI patients. However, the urine NAG was not effective at discriminating AKI phenotypes, except for HRS-AKI. The baseline urine NAG increased as the baseline AKI stage increased ( p < 0.001). In addition, within the same AKI stage, the urine NAG values were significantly lower in the AKI-resolved group than in the unresolved group. The urine NAG level was significantly lower in living patients compared with those who died or who underwent a liver transplant within 3 months ( p = 0.005). In the multivariate analysis, the increased urine NAG was a significant risk factor for the 3-month transplant-free survival (TFS) rate, especially in patients with Child-Pugh class ≤ B or MELD < 24. The urine NAG did not predict the response to terlipressin treatment in patients with HRS., Conclusions: Urine NAG is strongly associated with the severity of AKI in patients with liver cirrhosis and is useful for predicting the 3-month TFS.