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Purpose: This study aimed to investigate a deep learning model to classify amyloid plaque deposition in the brain PET images of patients suspected of Alzheimer's disease., Methods: A retrospective study was conducted on patients who were suspected of having a mild cognitive impairment or dementia, and brain amyloid 18 F florapronol PET/computed tomography images were obtained from 2019 to 2022. Brain PET images were visually assessed by two nuclear medicine specialists, who classified them as either positive or negative. Image rotation was applied for data augmentation. The dataset was split into training and testing sets at a ratio of 8 : 2. For the convolutional neural network (CNN) analysis, stratified k-fold ( k  = 5) cross-validation was applied using training set. Trained model was evaluated using testing set., Results: A total of 175 patients were included in this study. The average age at the time of PET imaging was 70.4 ± 9.3 years and included 77 men and 98 women (44.0% and 56.0%, respectively). The visual assessment revealed positivity in 62 patients (35.4%) and negativity in 113 patients (64.6%). After stratified k-fold cross-validation, the CNN model showed an average accuracy of 0.917 ± 0.027. The model exhibited an accuracy of 0.914 and an area under the curve of 0.958 in the testing set. These findings affirm the model's high reliability in distinguishing between positive and negative cases., Conclusion: The study verifies the potential of the CNN model to classify amyloid positive and negative cases using brain PET images. This model may serve as a supplementary tool to enhance the accuracy of clinical diagnoses., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Direct-acting antiviral agents (DAAs) achieve high sustained virologic response (SVR) in chronic hepatitis C patients; yet a proportion of patients still experience de novo liver complications after SVR. Identification of risk factors is clinically important. FIB-4 index is a useful noninvasive tool to assess fibrosis, while neutrophil-to-lymphocyte ratio (NLR) is a biomarker for systemic inflammation. Our study aimed to investigate whether the addition of NLR can increase the prediction power of pre-DAA FIB-4 for de novo liver complications after SVR., Methods: We recruited patients via The Taiwan HCV Registry (TACR) and National Health Insurance Registry Database. The inclusion criteria were patients who achieved SVR12 after DAA and were followed for at least 24 months after SVR12. Liver complications included ascites, hepatic encephalopathy, variceal bleeding, and HCC., Results: Totally 7657 patients were recruited from 2013 to 2018. Among them, 3674 patients (48.0%) had a FIB-4 value > 3.25 and 491 patients (6.4%) had a NLR >4 before DAA. After two-year of follow-up after SVR 12, 214 patients (2.8%) developed de novo liver complications. Factors associated with liver complications included male gender, diabetes mellitus, hyperlipidemia, chronic kidney disease, and pre-DAA FIB-4 >3.25 in multivariate analyses. Addition of NLR slightly did not increase the power of predicting liver complications., Conclusions: The overall incidence of de novo liver complications after SVR is low during short-term follow-up. Elevated pre-DAA FIB-4 is associated with de novo liver complications after SVR, whereas the addition of pre-DAA NLR does not increase the prediction power., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Recent research suggests that advanced liver fibrosis could be reversed, but the therapeutic agents needed for the prevention of liver fibrosis remain to be elucidated. The beneficial effects of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) on liver fibrosis have been reported. However, the large-scale production of MSC-EVs remains challenging. The present study investigated the therapeutic effects of mouse MSC-derived EV mimetics (MEVMs) in combination with curcumin (antifibrotic compound) using a mouse model of thioacetamide-induced liver fibrosis. MEVMs were prepared through the serial extrusion of MSCs. These MEVMs were similar in size and morphology to the EVs. The biodistribution study showed that fluorescently labeled MEVMs predominantly accumulated in the liver. The establishment of liver fibrosis was confirmed via increased collagen (histology), liver fibrosis score, α-smooth muscle actin (α-SMA), and vimentin proteins levels. Treatment with MEVMs, curcumin, or their combination decreased the amount of collagen in liver tissues, with the antifibrotic effects of MEVMs being further confirmed by the liver fibrosis score. All treatments decreased the expression of collagen 1α , α-SMA, and vimentin. MEVMs showed superior effects than curcumin. Thus, MSC-derived EVMs could be a potential alternative for the treatment of liver fibrosis., Competing Interests: The authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (© 2024 The Author(s). Published by Elsevier BV on behalf of The Japanese Society for Regenerative Medicine.)

In the field of regenerative medicine, umbilical cord-derived mesenchymal stem cells (UC-MSCs) have a plausible potential. However, traditional two-dimensional (2D) culture systems remain limited in replicating the complex in vivo microenvironment. Thus, three-dimensional (3D) cultures offer a more physiologically relevant model. This study explored the impact of 3D culture conditions on the UC-MSC secretome and its ability to promote angiogenesis, both in vitro and in vivo . In this study, using two distinct methods, we successfully cultured UC-MSCs: in a monolayer (2D-UC-MSCs) and as spheroids formed in U-shaped 96-well plates (3D-UC-MSCs). The presence and expression of proangiogenic miRNAs in the conditioned media (CM) of these cultures were investigated, and differential expression patterns were explored. Particularly, the CM of 3D-UC-MSCs revealed significantly higher levels of miR-21-5p, miR-126-5p, and miR-130a-3p compared to 2D-UC-MSCs. Moreover, the CM from 3D-UC-MSCs revealed a higher effect on endothelial cell proliferation, migration, and tube formation than did the CM from 2D-UC-MSCs, indicating their proangiogenic potential. In an in vivo Matrigel plug mouse model, 3D-UC-MSCs (cells) stimulated greater vascular formation compared to 2D-UC-MSCs (cells). 3D culture of UC-MSCs' secretome improves the promotion of angiogenesis., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy., Methods: A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA., Results: A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not., Conclusions: Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve., Plain Language Summary: The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival., (© 2024 American Cancer Society.)

