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Background: Synovial fluid alpha-defensin lateral flow assay (ADLFA) is a quick adjunctive test in diagnosing periprosthetic joint infection (PJI) after primary arthroplasty. However, evidence is lacking for postrevision arthroplasty cases. Thus, we investigated the performance of ADLFA in revision cases and compared it to a control cohort of primary arthroplasty cases. Methods: One hundred eleven suspected PJI cases with previous total knee or hip arthroplasty between 2017 and 2021 were retrospectively included; they were minimally followed up for 12 months after joint aspiration. Cases were stratified into the revision and control (primary) group using propensity score matching in a 1:2 ratio. The 2018 Musculoskeletal Infection Society criteria were the gold standard for PJI and the Delphi-based consensus criteria for persistent infection. Results: After matching, the two groups exhibited comparable baselines. The sensitivity and specificity for revision cases were 50.0% (95% confidence interval [CI] =23.0%–77.0%) and 100.0% (95% CI = 83.2%–100.0%), respectively, and for primary cases, it was 75.0% (95% CI = 55.1%–89.3%) and 100.0% (95% CI = 90.3%–100.0%), respectively. Thus, ADLFA was less sensitive for revision arthroplasty but equally specific for both primary and revision cases. Furthermore, the sensitivity for ADLFA varied considerably between revision surgeries for septic causes and aseptic causes, but specificity remained 100.0%. Conclusion: ADLFA was highly specific but not sensitive in diagnosing PJI in postrevision arthroplasty cases. It is suited as a convenient confirmatory adjunct alongside the existing criteria.

Abstract Background The literature comparing the long-term outcomes and survivorship of computer navigation-assisted and conventional total knee replacement (TKR) is sparse. Moreover, of the available comparative studies with follow-up duration of more than 10 years, the results seem to be conflicting. The purpose of this long-term study was to compare the clinical and radiological outcomes, and implant survivorship, of TKR performed with and without computer navigation. Methods We retrospectively compared the results of 49 computer-navigated TKRs and 139 conventional TKRs. The mean age of the patients was 67.9 (range 52–81) years for the navigation group and 67.1 (range 50–80) years for the conventional TKR group. The mean duration of follow-up for the conventional and navigation TKR groups was 12.9 and 13.2 years, respectively. Clinical and radiographic follow-up examinations of the patients were performed at 2 weeks, 1 month, 3 months and 6 months post-operatively, and at 1-year intervals thereafter. Results There were no significant differences in the post-operative Knee Society knee and function score between the two groups. The mean overall deviation from neutral alignment and the radiological outliers were significantly higher in the conventional TKR group. The overall survival rates at 17 years were 92.9% for the navigation group and 95.6% for the conventional TKR group (p = 0.62). Conclusions Navigated TKR resulted in fewer radiological outliers; however, this did not translate to better long-term functional outcomes or implant survival.

Background Total knee arthroplasty is a commonly performed elective orthopaedic surgery. Patients may endure substantial knee swelling following surgery, which are attributable to both effusion and edema. Studies have been aiming to identify an accurate and reliable method to quantify post-operative knee swelling to aid monitoring progress and treatment. The aim of this article was to review the means of clinically applicable measurements for knee swelling post TKA. Methods The medical literature was searched using PubMed to search for articles published using the terms knee edema, effusion, swelling, knee arthroplasty, knee replacement, total knee arthroplasty, total knee replacement, TKA, TKR. Year of publication was not restricted. Only English language publications were included. Only full-text published articles from peer-reviewed journals were eligible for inclusion. The knee swelling measurement methods used in post TKA were reviewed. Results Advancement in bioimpedance spectroscopy and handheld 3D scanning technology allows quick and precise quantification of knee swelling volume that the traditional clinical circumferential measurement and volumetric measurement lack. Handheld 3D scanning is also a potential tool to estimate the change of knee effusion volume and muscular volume after the surgery. Magnetic resonance imaging is accurate in effusion measurement but also the most time and resource demanding method. Conclusion Bioimpedance spectroscopy and 3D scanning technology can be the future tools for clinically measurement of knee swelling after total knee arthroplasty.

Background: Hepatocellular carcinoma (HCC) recurrence frequently occurs after curative surgery. Histological microvascular-invasion (MVI) predicts recurrence but cannot provide pre-operative prognostication, whereas clinical prediction scores have variable performances., Methods: Recurr-NET, a multimodal multiphasic residual-network random survival forest deep-learning model incorporating pre-operative CT and clinical parameters, was developed to predict HCC recurrence. Pre-operative triphasic CT scans were retrieved from patients with resected histology-confirmed HCC from four centers in Hong Kong (Internal-cohort). The internal-cohort was randomly divided in an 8:2 ratio into training and internal-validation. External-testing was performed in an independent cohort from Taiwan., Results: Among 1231 patients (Age 62.4, 83.1% male, 86.8% viral hepatitis, median follow-up 65.1 months), cumulative HCC recurrence at years 2 and 5 were 41.8% and 56.4% respectively. Recurr-NET achieved excellent accuracy in predicting recurrence from years 1-5 (Internal cohort AUROC 0.770-0.857; External AUROC 0.758-0.798), significantly out-performing MVI (Internal AUROC 0.518-0.590; External AUROC 0.557-0.615) and multiple clinical risk scores (ERASL-PRE, ERASL-POST, DFT, and Shim scores) (Internal AUROC 0.523-0.587, External AUROC: 0.524-0.620) respectively (all p<0.001). Recurr-NET was superior to MVI in stratifying recurrence risks at year 2 (Internal: 72.5% vs. 50.0% in MVI; External: 65.3% vs. 46.6% in MVI) and year 5 (Internal: 86.4% vs. 62.5% in MVI; External: 81.4% vs. 63.8% in MVI) (all p<0.001). Recurr-NET was also superior to MVI in stratifying liver-related and all-cause mortality (all p<0.001). The performance of Recurr-NET remained robust in subgroup analyses., Conclusion: Recurr-NET accurately predicted HCC recurrence, out-performing MVI and clinical prediction scores respectively, highlighting its potential in pre-operative prognostication., (Copyright © 2024 American Association for the Study of Liver Diseases.)

