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Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.

Supplementary Figure from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.Significance:Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.See related commentary by Beytagh and Weiss, p. 2730.See related article by Mo et al., p. 2906.This article is highlighted in the In This Issue feature, p. 2711

For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging to two protein superfamilies: thiolases and acyl-CoA N-acyltransferases. In vitro characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort (n = 208) found three of these microbial thiolases and one acyl-CoA N-acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine.

Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of anHDAC2knockoutin vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators.GRAPHICAL ABSTRACT

There is little evidence regarding the association between living arrangement and depression, and no studies have examined the age- and gender-specific differences in this association. The present study sought to examine the longitudinal changes in depression patterns between isolative living versus living in company among middle-aged and older men and women by obtaining data from waves 1-7 of the Korean Longitudinal Study of Aging (KloSA), which comprises a sample of persons at least 45 years of age in the Republic of Korea (2273 middle-aged and 1387 older men, 2805 middle aged and 1862 older women). Depression scores were based on the self-reported Center for Epidemiologic Studies Depression Scale (CES-D-10) short forms. Using mixed-effect linear regression models, we estimated depression patterns by living arrangement across age- and gender groups. Our findings from the mixed-effects model revealed that over a 14-year follow-up period, there were significant decreasing patterns of depression were among middle-aged men and women, and older men living alone compared to living with a spouse and living with others. However, living alone still had the highest depression compared to other living arrangement types. On the other hand, the depression of older women living alone changed to a level similar to those living with others during the follow-up period. In conclusion, these findings indicate that living alone significantly increases the risk of depression, but the risk decreases over time. Additionally, depression patterns by living arrangement proved to differ across age and gender groups.

This study aimed to construct a structural equation model to explore the relationship between Type D personality, cognitive illness perception, depression, approach-coping, and self-management. The study was conducted at two long-term care hospitals with 300 or more beds in Korea. Participants were 287 older patients from whom data were collected from February 17 to March 10, 2021, using a structured questionnaire comprising items on the following variables: Type D personality, cognitive illness perception, depression, approach coping, and self-management. Type D personality (β=-.601, p=.001), cognitive illness perception (β =.692, p.001), depression (β =-.204, p =.011), and approach-coping (β =.326, p.001) explained 78.8% of the total variance of self-management, highlighting their impact on how patients accept and manage a disease and their relevance to the self-management of older adults in long-term care hospitals.

The SARS-CoV-2 Omicron variant evades vaccine-induced immunity. While a booster dose of ancestral mRNA vaccines effectively elicits neutralizing antibodies against variants, its efficacy against Omicron in older adults, who are at the greatest risk of severe disease, is not fully elucidated. Here, we evaluated multiple longitudinal immunization regimens of mRNA BNT162b2 to assess the effects of a booster dose provided >8 months after the primary immunization series across the murine lifespan, including in extremely aged 21-month-old mice. Boosting dramatically enhanced humoral and cell-mediated responses with evidence of Omicron cross-recognition. Furthermore, while younger mice were protected without a booster dose, boosting provided sterilizing immunity against Omicron-induced lung infection in extremely aged mice. Correlational analyses revealed that neutralizing activity against Omicron was strongly associated with protection. Overall, our findings indicate age dependent vaccine efficacy and demonstrate the potential benefit of mRNA booster immunization to protect vulnerable older populations against SARS-CoV-2 variants.

To develop a radiomics score using ultrasound images to predict thyroid malignancy and to investigate its potential as a complementary tool to improve the performance of risk stratification systems. We retrospectively included consecutive patients who underwent fine-needle aspiration (FNA) for thyroid nodules that were cytopathologically diagnosed as benign or malignant. Nodules were randomly assigned to a training and test set (8:2 ratio). A radiomics score was developed from the training set, and cutoff values based on the maximum Youden index (Rad_maxY) and for 5%, 10%, and 20% predicted malignancy risk (Rad_5%, Rad_10%, Rad_20%, respectively) were applied to the test set. The performances of the American College of Radiology (ACR) and the American Thyroid Association (ATA) guidelines were compared with the combined performances of the guidelines and radiomics score with interpretations from expert and nonexpert readers. A total of 1624 thyroid nodules from 1609 patients (mean age, 50.1 years [range, 18–90 years]) were included. The radiomics score yielded an AUC of 0.85 (95% CI: 0.83, 0.87) in the training set and 0.75 (95% CI: 0.69, 0.81) in the test set (Rad_maxY). When the radiomics score was combined with the ACR or ATA guidelines (Rad_5%), all readers showed increased specificity, accuracy, and PPV and decreased unnecessary FNA rates (all p .05). Radiomics help predict thyroid malignancy and improve specificity, accuracy, PPV, and unnecessary FNA rate while maintaining the sensitivity of the ACR and ATA guidelines for both expert and nonexpert readers. • The radiomics score yielded an AUC of 0.85 and 0.75 in the training and test set, respectively. • For all readers, combining a 5% predicted malignancy risk cutoff for the radiomics score with the ACR and ATA guidelines significantly increased specificity, accuracy, and PPV and decreased unnecessary FNA rates, with no decrease in sensitivity. • Radiomics can help predict malignancy in thyroid nodules in combination with risk stratification systems, by improving specificity, accuracy, and PPV and unnecessary FNA rates while maintaining sensitivity for both expert and nonexpert readers.