Exosomes are extracellular vesicles well known for facilitating cell-to-cell communication by distributing essential macromolecules like proteins, DNA, mRNA, lipids, and miRNA. These vesicles are abundant in fluids distributed throughout the body, including urine, blood, saliva, and even bile. They are important diagnostic tools for breast, lung, gastrointestinal cancers, etc. However, their application as cancer biomarkers has not yet been implemented in most parts of the world. In this review, we discuss how OMICs profiling of exosomes can be practiced by substituting traditional imaging or biopsy methods for cancer detection. Previous methods like extensive imaging and biopsy used for screening were expensive, mostly invasive, and could not easily provide early detection for various types of cancer. Exosomal biomarkers can be utilized for routine screening by simply collecting body fluids from the individual. We anticipate that the use of exosomes will be brought to light by the success of clinical trials investigating their potential to enhance cancer detection and treatment in the upcoming years., (© 2024. The Author(s).)

Exosomes are a subgroup of extracellular vesicles that function as transmitters, allowing cells to communicate more effectively with each other. However, exosomes may have both beneficial and harmful impacts on central nervous system disorders. Hence, the fundamental molecular mechanisms of the origin of illness and its progression are currently being investigated. The involvement of exosomes in the origin and propagation of neurodegenerative illness has been demonstrated recently. Exosomes provide a representation of the intracellular environment since they include various essential bioactive chemicals. The latest studies have demonstrated that exosomes transport several proteins. Additionally, these physiological vesicles are important in the regeneration of nervous tissue and the healing of neuronal lesions. They also offer a microenvironment to stimulate the conformational variation of concerning proteins for aggregation, resulting in neurodegenerative diseases. The biosynthesis, composition, and significance of exosomes as extracellular biomarkers in neurodegenerative disorders are discussed in this article, with a particular emphasis on their neuroprotective effects., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) reduce the risk of hepatocellular carcinoma (HCC) in patients of hepatitis B. This study compared the difference between ETV and TDF on risk of HCC recurrence and mortality in patients with HBV-related HCC after curative intent treatment., Methods: Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared., Results: We identified 390 HBV-related HCC patients with curative intent treatment for HCC and treated with ETV (n = 328) or TDF (n = 62) between January 2011 and December 2020. The median age was 60 years, and 90.7% patients were males. After a median follow-up of 29 months, 186 patients developed recurrent HCC and 111 died. The baseline characteristics were comparable except more ALBI grade 3 patients in TDF group (76% vs. 48%, P < 0.001). Compared to ETV group, TDF users had lower all-cause mortality (adjusted hazard ratio [aHR]: 0.38, P = 0.003), and HCC-related mortality (aHR: 0.23, P = 0.005). Lower recurrence rate was noticed in TDF users after inverse probability of treatment weighting (IPTW). TDF users had improved ALBI grade and FIB-4 index compared with ETV groups., Conclusion: TDF therapy is associated with a reduced risk of HCC-related outcomes among patients with HBV-related HCC after curative intent treatment compared with ETV usage., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to perform a systematic review and meta-analysis on the efficacy of empirical high-dose radioiodine therapy in treating differentiated thyroid cancer patients with thyroglobulin (Tg)-elevated negative iodine scintigraphy (TENIS) syndrome., Methods: We searched PubMed, EMBASE, and the Cochrane Library to identify relevant studies published until April 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and registered in an international prospective register of systematic reviews (PROSPERO). Meta-analyses of proportions and odds ratios were performed to assess the beneficial effect of empirical high-dose radioiodine therapy in patients with TENIS syndrome. Subgroup analysis was also performed according to the presence of micrometastasis or macrometastasis., Results: We identified 14 studies including 690 patients who received empirical high-dose radioiodine therapy for TENIS syndrome. Those who had micrometastasis exhibited additional lesions not previously observed on diagnostic whole-body scan (prop = 0.64, 95% confidence interval [CI], 0.51-0.77) and had reduced serum Tg levels (prop = 0.69; 95% CI, 0.52-0.84) after empirical radioiodine treatment. No such findings were observed among patients with macrometastasis. Moreover, we found that the empirical radioiodine treatment group had lower serum Tg levels than did controls (odds ratio = 0.27; 95% CI, 0.09-0.87), which suggests a lower risk of disease progression., Conclusions: Our findings indicate that empirical high-dose radioiodine therapy promoted beneficial effects and could be recommended for patients with TENIS syndrome, especially those with micrometastasis., Competing Interests: Conflicts of interest and sources of funding: none declared. This work was supported by the National Cancer Center Grants (NCC-2112570-1) from the National Cancer Center (Republic of Korea)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

An efficient cyclization for the synthesis of 1,2,4,5-tetra-substituted benzenes via copper catalyzed dimerization of γ,δ-unsaturated ketones has been described. This one-pot procedure employs the γ,δ-unsaturated ketones as the sole substrate with multiple C-C bond formation. This protocol features broad substrate scope and provides a facile and robust method to construct polysubstituted benzene derivatives under mild conditions.

Introduction: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB., Methods: Patients with CHB were consecutively recruited between 2006 and 2021. The presence of MD was based on the 5 cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria., Results: Eleven thousand five hundred two treatment-naive noncirrhotic patients with CHB were included with a median follow-up of 5.3 years. Patients in the MD group (n = 7,314) were older and had lower hepatitis B virus DNA levels than non-MD patients (n = 4,188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, P < 0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI: 1.03-1.63, P = 0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, P = 0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within 5 years, 95% CI: 0.44-0.74, P < 0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, P = 0.020). Among individuals with hepatic steatosis, patients with MASLD exhibited a higher cirrhosis risk than non-MD patients., Discussion: Concurrent and new-onset MDs increase the risks of cirrhosis and cirrhotic complications in patients with CHB, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression., (Copyright © 2024 by The American College of Gastroenterology.)