This study aimed to investigate the relationship between the IL-28B SNP rs8099917 genotype, miRNA-122 expression, and the immune mechanism of ACR after LT using anti-HCV antibody calibration. A total of 45 patients with HCV received LT. IL-28B SNP rs8099917 genotyping was used to divide patients into TT and GT groups. The relative expression levels of miRNA-122 were calculated by quantitative PCR. Anti-HCV titers before and after LT were tracked to observe the relationship with ACR. The ACR rates were 27.6% for genotype TT and 62.5% for genotype GT, indicating a significantly higher rate in the GT group compared to the TT group ( p = 0.024). In the rs8099917 genotype, TT was significantly associated with higher serum miRNA-122 levels than GT ( p < 0.001). The TT group had significantly better outcomes than the GT group ( p = 0.005). The Mann-Whitney U test showed significant differences in pre-LT and post-LT anti-HCV titers between the IL-28B genotypes (TT and GT) ( p values of 0.006 and 0.027, respectively). These results suggested that the IL-28B rs8099917 genotype TT may play a significant role in modulating immune responses, both in terms of anti-HCV titers and the risk of ACR, possibly mediated through miRNA-122 levels.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca 2+ ) homeostasis, with its Ca 2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-β signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca 2+ levels through a form of Ca 2+ influx, named store-operated Ca 2+ entry (SOCE), we examined whether moderating SOCE affected TGF-β signaling. Interestingly, blocking SOCE had little effect on TGF-β-induced gene expression. In contrast, inhibition of ER Ca 2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-β signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca 2+ at the basal level. Indeed, adjusting Ca 2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-β-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca 2+ concentrations and TGF-β signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Importance: Whether stereotactic body radiotherapy (SBRT) as a bridge to liver transplant for hepatocellular carcinoma (HCC) is effective and safe is still unknown., Objective: To investigate the feasibility of SBRT before deceased donor liver transplant (DDLT) for previously untreated unresectable HCC., Design, Setting, and Participants: In this phase 2 nonrandomized controlled trial conducted between June 1, 2015, and October 18, 2019, 32 eligible patients within UCSF (University of California, San Francisco) criteria underwent dual-tracer (18F-fluorodeoxyglucose and 11C-acetate [ACC]) positron emission tomography with computed tomography (PET-CT) and magnetic resonance imaging (MRI) with gadoxetate followed by SBRT of 35 to 50 Gy in 5 fractions, and the same imaging afterward while awaiting DDLT. Statistical analysis was performed on an intention-to-treat basis between October 1 and 31, 2023., Intervention: Patients received SBRT followed by DDLT when matched deceased donor grafts were available., Main Outcomes and Measures: Coprimary end points were progression-free survival (PFS) and objective response rates (ORRs) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), modified RECIST (mRECIST), and PET Response Criteria in Solid Tumors (PERCIST). Secondary end points were local control rate, overall survival (OS), and safety., Results: A total of 32 patients (median age, 59 years [IQR, 54-63 years]; 22 men [68.8%]) with 56 lesions received SBRT. After a median follow-up of 74.6 months (IQR, 40.1-102.9 months), the median PFS was 17.6 months (95% CI, 6.6-28.6 months), and the median OS was 60.5 months (95% CI, 29.7-91.2 months). The 5-year PFS was 39.9% (95% CI, 19.9%-59.9%), and the 5-year OS was 51.3% (95% CI, 31.7%-70.9%). In terms of number of patients, ORRs were 62.5% ([n = 20] 95% CI, 54.2%-68.7%) by RECIST 1.1, 71.9% ([n = 23] 95% CI, 63.7%-79.0%) by mRECIST, and 78.1% ([n = 25] 95% CI, 73.2%-86.7%) by PERCIST. In terms of number of lesions, ORRs were 75.0% ([n = 42] 95% CI, 61.6%-80.8%) by RECIST 1.1, 83.9% ([n = 47] 95% CI, 74.7%-90.6%) by mRECIST, and 87.5% ([n = 49] 95% CI, 81.3%-98.6%) by PERCIST. Twenty patients with 36 lesions received DDLT, of whom 15 patients (75.0%) with 21 lesions (58.3%) exhibited pathologic complete response. Multivariable analyses revealed that pretreatment metabolic tumor volume (MTV) based on ACC (hazard ratio [HR], 1.06 [95% CI, 1.01-1.10]; P = .01) and complete metabolic response (CMR) by PERCIST (HR, 0.31 [95% CI, 0.10-0.96]; P = .04) were associated with PFS, while pretreatment MTV based on ACC (HR, 1.07 [95% CI, 1.03-1.16]; P = .01), total lesion activity based on ACC (HR, 1.01 [95% CI, 1.00-1.02]; P = .02), and CMR by PERCIST (HR, 0.21 [95% CI, 0.07-0.73]; P = .01) were associated with OS. Toxic effects associated with SBRT were reported for 9 patients (28.1%), with 1 grade 3 event., Conclusions and Relevance: This phase 2 nonrandomized controlled trial demonstrated promising survival and safety outcomes of SBRT before DDLT for unresectable HCC. Future randomized clinical trials are warranted.

Background and Aims: The impact of antibody responses following direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined., Methods: In this observational cohort study, we aimed to explore the association between changes in anti-HCV antibody titers following pre-LT DAA therapy and allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR)., Results: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (the DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (the DAA-naïve group). A higher incidence of post-LT BCs was observed in the DAA group ( p = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation ( p = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation ( p < 0.005)., Conclusions: In conclusion, we speculate that the upregulation of anti-HCV antibody titers, which might have been induced via the restoration of HCV-specific immune responses through pre-LT DAA therapy, was associated with post-LT allograft injury.

Introduction: Head and neck cancer ranks as the seventh most common cancer worldwide. Proton therapy is widely used in head and neck cancer. Osteoradionecrosis(ORN) is currently a commonly investigated side effect of proton therapy. A meta-analysis is needed to investigate this topic., Material/methods: Two authors searched three databases, including PubMed, Embase, and Cochrane Library; the search period was from inception to June 2023. The search keyword was set to be ((("osteoradionecrosis") OR ("osteonecrosis")) AND ("proton"))., Results: We initially collected 410 articles, and after article selections, 22 articles remained in our systematic reviews. Due to the overlapping of patient populations, 17 studies were finally included in our meta-analysis. The pooled grade 3 or more ORN rate is 0.01(95 % CI = 0.01-0.03). Subgroup analysis showed that IMPT didn't reduce grade 3 or more ORN compared with 3DCPT (p = 0.15)., Conclusions: Our meta-analysis showed that severe ORN rarely occurred in proton therapy for head and neck cancer patients., 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 Elsevier Ltd. All rights reserved.)

Hantaviruses zoonotically infect humans worldwide with pathogenic consequences and are mainly spread by rodents that shed aerosolized virus particles in urine and feces. Bioinformatics methods for hantavirus diagnostics, genomic surveillance and epidemiology are currently lacking a comprehensive approach for data sharing, integration, visualization, analytics and reporting. With the possibility of hantavirus cases going undetected and spreading over international borders, a significant reporting delay can miss linked transmission events and impedes timely, targeted public health interventions. To overcome these challenges, we built HantaNet, a standalone visualization engine for hantavirus genomes that facilitates viral surveillance and classification for early outbreak detection and response. HantaNet is powered by MicrobeTrace, a browser-based multitool originally developed at the Centers for Disease Control and Prevention (CDC) to visualize HIV clusters and transmission networks. HantaNet integrates coding gene sequences and standardized metadata from hantavirus reference genomes into three separate gene modules for dashboard visualization of phylogenetic trees, viral strain clusters for classification, epidemiological networks and spatiotemporal analysis. We used 85 hantavirus reference datasets from GenBank to validate HantaNet as a classification and enhanced visualization tool, and as a public repository to download standardized sequence data and metadata for building analytic datasets. HantaNet is a model on how to deploy MicrobeTrace-specific tools to advance pathogen surveillance, epidemiology and public health globally.

Clavicipitic acid, a communesin alkaloid precursor, has attracted significant attention due to its unique azepino[5,4,3-cd]indole framework. Herein, we report a novel biomimetic synthesis of clavicipitic acid diastereomers by utilizing a DDQ-mediated cross-dehydrogenative coupling (CDC) reaction. The synthesis involves Suzuki coupling for the prenylation of a 4-bromotryptophan derivative, followed by an intramolecular CDC reaction to construct the azepinoindole core. The trans isomer was obtained as the major product, and the two diastereomers were separable. The CDC reaction conditions, including temperature, solvent, and protecting groups, were investigated, and a plausible mechanism for the observed diastereoselectivity was proposed.