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups (∼80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.Alum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.

This study aimed to examine changes in physical activity (PA) over time (2009–2017) in the same participants and to determine an association between changes in PA and health-related quality of life (HRQoL) in early older adults (n = 994) using data from the Korea Health Panel Survey. HRQoL was measured using the EuroQol system, and the amount of PA was grouped into four activity levels: remained inactive, became inactive, became active, and remained active. The association of changes in PA over 8 years with HRQoL was examined using logistic regression analysis while controlling for socioeconomic and behavioral factors. Total PA decreased from 1859.72 ± 1760.01 MET-minutes in 2009 to 1264.80 ± 1251.14 MET-minutes in 2017 (P

Background: Based on the common-sense model of self-regulation, this study aimed to examine the process of self-management through the proposed framework of “Self-system (type D personality)”→ “Cognitive illness perception,” “Emotional illness perception (Depression)”→ “Coping strategies (Approach coping)”→ “Illness Appraisal (Self-management),” using a structural equation model.Methods: The study was conducted at two care hospitals with 300 or more beds located in Jeolla Province, South Korea. The participants were 287 hospitalized older adults. The data collection period was February 17–March 10, 2021. The data were analyzed using SPSS WIN 23.0 and AMOS 23.0. To investigate the overall relationships among the factors influencing self-management among participants, a hypothetical model was created based on the common-sense model of self-regulation. The fit of the model and significance of its paths were analyzed. Results: The hypothetical model showed a good fit based on the following results: CMIN/DF(Q)=2.852, CFI=.955, TLI=.947, and RMSEA=.08. Type D personality had a significant direct effect on cognitive illness perception (β=-.491, pβ=.844, pβ=.650, pβ=-.433, pβ=.326, pConclusion: These findings demonstrated the following mechanism: “type D personality” → “cognitive illness perception” and “depression” → “approach coping” → “self-management,” and highlighted the potential threat of type D personalities and depression on self-management. Cognitive illness perception and approach coping both contribute toward older adults’ self-management.

SUMMARYDevelopment of affordable and effective vaccines that can also protect vulnerable populations such as the elderly from COVID-19-related morbidity and mortality is a public health priority. Here we took a systematic and iterative approach by testing several SARS-CoV-2 protein antigens and adjuvants to identify a combination that elicits neutralizing antibodies and protection in young and aged mice. In particular, SARS-CoV-2 receptorbinding domain (RBD) displayed as a protein nanoparticle (RBD-NP) was a highly effective antigen, and when formulated with an oil-in-water emulsion containing Carbohydrate fatty acid MonoSulphate derivative (CMS) induced the highest levels of cross-neutralizing antibodies compared to other oil-in-water emulsions or AS01B. Mechanistically, CMS induced antigen retention in the draining lymph node (dLN) and expression of cytokines, chemokines and type I interferon-stimulated genes at both injection site and dLN. Overall, CMS:RBD-NP is effective across multiple age groups and is an exemplar of a SARS-CoV-2 subunit vaccine tailored to the elderly.

SUMMARYA unifying feature of the RAS superfamily is a functionally conserved GTPase cycle that proteins use to transition between active and inactive states. Here, we demonstrate that active site autophosphorylation of some small GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, thus altering the on/off switch that forms the basis for their signaling functions. Using x-ray crystallography, nuclear magnetic resonance spectroscopy, biolayer interferometry binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II domain and that autophosphorylation promotes nucleotide exchange by opening of the active site and extraction of the stabilizing Mg. Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from the non-phosphorylated counterpart.

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups (∼80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.One Sentence SummaryAlum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.