Bone cancer among adolescents and children exhibits varying survival outcomes based on disease state. While localized bone cancer cases have a survival rate exceeding 70%, metastatic, refractory, and recurrent forms are associated with significantly poorer prognoses. Initially believed to be mere vehicles for cellular waste disposal, exosomes are now recognized as extracellular vesicles facilitating intercellular communication. These vesicles influence cellular behaviors by transporting various biomolecules, such as proteins, DNA, RNA, and lipids, among cells. The role of exosomes in regulating the progression of bone cancer is increasingly evident, impacting critical processes like tumorigenesis, proliferation, metastasis, angiogenesis, immune evasion, and drug resistance. Current research underscores the substantial potential of exosomes in promoting the progression and development of bone cancer. This review delves into the complex process of exosome biogenesis, the variety of cell-derived exosome sources, and their applications in drug delivery and therapeutics. It also examines ongoing clinical trials focused on exosome cargo levels and discusses the challenges and future directions in exosome research. Unlike costly and invasive traditional diagnostic methods, exosomal biomarkers offer a non-invasive, cost-effective, and readily accessible routine screening through simple fluid collection that aims to inspire researchers to investigate the potential of exosomes for cancer theragnostic. Through comprehensive exploration of these areas, the review seeks to enhance understanding and foster innovative solutions to cancer biology in the near future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: This study examines the diagnostic potential of whole-body blood pool scintigraphy (WBBPS) using technetium-99 m-labeled red blood cells to detect congenital vascular malformations (CVMs). It aims to compare its efficacy with traditional imaging techniques such as magnetic resonance imaging (MRI) and ultrasonography (USG), emphasizing its potential advantages in terms of characterization of lesions and capacity for whole-body assessment., Methods: The efficacy of WBBPS and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging in diagnosing CVMs, comparing them with USG and MRI results, was evaluated in this retrospective study. Of the 38 patients, 21 were evaluated using these diagnostic methods, with CVMs classified according to the International Society for the Study of Vascular Anomalies guidelines. Also, this study aimed to elucidate the characteristics between WBBPS, SPECT/CT, USG, or MRI findings and their consistency with the final diagnosis., Results: A total of 21 participants were included in this study, with an average age of 17.7 years old, with female predominance (57.1%). The most common diagnosis was vascular malformations (VMs) (71.4%), followed by combined vascular malformations (14.3%) and lymphatic malformations (9.5%). WBBPS demonstrated positive results in 95.2% of cases. Distinct imaging patterns for each condition were observed, with WBBPS being crucial in locating lesions., Conclusion: The study findings suggested that WBBPS with SPECT/CT could be helpful in detecting occult VM lesions and ruling out a lymphatic malformation diagnosis. Thus, it can be employed in the evaluation of CVMs., Competing Interests: Conflict of InterestJunik Son, Chae Moon Hong, Jaetae Lee, Ho Yun Chung, and Byeong-Cheol Ahn declare no competing interests., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background & Aims: Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear., Methods: Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups., Results: From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010)., Conclusions: In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to determine the usefulness of adding SPECT/CT to radioiodine whole-body scans (WBSs) for the treatment of differentiated thyroid cancer (DTC)., Patients and Methods: A systematic review and meta-analysis were performed following the PRISMA guidelines (PROSPERO registration: CRD42022341732) to compare the feasibility of conclusive readings and the frequency of changes in treatment plans in patients with DTC undergoing WBS + SPECT/CT versus WBS. MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles concerning thyroid cancer, radioactive iodine, and SPECT/CT or SPECT, published before August 16, 2023. Studies not comparing WBS + SPECT/CT with WBS, those lacking target outcomes, and those not involving human subjects were excluded. The risk of bias was assessed using the RoBANS 2.0 (Risk of Bias Assessment Tool for Nonrandomized Studies) tool. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to evaluate the quality of evidence and strength of recommendations., Results: A total of 30 studies (prospective n = 9, retrospective n = 21) were included in the meta-analyses. Adding SPECT/CT to WBS was shown to increase conclusive readings for cervical lesions, extracervical lesions, and all regions. Lesion-based analyses showed improvements of 14%, 20%, and 18%, respectively, whereas scan-based analyses showed improvements of 27%, 9%, and 34%. The addition of SPECT/CT to WBS led to changes in 30% of treatment plans after diagnostic scans and 9% of treatment plans after posttherapeutic scans. The quality of evidence and strength of recommendations were low., Conclusions: Compelling evidence demonstrates that the addition of SPECT/CT to WBS improves lesion localization, diagnostic performance, and therapy plan for patients with DTC., Competing Interests: Conflicts of interest and sources of funding: All authors declare that they have no conflict of interest. This work was supported by the National Cancer Center Grant (NCC-2112570-1)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This meta-analysis and systematic review aimed to evaluate the therapeutic efficacy and advantages associated with the use of recombinant human thyroid-stimulating hormone (rhTSH) for radioactive iodine (RAI) therapy in patients with intermediate- to high-risk differentiated thyroid cancer., Patients and Methods: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles reporting clinical outcomes of rhTSH compared with thyroid hormone withdrawal (THW) in patients with intermediate- to high-risk differentiated thyroid cancer published between January 2012 and June 2023. Meta-analyses were performed (PROSPERO registration number: CRD42022340915) to assess the success rate of radioiodine remnant ablation (RRA) in patients with intermediate to high risk and determine the disease control rate among patients with distant metastases, evaluated using the RECIST criteria., Results: Thirteen studies involving 1858 patients were included in the meta-analysis. Pooled analyses revealed significantly higher overall RRA success rate in the rhTSH group compared with the THW group, with a risk ratio (RR) of 1.12 (95% confidence interval [CI], 1.01-1.25). However, in the subgroup analysis of high-risk patients, pooled analyses showed no significant differences in RRA success rate between the rhTSH group compared with the THW group with a pooled RR of 1.05 (95% CI, 0.88-1.24). In patients with distant metastases, there were no significant differences in the disease control rate between groups, with a pooled RR of 1.06 (95% CI, 0.78-1.44)., Conclusions: rhTSH for RAI therapy is a practical option for RAI therapy in patients with intermediate- to high-risk thyroid cancer, including those with distant metastases., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: This study aimed to investigate the predictive factors of severe radiation-induced lung injury (RILI) in patients with lung cancer and coexisting interstitial lung disease (ILD) undergoing conventionally fractionated thoracic radiotherapy., Materials and Methods: The study includes consecutive patients treated with thoracic radiotherapy for lung cancer at two tertiary centers between 2010 and 2021. RILI severity was graded using the National Cancer Institute Common Terminology Criteria version 5.0, with severe RILI defined as toxicity grade ≥4, and symptomatic RILI as grade ≥2. The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and C-reactive protein were collected within 4 weeks before starting radiotherapy. Neutrophil-lymphocyte ratios (NLR) were calculated as ANC/ALC. The median follow-up was 9 (range, 6-114) months., Results: Among 54 patients, 22 (40.7 %) had severe RILI. On multivariate logistic regression analysis, high pretreatment ANC (p = 0.030, OR = 4.313), pretreatment NLR (p = 0.007, OR = 5.784), and ILD severity (p = 0.027, OR = 2.416) were significant predictors of severe RILI. Dosimetric factors were not associated with severe RP. Overall survival was significantly worse for patients with severe RILI than those without, with 1-year cumulative overall survival rates of 7.4 % and 62.8 %, respectively., Conclusion: Pretreatment blood NLR, ANC, and ILD severity were associated with severe RILI. Overall survival was dismal for patients with severe RILI., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa . Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