Carvacrol is a monoterpenoid phenol that has excellent antimicrobial, antiviral, and anti-inflammatory activities. It can also improve wound healing. However, few studies have explored its antitumor effect on osteosarcoma. In this report, we tried to determine the potential efficacy of carvacrol against osteosarcoma cell lines. Our data revealed that carvacrol exposure inhibited the proliferation of osteosarcoma HOS and U-2 OS cells. In addition, carvacrol exposure enhanced the levels of cleaved PARP and caspase 3 and increased annexin V-positive cells, indicating that carvacrol exposure triggers apoptosis in osteosarcoma cell lines. Furthermore, the levels of reactive oxygen species (ROS) were enhanced after carvacrol exposure and cotreatment with NAC, the ROS scavenger, decreased the levels of cleaved PARP and caspase 3, suggesting the involvement of ROS in carvacrol-induced apoptosis. Importantly, we found that carvacrol exposure triggered several protein expressions related to endoplasmic reticulum (ER) stress, including GRP78/Bip, IRE1a, PERK, and CHOP, in HOS and U-2 OS cells, indicating that carvacrol exposure could result in ER stress in these cell lines. Cotreatment with the ER stress inhibitor 4-PBA increased the levels of cleaved PARP and caspase 3 and further suppressed cellular proliferation in carvacrol-exposed osteosarcoma cell lines. Overall, the results indicate that induced ER stress can protect cells from apoptosis, but increased ROS contributes to apoptosis in carvacrol-treated cells. In this report, we first demonstrate the role of ER stress in carvacrol-induced apoptosis and suggest that ER stress could be targeted to enhance the antitumor activity of carvacrol in osteosarcoma cell lines.

We devised a new method for asymmetric cyclopropanation by employing ( S )-(thiolan-2-yl)diphenylmethanol benzyl ether as an organocatalyst. Under optimal conditions, an in situ generated sulfur ylide reacts with ( E )-chalcones via a Johnson-Corey-Chaykovsky reaction to afford a variety of cyclopropanes in excellent yields and stereoselectivities. This strategy employs low-environmental-risk reaction conditions and reusable catalysts. Hence, it is a green and efficient method for constructing cyclopropane scaffolds.

Background and Purpose: Oral nucleos(t)ide analogs (NAs) are the mainstay treatment for chronic hepatitis B (CHB). Myotoxicity is an important extrahepatic effect related to NA treatment. Telbivudine is the NA for CHB that is frequently associated with muscle-related side effects. The risk factors for telbivudine-induced myopathy (TIM) are not yet clear., Methods: This study characterized the clinical, magnetic resonance images (MRI), and pathological features of 12 TIM cases. A group of telbivudine-tolerant (TT) patients with CHB who received regular telbivudine treatment during the same period without the occurrence of myopathy was collected. Demographic and clinical factors were compared between the patients with TIM and the TT controls. Factors independently associated with TIM were identified using logistic regression analysis., Results: The patients with TIM (males/females: 7/5, mean age: 57 years) developed myopathy after using telbivudine for a median period of 19.5 months. Muscle histopathology revealed abnormal proliferation, subsarcolemmal or sarcoplasmic accumulations, and ultrastructural defects of mitochondria. When compared with TT cases, patients with TIM had a lower estimated glomerular filtration rate and were more frequently positive for hepatitis B e antigen (HBeAg)., Conclusions: Mitochondrial abnormalities are characteristic histopathological features, and impaired renal function and HBeAg positivity are risk factors for TIM. Telbivudine-induced mitochondrial dysfunction and immune activation related to mitochondrial damage and HBeAg serostatus changes may underlie TIM. Constant clinical surveillance of myopathy during telbivudine treatment is needed due to the significant latency of its development. Dose adjustment for impaired renal function does not eliminate the risk of TIM occurrence., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 Korean Neurological Association.)

Background and Aims: Cytomegalovirus (CMV) infection is a common occurrence in liver transplantation (LT) even in an era of preventive strategies. However, the diagnosis of CMV colitis remains challenging. This study aimed to focus on the clinical significance of endoscopic biopsy-proven CMV colitis in patients following living donor liver transplantation (LDLT). Methods: From January 2007 to December 2021, a total of 55 CMV colitis cases were retrospectively enrolled and divided into a non-LDLT group in 53 and an LDLT group in 2 cases. Clinical demographics, diagnostic measurement, histopathology, and anti-viral therapy were investigated. Results: There were 1630 cases undergoing LDLT in the period 2007-2021, with only 2 recipients being confirmed to have CMV colitis in 2021 (2/114, 1-year incidence: 1.75%). Comparisons between the 53 non-LDLT cases and 2 LDLT cases are as follows: Serum anti-CMV immunoglobulin M (IgM) was shown to be positive (n = 3, 5.5% vs. n = 0, p = 1.0) and negative (n = 20, 37.7% vs. n = 2, 100%, p = 0.16); anti-CMV immunoglobulin G (IgG) was positive (n = 19, 35.8% vs. n = 2, 100%, p = 0.14) and none were negative; CMV DNAemia was shown to be detectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47) and undetectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47). Among the two recipients with CMV colitis, one had CMV DNAemia and the other had no CMV DNAemia upon the development of symptoms; negative anti-CMV-IgM and positive anti-CMV-IgG were observed both pre-transplant and post-transplant; finally, CMV colitis was documented based on the presence of inclusion bodies and positive immunohistochemistry (IHC) staining in histology. Conclusion: Patients with immunocompromised status, in particular organ transplantation, may have positive serum anti-CMV IgM/IgG antibodies both before and after transplantation. This study emphasized the fact that endoscopic biopsy with IHC staining may be a more powerful tool for making an accurate diagnosis of CMV colitis in the setting of living donor liver transplantation.

Preclinical experimental models of hepatocellular carcinoma (HCC) that recapitulate human disease represent an important tool to study tumorigenesis and evaluate novel therapeutic approaches. Non-invasive whole-body imaging using positron emission tomography (PET) provides critical insights into the in vivo characteristics of tissues at the molecular level in real-time. We present here a protocol for orthotopic HCC xenograft creation with and without hepatic artery ligation (HAL) to induce tumor hypoxia and the assessment of their tumor metabolism in vivo using [ 18 F]Fluoromisonidazole ([ 18 F]FMISO) and [ 18 F]Fluorodeoxyglucose ([ 18 F]FDG) PET/magnetic resonance (MR) imaging. Tumor hypoxia could be readily visualized using the hypoxia marker [ 18 F]FMISO, and it was found that the [ 18 F]FMISO uptake was higher in HCC mice that underwent HAL than in the non-HAL group, whereas [ 18 F]FDG could not distinguish tumor hypoxia between the two groups. HAL tumors also displayed a higher level of hypoxia-inducible factor (HIF)-1α expression in response to hypoxia. Quantification of HAL tumors showed a 2.3-fold increase in [ 18 F]FMISO uptake based on the standardized value uptake (SUV) approach.

Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.