Background: Liver dysfunction is common during coronavirus disease 2019 (COVID-19), while its clinical impact and association with chronic hepatitis B (CHB) remain uncertain. We aimed to investigate liver dysfunction in COVID-19 patients and its impacts on those with/without CHB., Methods: We conducted a retrospective cohort study of COVID-19 patients at National Taiwan University Hospital, stratified according to hepatitis B surface antigen (HBsAg) serostatus, with demographics, laboratory data, and hospitalization course reviewed, and clinical outcomes compared through multivariable analyses., Results: We enrolled 109 COVID-19 patients unvaccinated against SARS-CoV-2 by August 2021. The HBsAg-positive group (n = 34) had significantly higher alanine aminotransferase (ALT) (26 vs. 16 U/L, P = 0.034), platelet (224 vs. 183 k/μL, P = 0.010) and longer hospitalizations (17 vs. 13 days, P = 0.012) compared with HBsAg-negative group (n = 75), while percentages of hepatitis (2-fold ALT elevation), oxygen supplementation, ventilators usage, COVID-specific treatment, intensive care unit (ICU) admission and mortality were comparable. Older age (odds ratio [OR]: 1.04, 95 % confidence interval [CI]: 1.00-1.08, P = 0.032) and higher aspartate aminotransferase (AST) (OR: 1.08, 95 % CI: 1.004-1.16, P = 0.038) were associated with oxygen supplementation according to multivariable analyses. Higher AST predicted ICU admission (OR: 1.11, 95 % CI: 1.03-1.19, P = 0.008). Oxygen usage (OR: 5.64, 95 % CI: 1.67-19.09, P = 0.005) and shock (OR: 5.12, 95 % CI: 1.14-22.91, P = 0.033) were associated with liver dysfunction., Conclusions: CHB patients had higher ALT levels and longer hospitalizations during COVID-19. Higher AST levels predict severe COVID-19 and ICU admission., Competing Interests: Declaration of competing interest T.-H. S. received research grant from Gilead Sciences, and was on speaker's bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H. K. has served as a consultant for Abbvie, Abbott, Gilead Sciences, Roche, and Sysmex and on speaker's bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Sysmex. Others declare no conflict of interests., (Copyright © 2023. Published by Elsevier B.V.)

Objective: This study aimed to investigate the risk of second primary malignancy after radioiodine (RAI) therapy in patients with thyroid cancer, using the National Health Insurance Service (NHIS) database., Methods: We extracted data from the NHIS database of South Korea, which covers the entire population of the nation. Risk of second primary malignancy in the thyroid cancer patients who received RAI therapy were compared with the thyroid cancer patients who received surgery only., Results: Between January 1, 2004, and December 31, 2018, we identified 363,155 patients who underwent thyroid surgery due to thyroid cancer for analysis. The surgery only cohort was 215,481, and the RAI cohort was 147,674 patients. A total of 19,385 patients developed second primary malignancy (solid cancer, 18,285; hematologic cancer, 1,100). There was no significant increase in the risk of second primary malignancy in patients who received a total cumulative dose of 100 mCi or less (hazard ratio [HR], 1.013; 95% confidence interval [CI], 0.979-1.049). However, a statistically significant increase in the risk of second primary malignancy was observed in patients who received 101-200 mCi (HR, 1.214; 95% CI, 1.167-1.264), 201-300 mCi (HR, 1.422; 95% CI, 1.258-1.607), and > 300 mCi (HR, 1.693; 95% CI, 1.545-1.854)., Conclusion: Total cumulative doses of 100 mCi or less of RAI can be safely administered without concerns about second primary malignancy. However, the risk of second primary malignancy increases in a dose-dependent manner, and the risk-benefit needs to be considered for doses over 100 mCi of RAI therapy., Competing Interests: Conflict of InterestChae Moon Hong, Junik Son, Min Kyung Hyun, Jang Won Lee, and Jaetae Lee declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: The growing incidence of differentiated thyroid cancer (DTC) demands dependable prognostic factors to guide follow-up and treatment plans. This study investigated the prognostic value of response to therapy (RTT) assessment using TSH stimulated-thyroglobulin (sti-Tg) and nonstimulated-thyroglobulin (nonsti-Tg) and evaluates whether RTT using nonsti-Tg (nonstiRTT) can replace RTT using sti-Tg (stiRTT) in clinical practice to improve patients' quality of life during assessment., Methods: We enrolled 419 DTC patients who underwent total thyroidectomy, radioactive iodine (RAI) therapy, and Tg assessment. Patients with structural incomplete responses were excluded. Initial RTT assessments based on the 2015 American Thyroid Association guidelines (excellent response; ER, indeterminate response, biochemical incomplete response) were performed 6-24 months after RAI therapy. The second RTT assessments were performed 6-24 months after the first assessment. Statistical analysis for recurrence-free survival (RFS) was done with the log-rank test for stiRTT and nonstiRTT., Results: Although initial stiRTT and nonstiRTT were significant predictors for RFS (p < 0.0001), stiRTT provided better RFS prediction than nonstiRTT. The RFS analysis of the second RTT assessment demonstrated statistical significance only for stiRTT (p < 0.0001). In 116 patients classified as ER on initial stiRTT, there was no RFS difference between patients classified as ER on either second stiRTT or nonstiRTT., Conclusion: The prognostic power of stiRTT surpasses that of nonstiRTT in both the initial and second RTT assessment. Nevertheless, among patients classified as ER on initial stiRTT, a second stiRTT may not be required for those classified as ER on the second nonstiRTT., Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-023-00811-8., Competing Interests: Competing InterestsJunik Son, Chae Moon Hong, Do-Hoon Kim, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn declare no competing interests., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Positron emission tomography (PET) viability scan is used to determine whether patients with a myocardial scar on single-photon emission computed tomography (SPECT) may need revascularization. However, the clinical utility of revascularization decision-making guided by PET viability imaging has not been proven yet. The purpose of this study was to investigate the impact of PET to determine revascularization on clinical outcomes., Methods: Between September 2012 and May 2021, 53 patients (37 males; mean age = 64 ± 11 years) with a myocardial scar on MIBI SPECT who underwent PET viability test were analyzed in this study. The primary outcome was a temporal change in echocardiographic findings. The secondary outcome was all-cause mortality., Results: Viable myocardium was presented by PET imaging in 29 (54.7%) patients. Revascularization was performed in 26 (49.1%) patients, including 18 (34.0%) with percutaneous coronary intervention (PCI) and 8 (15.1%) with coronary artery bypass grafting. There were significant improvements in echocardiographic findings in the revascularization group and the viable myocardium group. All-cause mortality was significantly lower in the revascularization group than in the medical therapy-alone group (19.2% vs. 44.4%, log-rank P = 0.002) irrespective of viable (21.4% vs. 46.7%, log-rank P = 0.025) or non-viable myocardium (16.7% vs. 41.7%, log-rank P = 0.046). All-cause mortality was significantly lower in the PCI group than in the medical therapy-alone group (11.1% vs. 44.4%, log-rank P < 0.001)., Conclusion: Revascularization improved left ventricular systolic function and survival of patients with a myocardial scar on SPECT scans, irrespective of myocardial viability on PET scans., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients., Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development., Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts., Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management., Impact and Implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative., Competing Interests: T-CT has served on speaker’s bureaus for Fujirebio, Bristol-Myers Squibb, and Gilead Sciences and received grant support from Gilead Sciences. TH served as a speaker for Gilead Sciences, Eisai Co., Ltd, and Fujirebio. FS served as a speaker for Gilead Sciences. HK served as a speaker for Gilead Sciences, AbbVie Inc., MSD K.K., Eisai Co., Ltd, and Sumitomo Pharma. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Electrochemical synthesis can provide more sustainable routes to industrial chemicals 1-3 . Electrosynthetic oxidations may often be performed 'reagent-free', generating hydrogen (H 2 ) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications 4 , but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option 1,5,6 , but many reductions require anhydrous, air-free reaction conditions. In such cases, H 2 represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions 7-12 . Here we report a mediated H 2 anode that achieves indirect electrochemical oxidation of H 2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H 2 anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry 13-15 . Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H 2 anode technology disclosed here offers a general strategy to support H 2 -driven electrosynthetic reductions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB., Methods: Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups., Results: 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25-0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30-0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19-1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data., Conclusions: Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients., (© 2023. Asian Pacific Association for the Study of the Liver.)