Conclusion: FLD, older age group, and alcohol consumption are major risk factors of GBP formation in Taiwanese population. The presence of GBPs might be revealed in second-look examinations of abdominal sonographies., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aim: Liver fibrosis and steatosis are important factors affecting chronic hepatitis B (CHB) disease outcome. Multiparametric magnetic resonance (MR) imaging of the liver measures fibroinflammation, fat, and iron through iron-corrected T1 relaxation time (cT1), proton density fat fraction (PDFF), and T2*-weighted imaging, respectively. We assessed the utility of MR metrics for prognostication in CHB., Methods: Chronic hepatitis B patients receiving nucleos(t)ide analogs with advanced fibrosis documented by vibration-controlled transient elastography were recruited. Paired multiparametric MR liver and transient elastography were performed at baseline and after at least 2 years. Adverse outcomes including death, hepatocellular carcinoma (HCC), and liver decompensation were monitored., Results: One hundred and ninety-two patients (mean age 60.3 ± 8.5 years; 76.0% male) were recruited. Eight patients (4.2%) developed HCC after 11.6 (8.8-22.8) months, and increased baseline liver iron independently predicted HCC (hazard ratio 2.329 [1.030-5.266]; P = 0.042). Liver MR metrics were not predictive of death or hepatic decompensation. Among 150 patients with follow-up liver MR at 30.3 (25.2-35.6) months, longitudinal liver PDFF increase was associated with liver cT1 increase (odds ratio 1.571 [1.217-2.029]; P = 0.001). Ninety patients received simultaneous multiparametric MR pancreas during the follow-up MR. Pancreatic PDFF correlated with liver PDFF (r = 0.501, P < 0.001), while pancreatic T1 had no correlation with liver cT1 (r = -0.092, P = 0.479). Pancreatic T1 and PDFF were not associated with adverse outcomes., Conclusion: Among CHB patients with advanced disease, liver iron level on MR predicts HCC. Multiparametric MR can also simultaneously assess the pancreas and the liver. Multiparametric MR should be further studied as a one-stop option for monitoring and prognosticating CHB., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Most cases of advanced liver diseases are associated with low serum 25-hydroxyvitamin D and vitamin D deficiency. This phenomenon may occur in living donor liver transplantation (LDLT)., Aims: We conducted this study to explore the interplay between VDR and CYP2R1 in liver graft and compared our findings with the pathological interpretation of serum 25(OH)D concentration., Methods: In total, 60 patients received liver graft biopsy after LDLT and were separated (1:1) into two groups: graft rejection group and graft non-rejection group. We extracted both of the recipients' and donors' serum DNA to investigate the vitamin D receptor (VDR) rs2228530 and CYP2R1 rs10741657 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction. We also extracted DNA from liver graft tissues to explore the genetic alleles of VDR rs2228530 and CYP2R1 rs10741657 after LDLT. Serum biochemistry profile and 25(OH)D concentrations were measured before and after LDLT., Results: There were no significant differences in serum VDR rs2228530 and CYP2R1 rs10741657 genetic alleles between recipients and donors. The percentage of genetic modification was 33.4% (10/30) for the rejection and non-rejection groups in VDR rs2228530, and 66.7% (20/30) for both groups in CYP2R1 rs10741657. Serum 25(OH)D concentrations were significantly lower after LDLT D30 than that before LDLT in the rejection ( p = 0.0001) and non-rejection graft pathology ( p = 0.0017) groups., Conclusions: The presence of low serum 25(OH)D concentrations after LDLT suggested that post-transplant low serum 25(OH)D concentrations may develop with the homogenous phenomenon of VDR rs2228530 and CYP2R1 rs10741657 genetic modifications in recipients regardless of graft pathology.

Background: Liver cirrhosis is a well-known risk factor of sepsis after emergent gastrointestinal (GI) endoscopy. Elective GI endoscopy before living donor liver transplantation (LDLT), however, may also carry the septic risk among these patients., Methods: This retrospective study reviewed the medical records of 642 cirrhotic recipients who underwent GI endoscopy from 2008 to 2016. We analyzed the incidence and risk factors of post-endoscopy sepsis during 2008-2012 (experience cohort). Our protocol changed after 2013 (validation cohort) to include antibiotic prophylaxis., Results: In experience cohort, 36 cases (10.5%) of the 342 LDLT candidates experienced sepsis within 48 h after endoscopy. The sepsis rate was significantly higher in patients with hepatic decompensation than patients without (22.2% vs. 9.6% vs. 2.6% in Child C/B/A groups respectively; ×2 = 20.97, P < 0.001). Using multivariate logistic regression analysis, the factors related to post-endoscopy sepsis were the Child score (OR 1.46; 95% CI 1.24-1.71), Child classes B and C (OR 3.80 and 14.13; 95% CI 1.04-13.95 and 3.97-50.23, respectively), hepatic hydrothorax (OR 4.85; 95% CI 1.37-17.20), and use of antibiotic prophylaxis (OR 0.08; 95% CI 0.01-0.64). In validation cohort, antibiotics were given routinely, and all cases of hepatic hydrothorax (n = 10) were drained. Consequently, 4 (1.3%) episodes of sepsis occurred among 300 LDLT candidates, and the incidence was significantly lower than before (1.3% vs. 10.5%, P < 0.001)., Conclusions: Patients with decompensated cirrhosis and hepatic hydrothorax have higher risk of sepsis following endoscopy. In advanced cirrhotic patients, antibiotic prophylaxis and drainage of hydrothorax may be required to prevent sepsis before elective GI endoscopy., (© 2022. The Author(s).)

Competing Interests: The authors declare no funding or conflicts of interest.

Background: Owing to the cytotoxic effect, it is challenging for clinicians to decide whether post-operative adjuvant therapy is appropriate for a non-small cell lung cancer (NSCLC) patient. Radiomics has proven its promising ability in predicting survival but research on its actionable model, particularly for supporting the decision of adjuvant therapy, is limited., Methods: Pre-operative contrast-enhanced CT images of 123 NSCLC cases were collected, including 76, 13, 16, and 18 cases from R01 and AMC cohorts of The Cancer Imaging Archive (TCIA), Jiangxi Cancer Hospital and Guangdong Provincial People's Hospital respectively. From each tumor region, 851 radiomic features were extracted and two augmented features were derived therewith to estimate the likelihood of adjuvant therapy. Both Cox regression and machine learning models with the selected main and interaction effects of 853 features were trained using 76 cases from R01 cohort, and their test performances on survival prediction were compared using 47 cases from the AMC cohort and two hospitals. For those cases where adjuvant therapy was unnecessary, recommendations on adjuvant therapy were made again by the outperforming model and compared with those by IBM Watson for Oncology (WFO)., Results: The Cox model outperformed the machine learning model in predicting survival on the test set (C-Index: 0.765 vs. 0.675). The Cox model consists of 5 predictors, interestingly 4 of which are interactions with augmented features facilitating the modulation of adjuvant therapy option. While WFO recommended no adjuvant therapy for only 13.6% of cases that received unnecessary adjuvant therapy, the same recommendations by the identified Cox model were extended to 54.5% of cases (McNemar's test p = 0.0003)., Conclusions: A Cox model with radiomic and augmented features could predict survival accurately and support the decision of adjuvant therapy for bettering the benefit of NSCLC patients., 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 Chan, Ding, Shao, Huang, Hui, Cho, Wong, Tong, Chiu, Huang and Zhou.)

Background: Single-shot diffusion-weighted imaging (ssDWI) has been shown useful for detecting active bowel inflammation in Crohn's disease (CD) without MRI contrast. However, ssDWI suffers from geometric distortion and low spatial resolution., Purpose: To compare conventional ssDWI with higher-resolution ssDWI (HR-ssDWI) and multi-shot DWI based on multiplexed sensitivity encoding (MUSE-DWI) for evaluating bowel inflammation in CD, using contrast-enhanced MR imaging (CE-MRI) as the reference standard., Study Type: Prospective., Subjects: Eighty nine patients with histological diagnosis of CD from previous endoscopy (55 male/34 female, age: 17-69 years). FIELD STRENGTH/SEQUENCES: ssDWI (2.7 mm × 2.7 mm), HR-ssDWI (1.8 mm × 1.8 mm), MUSE-DWI (1.8 mm × 1.8 mm) based on echo-planar imaging, T2-weighted imaging, and CE-MRI sequences, all at 1.5 T., Assessment: Five raters independently evaluated the tissue texture conspicuity, geometry accuracy, minimization of artifacts, diagnostic confidence, and overall image quality using 5-point Likert scales. The diagnostic performance (sensitivity, specificity and accuracy) of each DWI sequences was assessed on per-bowel-segment basis., Statistical Tests: Inter-rater agreement for qualitative evaluation of each parameter was measured by the intra-class correlation coefficient (ICC). Paired Wilcoxon signed-rank tests were performed to evaluate the statistical significance of differences in qualitative scoring between DWI sequences. A P value <0.05 was considered to be statistically significant., Results: Tissue texture conspicuity, geometric distortions, and overall image quality were significantly better for MUSE-DWI than for ssDWI and HR-ssDWI with good agreement among five raters (ICC: 0.70-0.89). HR-ssDWI showed significantly poorer performance to ssDWI and MUSE-DWI for all qualitative scores and had the worst diagnostic performance (sensitivity of 57.0% and accuracy of 87.3%, with 36 undiagnosable cases due to severe artifacts). MUSE-DWI showed significantly higher sensitivity (97.5% vs. 86.1%) and accuracy (98.9% vs. 95.1%) than ssDWI for detecting bowel inflammation., Data Conclusion: MUSE-DWI was advantageous in assessing bowel inflammation in CD, resulting in improved spatial resolution and image quality., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca 2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca 2+ is intricately compartmentalized, and the Ca 2+ flow is tightly controlled by a network of Ca 2+ transport and buffering proteins. Impaired Ca 2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca 2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca 2+ signaling as a potential therapeutic approach.

Immunotherapy has achieved modest clinical activity in HCC patients. Propensity score matching analysis was conducted to compare the efficacy and safety of combined stereotactic SBRT-IO versus TACE in patients with locally advanced HCC in a tertiary center of Hong Kong. Patients with locally advanced HCC who were medically inoperable for, refractory to, or refused to curative surgical interventions were eligible. The primary outcome was PFS; the secondary outcomes were OS, ORR as per mRECIST version 1.1, and TRAEs. Matching pair analysis was performed to compare the clinical outcomes. A total of 226 patients were eligible. Approximately 16 patients in the SBRT-IO group were matched with 48 patients treated with TACE. The median tumor size was 10 cm (range: 2.9-19.6 cm) and 20.3% of the patients had portal vein invasion. The 12- and 24-month PFS were significantly better in the SBRT-IO group (93.3% vs 16.7% and 77.8% vs 2.1%, respectively, p <0.001); the 12- and 24-month OS were also better in the SBRT-IO arm (93.8% vs 31.3% and 80.4% vs 8.3%, respectively, p <0.001). The ORR was 87.5% (CR: 50%, PR: 37.5%) in SBRT-IO arm compared to 16.7% (CR: 2.4%, PR: 14.3%) in those receiving TACE alone (p <0.001). There were fewer ≥grade 3 TRAE (60.4% vs 18.8%, p = 0.004) and treatment discontinuations (25% vs 12.5%, p = 0.295) due to adverse events in the SBRT-IO arm. SBRT-IO had significant superior survival and less treatment toxicity than TACE in patients with locally advanced HCC. Our results provide rationale for studying this combination therapy in prospective randomized trials., Competing Interests: C-LC reports receiving research funding of AstraZeneca, Merck Kgga, and Taiho. He had a consulting or advisory role at AstraZeneca and Eiasi. The remaining 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 © 2021 Chiang, Chiu, Lee, Kong and Chan.)

Objective: To compare hepatitis C virus (HCV) RNA levels from serum and explanted native liver samples from patients undergoing living donor liver transplantation (LDLT)., Methods: This was a prospective observational study. Serum and liver samples were collected from consecutive serum anti-HCV-positive transplant recipients between February 2016 to August 2019. HCV RNA was extracted from liver samples and subjected to one-step reverse-transcription qPCR. using the TopScript One Step qRT-PCR Probe Kit with HCV qPCR probe assay and human GAPDH qPCR probe assay on a ViiA7 Real-Time PCR System., Results: Among the 80 patients, 36% (29/80) were HCV RNA positive in serum and 85% (68/80) had positive hepatic HCV RNA. Post-liver transplantation, 4% (3/80) patients were serum positive., Conclusions: Our study suggests that pre-transplant serum HCV RNA levels may give an underestimate of the number of positive HCV RNA cases and that hepatic HCV RNA data may be more accurate.

Objective: To compare the biomechanical properties and gapping characteristics of four novel tenorrhaphy patterns in a canine flexor tendon model., Study Design: Ex vivo, randomized, biomechanical study., Sample Population: Superficial digital flexor tendons of 60 forelimbs (30 dogs)., Methods: Each tendon was transected 25 mm distal to its musculotendinous junction prior to tenorrhaphy with 2-0 polypropylene. Repair patterns included the three-loop pulley (3LP, control), exposed double-cross-lock (ExDCrL), embedded double-cross-lock (EmDCrL), triple-circle-lock (TCiL), and Modified-Tang patterns (MTang) were randomly assigned to each experimental group (n = 12/group). Yield, peak, and failure loads, gap formation and failure modes were compared., Results: Tendons repaired with ExDCrL (p < .0001), EmDCrL (p < .0001), and MTang (p < .0001) sustained yield, peak, and failure loads ~2.2x, ~2.0x, and ~1.9x, respectively, greater than those repaired with 3LP. Loads to 1 and 3 mm gapping were also higher for ExDCrL (p < .0001), EmDCrL (p < .0004), and MTang constructs (p < .0017) compared to 3LP. Although TCiL constructs sustained higher loads, their resistance to gap formation did not differ from that of 3LP repairs. Failure mode differed between groups (p < .0001), EmDCrL, ExDCrL, MTang, and TCiL constructs failing predominantly by suture breakage compared to 3LP repairs that failed by suture pull-through., Conclusion: Use of novel patterns ExDCrL, EmDCrL, and MTang improved resistance to loads and gap formation and were biomechanically superior compared to 3LP in healthy canine tendon repairs., Clinical Significance: These results justify in vivo evaluation of ExDCrL, EmDCrL, or MTang pattern for tenorrhaphy in dogs., (© 2021 American College of Veterinary Surgeons.)

Objective: To compare the efficacy of a variable-angle endoscope (VAE) for canine thoracoscopic exploration to a traditional fixed-angle endoscope (FAE)., Study Design: Randomized, prospective, comparative study., Sample Population: Five fresh canine cadavers., Methods: Twelve predetermined anatomical locations were labeled after median sternotomy in each cadaveric thorax. Two board-certified veterinary surgeons performed thoracoscopic evaluation of each thorax using a fixed-angle (30°) and a variable-angle (0°-120°) endoscope with and without lungs mechanically ventilated. The order of surgeon, lung ventilation, and endoscope were determined using a randomized block design. Time to visualize each anatomical location was compared for surgeon, endoscope, and lung ventilation status. Primary outcome measures were time to individual anatomical location, total simulated thoracoscopic exploration time, and ability to identify anatomical location within the designated time period., Results: Lung ventilation (difference = 184 seconds, P = .015, 95% CI = 45-342 seconds) and endoscope type (difference = 112 seconds, P = .029; 95% CI = 10-213 seconds) had an effect on the cumulative time for complete thoracoscopic exploration. The VAE shortened the time to identify three of the 12 anatomical locations when controlling for the effects of lung ventilation. Use of the VAE did not improve time to identification for any locations compared to the FAE when lungs were not ventilated. The VAE facilitated significantly shorter cumulative thoracoscopic exploration time compared with the FAE. Failure to identify predetermined locations was more common with the FAE than with the VAE., Conclusion: Use of a rigid VAE decreased cumulative thoracoscopic exploration time and provided an alternative to one-lung ventilation for circumventing the visual impediments of lung ventilation., Clinical Significance: This cadaveric study provides evidence that one-lung ventilation and use of a VAE may improve surgeon efficiency during exploratory thoracoscopy., (© 2020 The American College of Veterinary Surgeons.)