Aim: Alpha-fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP-increase and high AFP levels in the prediction of HCC., Methods: At-risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non-HCC groups. Their AFP levels at 12, 9, and 6 months (-6M) before the outcome date were evaluated. Group-based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC., Results: Overall, 2776 patients were included in the HCC (n = 326) and non-HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non-HCC groups. Trajectory analysis identified AFP-increase group (11%) increased 24-fold risks of HCC compared with the AFP-stable (89%) group. Compared with patients without the AFP-increase, a serial 3-month AFP-increase ≥10% elevated HCC risk by 12.1-fold (95% CI: 6.5-22.4) in 6 months, and the HCC risks increased 13-60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP-increase ≥10% and AFP ≥20 ng/ml at -6M significantly increased 41.7-fold (95% CI: 13.8-126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6-month AFP-increase ≥10% and AFP ≥20 ng/ml increased 22.1-fold (95% CI: 12.52-39.16) HCC risks in 6 months. Most HCCs were detected at an early stage., Conclusions: Serial 3-6-month AFP-increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months., (© 2023 Japan Society of Hepatology.)

Background: The objective of this study is to evaluate the diagnostic accuracy of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detecting recurrence in patients with differentiated thyroid cancer (DTC) who have negative whole-body scans (WBSs) but elevated serum thyroglobulin (Tg) or thyroglobulin antibody (TgAb) levels. Methods: This systematic review/meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy criteria (International Prospective Register of Systematic Reviews registration number: CRD42022340924). A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases identified articles reporting the diagnostic accuracy of FDG PET/CT for the detection of recurrence in patients with DTC with negative WBS and elevated serum Tg or TgAb levels published between January 2012 and June 2023. Meta-analyses were performed to determine the diagnostic accuracy of FDG PET/CT on the total target population as well as on subgroups stratified by serum Tg or TgAb, and thyrotropin (TSH) stimulation status at the time of FDG PET/CT. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was applied to evaluate the quality of evidence and the strength of recommendations to facilitate translation of the meta-analysis results into practical recommendations for clinical guidelines. Results: A total of 24 studies involving 1988 patients were included for analysis. The overall pooled sensitivity and specificity values were 0.87 (95% confidence interval [CI] = 0.83-0.92; I 2  = 75%) and 0.84 (CI = 0.80-0.89; I 2  = 44%), respectively. Subgroup analyses revealed no significant differences in the diagnostic accuracy of FDG PET/CT in patients stratified by serum Tg or TgAb levels, and TSH stimulation status at the time of PET/CT. Treatment plans were changed following FDG PET/CT imaging in 40% (CI = 34-47%; I 2  = 39%) of cases. The quality level of evidence for using FDG PET/CT was moderate in both sensitivity and specificity according to the GRADE system. Conclusion: There is moderate quality evidence demonstrating the high diagnostic accuracy of FDG PET/CT in detecting recurrence in patients with DTC with negative WBS and elevated serum Tg or TgAb levels. This evidence corroborates the current guidelines' endorsement of FDG PET/CT as a diagnostic tool in such patients.