Introduction: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349., Material and Methods: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach., Results: An Interrupted Time-Series (ITS) analysis showed a 15.4% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process., Discussion: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials., Trial Registration: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015., (Published by Elsevier Inc.)

Introduction: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial., Material and Methods: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants., Results: Central monitoring utilized primary study data in a five-tiered approach, including (1) real-time data checks & topic-specific intervention reports, (2) missing forms reports, (3) quality assurance metrics, (4) critical data reports and (5) protocol deviation identification, aimed to detect and resolve quality challenges. Over the course of the study, 240 data checks and reports were programed across the five tiers used., Discussion: This use of primary study data to identify issues rapidly allowed the study sponsor to focus quality assurance and data cleaning activities on prioritized data, related to protocol compliance and accurate reporting of study results. Our approach enabled us to become more efficient and effective as we informed sites about deviations, resolved missing or inconsistent data, provided targeted guidance, and gained a deeper understanding of challenges experienced at clinical trial sites., Trial Registration: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015., (Published by Elsevier Inc.)

Purpose: To evaluate the prognostic value of baseline and restaging CT-based radiomics with features associated with gene expression in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiation (nCRT) plus surgery., Methods: We enrolled 106 ESCC patients receiving nCRT from two institutions. Gene expression profiles of 28 patients in the training set were used to detect differentially expressed (DE) genes between patients with and without relapse. Radiomic features that were correlated to DE genes were selected, followed by additional machine learning selection. A radiomic nomogram for disease-free survival (DFS) prediction incorporating the radiomic signature and prognostic clinical characteristics was established for DFS estimation and validated., Results: The radiomic signature with DE genes feature selection achieved better performance for DFS prediction than without. The nomogram incorporating the radiomic signature and lymph nodal status significantly stratified patients into high and low-risk groups for DFS ( p < 0.001). The areas under the curve (AUCs) for predicting 5-year DFS were 0.912 in the training set, 0.852 in the internal test set, 0.769 in the external test set., Conclusions: Genomics association was useful for radiomic feature selection. The established radiomic signature was prognostic for DFS. The radiomic nomogram could provide a valuable prediction for individualized long-term survival.

Objective: Assessing the 6-month efficacy of combined high-intensity focused ultrasound (HIFU) ablation with percutaneous ethanol injection (PEI) in benign thyroid nodules by comparing it with HIFU ablation alone., Methods: One hundred and eighty-one (55.2%) patients underwent HIFU alone (group I) while 147 (44.8%) underwent concomitant HIFU and PEI treatment for solid or predominantly solid nodules (group II). Intravenous sedation and analgesia were given before the start of treatment. Extent of nodule shrinkage (by volume reduction ratio (VRR)), pain scores (by 0-10 visual analogue scale) during and after ablation, and rate of vocal cord palsy (VCP), skin burn, and nausea/vomiting were compared between the two groups., Results: The mean amount of ethanol injected in group II was 1.3 ± 0.7 ml. The 3- and 6-month VRR were significantly greater in group II (60.41 ± 20.49% vs. 50.13 ± 21.06%, p = 0.001; and 71.08 ± 21.25% vs. 61.37 ± 22.76%, p = 0.001, respectively), and "on-beam" treatment time was significantly shorter in group II (26.55 min vs. 30.26 min, p = 0.001). Group II patients reported significantly lower pain score during treatment (2.24 ± 3.07 vs. 4.97 ± 3.21, p < 0.001) and 2 h after treatment (2.23 ± 2.50 vs. 2.97 ± 4.39, p = 0.044). Rates of VCP, skin burn, and nausea or vomiting were not significantly different (p > 0.05)., Conclusions: The combined HIFU and PEI approach with improved administration of intravenous sedation and analgesia was associated with a significantly better 6-month efficacy than HIFU alone in benign thyroid nodules without compromising the safety and comfort of patients., Key Points: • Concomitant HIFU and PEI have a better treatment efficacy than HIFU alone. • Concomitant HIFU and PEI have a comparable safety profile as HIFU alone.

Background and Aims: Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients., Methods: This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups., Results: A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups., Conclusions: This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.

Osteoarthritis (OA) pain is associated with peripheral and central sensitization in humans and results in widespread increased sensitivity across the body. Sensitization contributes to the OA-associated pain (OAP) state. We recently identified increased levels of an endogenous neurotrophic factor, artemin (ARTN), in dogs with OAP compared to healthy pain-free controls. Circulating ARTN released from damaged tissues in OA, may play a central role in widespread sensitivity and pain. However, the relationship between ARTN and somatosensory sensitivity remains unknown. The study aimed to assess the relationship between serum ARTN concentrations and measures of sensitivity in dogs with OAP using quantitative sensory testing. We hypothesized that there would be a positive association between circulating ARTN and increased sensitivity to mechanical and thermal stimuli in dogs with OAP. We used linear and logistic regression models to assess the relationship between ARTN, sensitization, and pain within a cohort of 43 dogs with spontaneous OAP. Serum ARTN was not associated with the degree of sensitization within dogs with OAP. Further, across dogs with varying OAP severity, we did not find any association between ARTN, and clinical measures of joint pain and disability. Although a relationship between ARTN and joint pain was not ruled out.

Increasing evidence has suggested that elevated systemic inflammation with a high neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis after liver transplantation (LT). The ongoing molecular events involved in poor survival remain unclear. This retrospective study evaluated LT recipients whose data was collected at Kaohsiung Chang Gung Memorial Hospital between 2005 and 2014. Clinical records of 347 patients with hepatocellular carcinoma from seven days before LT to 30 days after LT illustrated that longitudinal values of lymphocytes, RBC, and hemoglobin were persistently low in patients with peritransplant high NLR (PTH-NLR, pre-LT ≥ 4 and post-LT ≥ 5), which indicated a significantly worse survival rate in association with increased RDW-CV and pancytopenia when compared to other patients ( p = 0.008). We further found that PTH-NLR patients had decreased DNA damage response (DDR) genes and detoxifying enzymes of ADH and ALDH families, and increased mitochondrial stress response genes in their liver tissues. Reduced lineage markers of liver progenitor cells were also observed in PTH-NLR patients signifying the presence of unresolved impairments after LT. Our results demonstrate the association between hematopoietic deficiencies and lack of protection against DDR with PTH-NLR in LDLT recipients with HCC and may imply abnormal hematological and organismal defects in those patients.