Background: Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC., Methods: We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival., Results: A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20-2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30-2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06-2.84) after surgery., Conclusion: Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection., Competing Interests: Declaration of competing interest T.-H. S. received research grant from Gilead Sciences, and was on speaker's bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H. K. has served as a consultant for Abbvie, Gilead Sciences, Merck Sharp and Dohme, and Roche and on speaker's bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme. Others declare no conflict of interests., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising regenerative therapeutic approach for wound healing. To determine the effects of cultured MSCs as a 2D monolayer (2D-MSCs) and 3D spheroids (3D-MSCs) on their secretomes, and to examine the effect of 3D-MSC secretomes on endothelial cells (ECs) and MSCs in a burn injury mouse model. MSCs were cultured as 2D monolayers (2D-MSCs) and 3D spheroids (3D-MSCs) and their cellular characteristics were evaluated by western blotting. 2D-MSC and 3D-MSC secretomes (condition medium: CM) were analyzed using an angiogenic array. The activation of ECs by 2D-MSC and 3D-MSC CMs was examined in cellular proliferation, migration, and tube formation assays. The wound healing effects of 2D-MSCs and 3D-MSCs were determined in vivo using a burn injury mouse model. 3D culture conditions altered the markers of components that regulate cell survival, cytoskeletal, adhesion, and proliferation. Interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), IL-8, and chemokine (CXC motif) ligand 1 (CXCL1) were present at high levels in the CM of 3D-MSCs compared with 2D-MCs. 3D-MSC-CMs promoted the proliferation, migration, and tube formation of ECs. Furthermore, 3D-MSC treatment enhanced wound healing in a burn injury mouse model. 3D culture improves proangiogenic factors in the MSC secretome and 3D-MSCs represent a new cell-based treatment strategy for wound healing., Competing Interests: Declaration of competing interest All the authors report no relevant conflicts of interest for this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To investigate the role of the lncRNA MEG3 (MEG3) in opposing the biochemical processes thought to be involved in the development of atherosclerosis (AS)., Methods: Thirty patients with AS and thirty healthy control subjects were enrolled in this study. The expression of MEG3, miR-200b-3p and ABCA1 was analyzed by RT-qPCR in the individuals and the macrophages-derived foam cells. Lipid accumulation was detected by oil red O staining. Cholesterol efflux was measured by ELISA assay in the foam cells. Expression of miR-200b-3p was identified by sequencing. Targeting relationships were determined by dual luciferase assay between MEG3 and miR-200b-3p, miR-200b-3p and ABCA1., Results: In the patients with AS, MEG3 and ABCA1 expression were decreased and miR-200b-3p expression was upregulated. Foam cells transfected with an expression vector (pcDNA3.1) containing MEG3 (pcDNA3.1-MEG3) induced decrease of lipid accumulation and increase of cholesterol efflux compared to cells transfected with control plasmid alone. Foam cells transfected by pcDNA3.1-MEG3 also showed decreased miR-200b-3p and increased ABCA1 expression. Interestingly, co-expression of miR-200b-3p partially prevented these effects of MEG3 expression., Conclusion: Expression of MEG3 is downregulated in the patients with AS and foam cells. Overexpressed MEG3 may act as an anti-atherosclerotic factor by reducing lipid accumulation and accelerating cholesterol efflux through the miR-200b-3p/ABCA1 axis., (© 2023 by the Association of Clinical Scientists, Inc.)

Background/purpose: Distinct hepatitis relapse has been observed after discontinuing entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients. End-of-therapy (EOT) serum cytokines were compared and used for outcome prediction., Methods: A total of 80 non-cirrhotic CHB patients in a tertiary medical center in Taiwan who discontinued ETV (n = 51) or TDF (n = 29) therapy after fulfilling the APASL guidelines were prospectively enrolled. Serum cytokines were measured at EOT and 3rd month afterwards. Multivariable analysis was performed to predict virological relapse (VR, HBV DNA >2000 IU/mL), clinical relapse (CR, VR and alanine aminotransferase > 2-fold upper limit of normal) and hepatitis B surface antigen (HBsAg) seroclearance., Results: Compared with TDF group, ETV stoppers had greater interleukin 5 (IL-5), IL-12 p70, IL-13, IL-17 A and tumor necrosis factor alpha (TNF-alpha) (all P < 0.05) at EOT. Older age, TDF use, higher EOT HBsAg and IL-18 (Hazard ratio [HR], 1.01; 95% CI, 1.00-1.02) levels at EOT predicted VR, while older age, higher EOT HBsAg and IL-7 (HR, 1.25; 95% CI, 1.00-1.56) levels predicted CR. In TDF stoppers, higher IL-7 (HR, 1.29; 95% CI, 1.05-1.60) and IL-18 (HR, 1.02; 95% CI, 1.00-1.04) levels predicted VR, while IL-7 (HR, 1.34; 95% CI, 1.08-1.65) and interferon-gamma (IFN-gamma) (HR, 1.08; 95% CI, 1.02-1.14) levels predicted CR. A lower EOT HBsAg level was associated with HBsAg seroclearance., Conclusion: Distinct cytokine profiles were observed after stopping ETV or TDF. Higher EOT IL-7, IL-18, and IFN-gamma could be probable predictors for VR and CR in patients discontinuing NA therapies., Competing Interests: Declaration of competing interest T.-H. S. received research grant from Gilead Sciences, and was on speaker's bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H. K. has served as a consultant for Abbvie, Gilead Sciences, Merck Sharp and Dohme, and Roche and on speaker's bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme. No disclosure for other authors., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Globally, neurological diseases pose a major burden to healthcare professionals in terms of the management and prevention of the disorder. Among neurological diseases, Alzheimer's disease (AD) accounts for 50%-70% of dementia and is the fifth leading cause of mortality worldwide. AD is a progressive, degenerative neurological disease, with the loss of neurons and synapses in the cerebral cortex and subcortical regions. The management of AD remains a debate among physicians as no standard and specific "disease-modifying" modality is available. The concept of 'Regenerative Medicine' is aimed at regenerating the degenerated neural tissues to reverse the pathology in AD. Genetically modified engineered stem cells modify the course of AD after transplantation into the brain. Extracellular vesicles (EVs) are an emerging new approach in cell communication that involves the transfer of cellular materials from parental cells to recipient cells, resulting in changes at the molecular and signaling levels in the recipient cells. EVs are a type of vesicle that can be transported between cells. Many have proposed that EVs produced from mesenchymal stem cells (MSCs) may have therapeutic promise in the treatment of AD. The biology of AD, as well as the potential applications of stem cells and their derived EVs-based therapy, were explored in this paper., Competing Interests: 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, (© 2023 The Authors.)

Protein induced by Vitamin K absence or antagonists-II (PIVKA-II) is a diagnostic marker of hepatocellular carcinoma (HCC). We aimed to investigate the predictive role of PIVKA-II and ASAP score for development of HCC in 1 year among untreated patients of chronic hepatitis B (CHB). We conducted this case-control study to include untreated CHB patients followed at the National Taiwan University Hospital and grouped into HCC and matched non-HCC groups. Their archived serum samples were assayed for PIVKA-II levels 1 year before HCC, at HCC or their last serum sample. A total of 69 HCC cases and 102 non-HCC controls were recruited. Baseline PIVKA-II level was significantly higher in the HCC group than in the control group and it could predict HCC development in 1 year with an area under the receiver operating characteristic curve of 0.76. Multivariable analysis adjusting age, sex, liver function and alpha-fetoprotein level showed that baseline PIVKA-II ≥31 mAU/mL (vs. <31 mAU/mL) increased 12.5-fold risk (95% CI: 4.9-31.7) of HCC in 1 year, and even in patients with normal alpha-fetoprotein levels. The ASAP score, a combination of age, sex, alpha-fetoprotein and PIVKA-II, increases the predictability for HCC in 1 year. We concluded that both high PIVKA-II level and ASAP score may predict HCC development in 1 year in untreated CHB patients, especially in patients with normal alpha-fetoprotein level., Competing Interests: None., (AJCR Copyright © 2023.)

Background: Hepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities., Results: We analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression., Conclusions: The diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients., (© 2023. The Author(s).)

Background & Aims: Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core-related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg., Methods: We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL., Results: There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P < .001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16-3.27). In contrast to the late decline of HBsAg levels (5-9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P < .001) in patients achieving undetectable HBcrAg levels., Conclusions: Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A non-noble Cu-catalyzed transfer aza-benzyl Michael addition via the C-C bond cleavage of aza-benzyl alcohols has been disclosed. The unstrained C(sp 3 )-C(sp 3 ) bond of an alcohol was selectively cleaved. This aza-benzyl transfer strategy provides a selective and environmentally benign approach for the C-alkylation of α,β-unsaturated carbonyl compounds that employs readily available alcohols as carbon nucleophiles and is characterized by a wide range of substrates and good to excellent yields.

Introduction: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC)-A/B HCC beyond the Milan criteria with survival benefit., Methods: Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened, and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7-11), or high (>11). Multivariable Cox proportional hazard regression analysis was used for outcome prediction., Results: Overall, 474 patients who received SR ( n = 247) and TACE ( n = 227) were enrolled. Patients who underwent SR were significantly younger with better liver reserve. There were 76 (31%) and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low ( n = 149), intermediate ( n = 203), and high ( n = 122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, p < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, p < 0.001) and high (5.6 vs. 1.5 years, p = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% confidence interval [CI]: 0.27-0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32-0.92). The survival benefit of SR especially confines to patients within 3 tumors., Conclusions: In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients., Competing Interests: T.-H.S. received research grant from Gilead Sciences and was on speaker's bureaus for AbbVie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H.K. has served as a consultant for AbbVie, Gilead Sciences, Merck Sharp and Dohme, and Roche and on speaker's bureaus for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp, and Dohme. Others declare no conflict of interests., (Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel.)

Exosomes, which are nano-sized transport bio-vehicles, play a pivotal role in maintaining homeostasis by exchanging genetic or metabolic information between different cells. Exosomes can also play a vital role in transferring virulent factors between the host and parasite, thereby regulating host gene expression and the immune interphase. The association of inflammation with disease development and the potential of exosomes to enhance or mitigate inflammatory pathways support the notion that exosomes have the potential to alter the course of a disease. Clinical trials exploring the role of exosomes in cancer, osteoporosis, and renal, neurological, and pulmonary disorders are currently underway. Notably, the information available on the signatory efficacy of exosomes in immune-related disorders remains elusive and sporadic. In this review, we discuss immune cell-derived exosomes and their application in immunotherapy, including those against autoimmune connective tissue diseases. Further, we have elucidated our views on the major issues in immune-related pathophysiological processes. Therefore, the information presented in this review highlights the role of exosomes as promising strategies and clinical tools for immune regulation., 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 © 2023 Gangadaran, Madhyastha, Madhyastha, Rajendran, Nakajima, Watanabe, Velikkakath, Hong, Gopi, Muthukalianan, Valsala Gopalakrishnan, Jeyaraman and Ahn.)

Background The impact of the coronavirus disease 2019 (COVID-19) pandemic substantially altered operations at hospitals that support graduate medical education. We examined the impact of the pandemic on an anesthesiology training program with respect to overall case volume, subspecialty exposure, procedural skill experience, and approaches to airway management. Methods Data for this single center, retrospective cohort study came from an Institutional Review Board approved repository for clinical data. Date ranges were divided into the following phases in 2020: Pre-Pandemic (PP), Early Pandemic (EP), Recovery 1 (R1), and Recovery 2 (R2). All periods were compared to the same period from 2019 for case volume, anesthesia provider type, trainee exposure to Accreditation Council for Graduate Medical Education (ACGME) index case categories, airway technique, and patient variables. Results 15,087 cases were identified, with 5,598 (37.6%) in the PP phase, 1,570 (10.5%) in the EP phase, 1,451 (9.7%) in the R1 phase, and 6,269 (42.1%) in the R2 phase. There was a significant reduction in case volume during the EP phase compared to the corresponding period in 2019 (-55.3%; P < .001) that improved but did not return to baseline by the R2 phase (-17.6%; P < .001). ACGME required minimum cases were reduced during the EP phase compared to 2019 data for pediatric cases (age < 12 y, -72.1%; P < .001 and age < 3 y, -53.5%; P < .006) and cardiopulmonary bypass cases (52.3%, P < .003). Surgical subspecialty case volumes were significantly reduced in the EP phase except for transplant surgery. By the R2 phase, all subspecialty volumes had recovered except for plastic surgery (14.9 vs. 10.5 cases/week; P < .006) and surgical endoscopy (59.2 vs. 40 cases/week; P < .001). Use of video laryngoscopy (VL) and rapid sequence induction and intubation (RSII) also increased from the PP to the EP phase (24.6 vs. 79.6%; P < .001 and 10.3 vs. 52.3%; P < .001, respectively) and remained elevated into the R2 phase (35.2%; P < 0.001 and 23.1%; P < .001, respectively). Conclusions The COVID-19 pandemic produced significant changes in surgical case exposure for a relatively short period. The impact was short-lived, with sufficient remaining time to meet the annual ACGME program minimum case requirements and procedural experiences. The longer-term impact may be a shift towards the increased use of VL and RSII, which became more prevalent during the early phase of the pandemic., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Grissom et al.)