Objectives: To develop: (1) two validated risk prediction models for coronavirus disease-2019 (COVID-19) positivity using readily available parameters in a general hospital setting; (2) nomograms and probabilities to allow clinical utilisation., Methods: Patients with and without COVID-19 were included from 4 Hong Kong hospitals. The database was randomly split into 2:1: for model development database (n = 895) and validation database (n = 435). Multivariable logistic regression was utilised for model creation and validated with the Hosmer-Lemeshow (H-L) test and calibration plot. Nomograms and probabilities set at 0.1, 0.2, 0.4 and 0.6 were calculated to determine sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)., Results: A total of 1330 patients (mean age 58.2 ± 24.5 years; 50.7% males; 296 COVID-19 positive) were recruited. The first prediction model developed had age, total white blood cell count, chest x-ray appearances and contact history as significant predictors (AUC = 0.911 [CI = 0.880-0.941]). The second model developed has the same variables except contact history (AUC = 0.880 [CI = 0.844-0.916]). Both were externally validated on the H-L test (p = 0.781 and 0.155, respectively) and calibration plot. Models were converted to nomograms. Lower probabilities give higher sensitivity and NPV; higher probabilities give higher specificity and PPV., Conclusion: Two simple-to-use validated nomograms were developed with excellent AUCs based on readily available parameters and can be considered for clinical utilisation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Biomedical data frequently contain imbalance characteristics which make achieving good predictive performance with data-driven machine learning approaches a challenging task. In this study, we investigated the impact of re-sampling techniques for imbalanced datasets in PET radiomics-based prognostication model in head and neck (HNC) cancer patients., Methods: Radiomics analysis was performed in two cohorts of patients, including 166 patients newly diagnosed with nasopharyngeal carcinoma (NPC) in our centre and 182 HNC patients from open database. Conventional PET parameters and robust radiomics features were extracted for correlation analysis of the overall survival (OS) and disease progression-free survival (DFS). We investigated a cross-combination of 10 re-sampling methods (oversampling, undersampling, and hybrid sampling) with 4 machine learning classifiers for survival prediction. Diagnostic performance was assessed in hold-out test sets. Statistical differences were analysed using Monte Carlo cross-validations by post hoc Nemenyi analysis., Results: Oversampling techniques like ADASYN and SMOTE could improve prediction performance in terms of G-mean and F-measures in minority class, without significant loss of F-measures in majority class. We identified optimal PET radiomics-based prediction model of OS (AUC of 0.82, G-mean of 0.77) for our NPC cohort. Similar findings that oversampling techniques improved the prediction performance were seen when this was tested on an external dataset indicating generalisability., Conclusion: Our study showed a significant positive impact on the prediction performance in imbalanced datasets by applying re-sampling techniques. We have created an open-source solution for automated calculations and comparisons of multiple re-sampling techniques and machine learning classifiers for easy replication in future studies.

Background Current coronavirus disease 2019 (COVID-19) radiologic literature is dominated by CT, and a detailed description of chest radiography appearances in relation to the disease time course is lacking. Purpose To describe the time course and severity of findings of COVID-19 at chest radiography and correlate these with real-time reverse transcription polymerase chain reaction (RT-PCR) testing for severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, nucleic acid. Materials and Methods This is a retrospective study of patients with COVID-19 confirmed by using RT-PCR and chest radiographic examinations who were admitted across four hospitals and evaluated between January and March 2020. Baseline and serial chest radiographs ( n = 255) were reviewed with RT-PCR. Correlation with concurrent CT examinations ( n = 28) was performed when available. Two radiologists scored each chest radiograph in consensus for consolidation, ground-glass opacity, location, and pleural fluid. A severity index was determined for each lung. The lung scores were summed to produce the final severity score. Results The study was composed of 64 patients (26 men; mean age, 56 years ± 19 [standard deviation]). Of these, 58 patients had initial positive findings with RT-PCR (91%; 95% confidence interval: 81%, 96%), 44 patients had abnormal findings at baseline chest radiography (69%; 95% confidence interval: 56%, 80%), and 38 patients had initial positive findings with RT-PCR testing and abnormal findings at baseline chest radiography (59%; 95% confidence interval: 46%, 71%). Six patients (9%) showed abnormalities at chest radiography before eventually testing positive for COVID-19 with RT-PCR. Sensitivity of initial RT-PCR (91%; 95% confidence interval: 83%, 97%) was higher than that of baseline chest radiography (69%; 95% confidence interval: 56%, 80%) ( P = .009). Radiographic recovery (mean, 6 days ± 5) and virologic recovery (mean, 8 days ± 6) were not significantly different ( P = .33). Consolidation was the most common finding (30 of 64; 47%) followed by ground-glass opacities (21 of 64; 33%). Abnormalities at chest radiography had a peripheral distribution (26 of 64; 41%) and lower zone distribution (32 of 64; 50%) with bilateral involvement (32 of 64; 50%). Pleural effusion was uncommon (two of 64; 3%). The severity of findings at chest radiography peaked at 10-12 days from the date of symptom onset. Conclusion Findings at chest radiography in patients with coronavirus disease 2019 frequently showed bilateral lower zone consolidation, which peaked at 10-12 days from symptom onset. © RSNA, 2020.

Endogenous Pain Modulation (EPM) impairment is a significant contributor to chronic pain. Conditioned pain modulation (CPM) testing assesses EPM function. Osteoarthritic (OA) dogs are good translational models, but CPM has not been explored. Our aim was to assess EPM impairment in OA dogs compared to controls using CPM. We hypothesized that CPM testing would demonstrate EPM impairment in OA dogs compared to controls. Dogs with stifle/hip OA and demographically-matched controls were recruited. The pre-conditioning test stimulus, using mechanical/thermal quantitative sensory testing (MQST or TQST), were performed at the metatarsus. A 22N blunt probe (conditioning stimulus) was applied to the contralateral antebrachium for 2 minutes, followed by MQST or TQST (post-conditioning test stimulus). The threshold changes from pre to post-conditioning (∆MQST and ∆TQST) were compared between OA and control dogs. Twenty-four client-owned dogs (OA, n = 11; controls, n = 13) were recruited. The ∆MQST(p < 0.001) and ∆TQST(p < 0.001) increased in control dogs but not OA dogs (∆MQST p = 0.65; ∆TQST p = 0.76). Both ∆MQST(p < 0.001) and ∆TQST(p < 0.001) were different between the OA and control groups. These are the first data showing that EPM impairment is associated with canine OA pain. The spontaneous OA dog model may be used to test drugs that normalize EPM function.

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.

Objective: Since it is unclear whether clinical parameters can independently predict the subsequent treatment response following high intensity focused ultrasound (HIFU) ablation of benign thyroid nodules, we aimed to examine clinical factors that may independently predict 12-month efficacy after HIFU treatment. Methods: One hundred and forty patients who had single ablation were categorized into two groups, those with 12-month nodule shrinkage above the median (Group I, n  = 70) and with shrinkage below or equal to the median (Group II, n  = 70). Baseline characteristics, treatment parameters, percentage change in serum TSH, Free thyroxine (FT4) and thyroglobulin (Tg) from baseline to Day 4 and appearance of microbubbles (hyperechoic marks (HEMs)) during treatment were compared between groups. To determine independent factors, a multivariate analysis was done by logistic regression analysis. Results: Baseline characteristics and treatment parameters were comparable between groups. However, on Day-4, group I had significantly lower serum TSH (0.49mIU/L vs. 0.84mIU/L, p  = 0.011) and higher FT4 (22.11 pmol/L vs. 18.47 pmol/L, p  = 0.008) than group II. The percentage change in TSH, FT4 and Tg were significantly greater in group I ( p  = 0.002, p  = 0.009 and p  = 0.001 respectively). The proportion of HEMs observed during treatment was also significantly higher in group I (42.69% vs. 31.72%, p  = 0.030). Among the significant factors, the percentage change in FT4 was the only independent factor for 12-month shrinkage (OR = 1.018, 95%CI =1.003-1.032, p  = 0.017). Conclusions: Percentage change in serum FT4 on post-treatment Day-4 was an independent blood parameter for the subsequent nodule shrinkage at 12 months. This finding could potentially facilitate the decision for earlier retreatment of treated nodules.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a significant role in biological processes in various cell types, including mesenchymal stem cells (MSCs). However, how miRNAs regulate the immunomodulatory functions of adipose-derived MSCs (AD-MSCs) remains unknown. Here, we showed that modulation of miR-301a in AD-MSCs altered macrophage polarization. Bone marrow (BM)-derived macrophages were stimulated with LPS (1 μg/ml) and co-cultured with miRNA transfected AD-MSCs for 24 h. The expression of M1 and M2 markers in macrophages was analyzed. Inhibition of miR-301a induced M2 macrophage with arginase-1, CD163, CD206, and IL-10 upregulation. Additionally, toll-like receptor (TLR)-4 mRNA expression in macrophages was downregulated in co-cultures with AD-MSCs transfected with a miR-301a inhibitor. Nitric oxide (NO) in the supernatant of AD-MSC/macrophage co-culture was also suppressed by inhibition of miR-301a in AD-MSCs. We further found that suppression of miR-301a in AD-MSCs increased prostaglandin E 2 (PGE2) concentration in the conditioned medium of the co-culture. Taken together, the results of our study indicate that miR-301a can modulate the immunoregulatory functions of AD-MSCs that favor the applicability as a potential immunotherapeutic agent.