Adhesive capsulitis shoulder is a common problem of patients presenting with shoulder pain and disability. The approach to such patients includes a variety of modalities. This systematic review evaluates the efficacy of intra-articular injections of platelet-rich plasma (PRP) in the treatment. A literature search was performed between January 2010 and 30 May 2022. MeSH terms used were 'Platelet-rich plasma' OR 'PRP' AND 'Frozen shoulder' OR 'Adhesive capsulitis shoulder' OR 'Periarthritis shoulder'. The search included published articles in the English language involving human subjects. Studies evaluating other types of shoulder disorders, in vitro studies, review articles, animal-model studies, and pre-clinical trials were excluded. The data regarding study characteristics, efficacy, and safety outcomes were analyzed. A total of 11 studies with 347 patients over 10 years were finally included in this review. Most publications were in 2019 and 2020, mostly from India. This review included seven comparative studies, three case series, and one case report. In seven studies, a single intra-articular PRP injection was administered, whereas in the rest of the studies two or multiple injections were given. Only one study demonstrated an equivocal efficacy of PRP and steroid intra-articular injection. The rest all depicted better clinical and functional outcomes with the PRP injection. Only one study compared the outcomes of hydro-dissection treatment in adhesive capsulitis with the intra-articular PRP injection. The rest all either examined PRP alone or compared it with the steroid intra-articular injection. None of the studies showed any major side effects. The intra-articular injections of PRP in the management of adhesive capsulitis of the shoulder provide a new treatment approach. Further studies are required to ascertain the efficacy and safety of the PRP intraarticular injection as a management alternative in adhesive capsulitis.

Alopecia is a common medical condition affecting both sexes. Dermal papilla (DP) cells are the primary source of hair regeneration in alopecia patients. Therapeutic applications of extracellular vesicles (EVs) are restricted by low yields, high costs, and their time-consuming collection process. Thus, engineered nanovesicles (eNVs) have emerged as suitable therapeutic biomaterials in translational medicine. We isolated eNVs by the serial extrusion of fibroblasts (FBs) using polycarbonate membrane filters and serial and ultracentrifugation. We studied the internalization, proliferation, and migration of human DP cells in the presence and absence of FB-eNVs. The therapeutic potential of FB-eNVs was studied on ex vivo organ cultures of human hair follicles (HFs) from three human participants. FB-eNVs (2.5, 5, 7.5, and 10 µg/mL) significantly enhanced DP cell proliferation, with the maximum effect observed at 7.5 µg/mL. FB-eNVs (5 and 10 µg/mL) significantly enhanced the migration of DP cells at 36 h. Western blotting results suggested that FB-eNVs contain vascular endothelial growth factor (VEGF)-a. FB-eNV treatment increased the levels of PCNA, pAKT, pERK, and VEGF-receptor-2 (VEGFR2) in DP cells. Moreover, FB-eNVs increased the human HF shaft size in a short duration ex vivo. Altogether, FB-eNVs are promising therapeutic candidates for alopecia.

A regio- and chemoselective sulfonylation of propargyl alcohols with sulfinamides in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was developed. It provided straightforward and mild access to multi-substituted allenyl sulfones by using sulfinamides as the sulfonyl sources. This transformation was promoted by HFIP and did not require any catalysts or oxidants, which allowed for the successful conversion of various tertiary and secondary propargyl alcohols into allenyl sulfones in high yields.

The two-dimensional (2D) monolayer culture as a conventional method has been widely applied in molecular biology fields, but it has limited capability to recapitulate real cell environments, being prone to misinterpretation with poor prediction of in vivo behavior. Recently, the three-dimensional (3D) spheroid culture has been studied extensively. Spheroids are self-assembled cell aggregates that have biomimicry capabilities. The behavior of thyroid cancer under the 3D spheroid culture environment has been studied; however, there are no reports regarding differences in the degree of thyroid cancer cell differentiation under 2D and 3D culture conditions. This study investigated the expression of thyroid differentiation proteins related to iodide-metabolizing mechanisms in thyroid cancer cells under different culture conditions. Four thyroid cancer cell lines and one thyroid follicular epithelial cell line were grown in adherent 2D cell culture and 3D spheroid culture with agarose-coated plates. We observed changes in proliferation, hypoxia, extracellular matrix (ECM), cytoskeleton, thyroid-specific proteins, and thyroid transcription factors. All cell lines were successfully established in the spheroid following cell aggregation. Proliferation considerably decreased, while hypoxia-inducible factor 1-α(HIF1-α) was promoted in 3D spheroids; moreover, 3D spheroids with thyroid cancers showed diminished thyroid differentiation markers, but thyroid follicular epithelial cells revealed either a maintenance or weak decline of protein expression. We verified that the 3D spheroid culture environment can be similar to in vivo conditions because of its alterations in numerous cellular and functional activities, including morphology, cellular proliferation, viability, hypoxia, ECM, cytoskeleton, and thyroid differentiation, compared to the conventional 2D monolayer culture environment. An in vitro experimental study using 3D spheroid culture is ideal for the faster discovery of new drugs.

The isomerization of allylic alcohols to the corresponding carbonyl compounds is a well-established reaction in organic synthesis. However, 1,3-carbon migration is a quite challenging field, and thus transformation has remained elusive until now. Herein, we present the ruthenium-catalyzed intramolecular 1,3-aryl migrative isomerization, which provides a mild and environmentally friendly method to synthesize various ketones with high step- and atom-economy and broad substrate scope. Meanwhile, the Ru(III)-catalyzed C(sp 3 )-C(aryl) bond cleavage of unactivated allylic alcohols may serve as a heuristic paradigm for transition-metal-catalyzed C-C activation.