Objective: To evaluate the longer-term disease relapse of ultrasound (US)-guided high-intensity focused ultrasound (HIFU) ablation as a treatment for persistent/relapsed Graves' disease (GD)., Methods: After ethics approval, consecutive patients with persistent or relapsed GD who underwent bilateral US-guided HIFU ablation from 2016 to 2017 were retrospectively analyzed. Altogether, 75 patients received HIFU ablation of the central portion of the right and left thyroid lobes with areas near the trachea-esophageal groove and common carotid artery un-ablated. They were followed for 24 months or longer. Baseline thyrotropin (TSH), free T4, anti-thyroid autoantibodies, and TSH receptor (TSHR) antibody were checked. Primary outcome was the 24-month relapse rate. Relapse referred to hyperthyroidism (free T4 (FT4) > 23 pmol/L) afterwards. Variables associated with relapse were analyzed by binary logistic regression., Results: The cohort comprised mostly females (84.0%) with a mean age of 42.05 ± 10.74 years. The 24-month relapse rate was 41.3% with 31 patients suffering a relapse. No patient suffered from hypothyroidism. Three patients (4.0%) suffered from temporary vocal cord palsy but these injuries recovered spontaneously after 2 months. In univariate analysis, higher daily dose of carbimazole (OR = 1.125, 95% CI = 1.023-1.237, p = 0.015) and higher baseline TSHR level (OR = 1.085, 95% CI = 1.022-1.152, p = 0.007) were significant factors for disease relapse. In the multivariate analysis, higher baseline TSHR level was a significant independent factor for disease relapse within 24 months (OR = 1.079, 95% CI = 1.014-1.148, p = 0.016)., Conclusions: US-guided HIFU of the thyroid gland was a safe and relatively efficacious treatment in the longer term for patients with persistent or relapsed GD., Key Points: • US-guided HIFU ablation is relatively efficacious in the longer term. • US-guided HIFU ablation of the thyroid is safe. • Higher TSHR level may lead to higher disease relapse after treatment.

Objective: To assess whether perithyroidal lignocaine infusion (PLI) could provide additional analgesia in high-intensity focused ultrasound (HIFU) treatment of benign thyroid nodules for patients already receiving their usual intravenous doses of Pethidine and Diazemuls., Methods: Two hundred and five patients who underwent HIFU ablation for a benign thyroid nodule were analyzed. Among them, 104 (50.7%) patients received PLI in addition to their boluses of Pethidine and Diazemuls before treatment (group I), while the rest (n = 101, 49.3%) received intravenous Pethidine and Diazemuls only (group II). After treatment, patients were asked to rate their overall pain experience on a visual analogue scale (VAS) (0-100) (0, no pain; 100, worse possible pain) during treatment. Binary logistic regression was performed to evaluate significant determinants for treatment pain including demographics, doses of medications, and treatment parameters., Results: VAS was significantly lower in group I (51.30 vs. 63.79, p = 0.002). In the multivariate analysis, older age at treatment (OR = 1.036, 95%CI = 1.008-1.065, p = 0.011), lower BMI (OR = 1.202, 95%CI = 1.083-1.334, p = 0.001), higher Diazemuls dose (OR = 1.066, 95%CI = 1.018-1.114, p = 0.006), and use of PLI (OR = 2.096, 95%CI = 1.121-3.922, p = 0.020) were independent determinants of less treatment pain., Conclusions: PLI can provide additional analgesia in patients already receiving their usual intravenous doses of Pethidine and Diazemuls during HIFU ablation of benign thyroid nodules. Older age, lower body mass index, and greater Diazemuls (i.e., a sedative) dose are significantly associated with less treatment pain., Key Points: • PLI provided an additional analgesic effect in HIFU ablation of thyroid nodules. • Older age and lower BMI were significantly associated with less pain. • Higher doses of Diazemuls lessened pain during HIFU ablation.

Objective: High-intensity focused ultrasound (HIFU) ablation is a promising treatment for benign thyroid nodules but single application is less effective in larger-sized nodules. We aimed to assess the efficacy and safety of two sequential applications in larger-sized nodules., Methods: Fifty patients underwent ablation of a large-sized nodule (baseline volume ≥ 20 mL and diameter ≤ 50 mm). Thirty-one (62.0%) patients underwent single application (group I) while 19 (38.0%) underwent two sequential applications (group II). Nodule shrinkage (by volume reduction ratio or VRR), pain scores during and after ablation, and rate of vocal cord palsy (VCP), skin burn, and nausea/vomiting were compared between the two groups. t test or the Mann-Whitney U test was used for continuous variables while chi-square test was used for categorical variables. To determine factors for VRR, multivariate analysis was done by logistic regression analysis., Results: Total energy delivered and treatment time were significantly more in group II (p < 0.001 and p = 0.001, respectively). Total energy per nodule volume (kJ/mL) was also significantly greater in group II (1.01 kJ/mL vs. 0.57 kJ/mL, p < 0.001). The 6-month VRR was significantly greater in group II (56.74 ± 11.47% vs. 43.49 ± 12.03%, p = 0.004). Pain severity and rates of VCP, skin burn, and nausea/vomiting were comparable between the two groups (p > 0.05). Sequential application was an independent determinant of 6-month VRR (OR = 13.936, 95% CI = 1.738-197.399, p = 0.036)., Conclusions: Sequential application led to better 6-month treatment efficacy than single application in large-sized nodules. Patients undergoing sequential application are not at greater risks of treatment-related side effects afterwards., Key Points: • Sequential application produces better 6-month efficacy over single application for large-sized nodules. • Sequential HIFU application is well-tolerated and safe in patients with large-sized nodules. • Sequential application takes longer and requires larger amount of pethidine and diazepam.

Objective: To determine the influence of 3 fixation systems on complications rate after tibial plateau leveling osteotomy (TPLO) in dogs >45.4 kg., Study Design: Retrospective case series., Sample Population: Dogs (N = 287, 342 stifles) >45.4 kg with cranial cruciate ligament tear treated with TPLO., Methods: The medical records of dogs treated with TPLO were reviewed for fixation and postoperative complications, with a follow-up of at least 6 weeks. A random effects logistic regression model was used to evaluate the association between the type of TPLO fixation system and complications., Results: The fixation systems included a 3.5-mm broad TPLO plate alone (8P; 78.4%), a 3.5-mm broad TPLO plate with SOP (String of Pearls) plate (8AP; 14.9%), and a 3.5-mm standard TPLO plate (6P; 6.7%). Among the included stifles, 214 (62.6%) fixation systems were classified as locking, and 128 (37.4%) were classified as nonlocking. The fixation system was predictive of complications. The 8P had the lowest odds ratio for complication among the 3 fixation systems. Odds of developing complications were higher with the 8AP fixation system than with the 8P fixation system. Locking fixation eliminated the association between weight and complication rate., Conclusion: Fixation of a TPLO with the 8AP increased the risk of complications compared with the 8P in this population of large dogs., Clinical Significance: Locking fixation of TPLO with a 3.5-mm broad TPLO plate alone should be considered in large dogs because it may reduce complications., (© 2019 The American College of Veterinary Surgeons.)