A unifying feature of the RAS superfamily is a conserved GTPase cycle by which these proteins transition between active and inactive states. We demonstrate that autophosphorylation of some GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, altering the on/off switch that forms the basis for their signaling functions. Using X-ray crystallography, nuclear magnetic resonance spectroscopy, binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II region and that autophosphorylation promotes nucleotide exchange by opening the active site and extracting the stabilizing Mg(2+). Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins in mammalian cells. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from their non-phosphorylated counterparts.

Background A novel prediction model for accurate determination of 5-year overall survival of gastric cancer patients was developed by an international collaborative group (G6+). This prediction model was created using a single institution's database of 11,851 Korean patients and included readily available and clinically relevant factors. Already validated using external East Asian cohorts, its applicability in the American population was yet to be determined. Study Design Using the Surveillance, Epidemiology, and End Results (SEER) dataset, 2014 release, all patients diagnosed with gastric adenocarcinoma who underwent surgical resection between 2002 and 2012, were selected. Characteristics for analysis included: age, sex, depth of tumor invasion, number of positive lymph nodes, total lymph nodes retrieved, presence of distant metastasis, extent of resection, and histology. Concordance index (C-statistic) was assessed using the novel prediction model and compared with the prognostic index, the seventh edition of the TNM staging system. Results Of the 26,019 gastric cancer patients identified from the SEER database, 15,483 had complete datasets. Validation of the novel prediction tool revealed a C-statistic of 0.762 (95% CI 0.754 to 0.769) compared with the seventh TNM staging model, C-statistic 0.683 (95% CI 0.677 to 0.689), (p Conclusions Our study validates a novel prediction model for gastric cancer in the American patient population. Its superior prediction of the 5-year survival of gastric cancer patients in a large Western cohort strongly supports its global applicability. Importantly, this model allows for accurate prognosis for an increasing number of gastric cancer patients worldwide, including those who received inadequate lymphadenectomy or underwent a noncurative resection.

Background/Aims Liver stiffness (LS) was assessed using transient elastography, and the enhanced liver fibrosis (ELF) test was performed to accurately assess fibrotic burden. We validated the LS-ELF algorithm and investigated whether the sequential LS-ELF algorithm performs better than concurrent combination of these analyses in chronic hepatitis B (CHB) patients. Methods Between 2009 and 2013, 222 CHB patients who underwent liver biopsy (LB), as well as LS measurement and the ELF test, were enrolled. Results Advanced fibrosis (≥F3) and cirrhosis (F4) were identified in 141 (63.6%) and 118 (53.2%) patients, respectively. Areas under receiver operating characteristic curve for LS predictions of ≥F3 (0.887 vs 0.703) and F4 (0.853 vs 0.706) were significantly higher than the ELF test (all p＜0.001). Based on the LS-ELF algorithm, 60.4% to 71.6% and 55.7% to 66.3% of patients could have avoided LB to exclude ≥F3 and F4, respectively, whereas 68.0% to 78.7% and 63.5% to 66.1% of patients could have avoided LB to confirm ≥F3 and F4, respectively. When confirmation and exclusion strategies were applied simultaneously, 69.4% to 72.5% and 60.8% to 65.3% of patients could have avoided LB and been diagnosed as ≥F3 and F4, respectively. The proportion of patients who correctly avoided LB for the prediction of ≥F3 (69.4% to 72.5% vs 42.3% to 59.0%) and F4 (60.8% to 65.3% vs 23.9% to 49.5%) based on the sequential LS-ELF algorithm was significantly higher than the concurrent combination (all p＜0.05). Conclusions The sequential LS-ELF algorithm conferred a greater probability of avoiding LB in CHB patients to diagnose advanced fibrosis and cirrhosis, and this test performed significantly better than the concurrent combination.

Gamma-glutamyl transpeptidase-to-platelet ratio (GPR) can evaluate the degree of liver fibrosis. We investigated whether GPR can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients.We retrospectively evaluated 1109 CHB patients that were enrolled between 2006 and 2012, and all patients had available data for the assessment of GPR at enrollment. Three risk groups were defined according to tertile stratification: GPR 0.05, low-risk (n = 370 [33.4%]); GPR 0.05-0.24, intermediate-risk (n = 370 [33.4%]); and GPR 0.24, high-risk (n = 369 [33.2%]). The predictive accuracy of GPR, fibrosis-4 (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) in predicting HCC development was tested.The median age of the study population (746 men and 363 women) was 50 years. During the follow-up period (median, 32 months; interquartile range, 19-57 months), 69 (6.2%) patients developed HCC. Together with age, male gender, diabetes mellitus, antiviral therapy, serum albumin, and alpha-fetoprotein, the relative risk of HCC development significantly increased from low-risk to high-risk GPR groups (hazard ratio [HR], up to 29.5; adjusted HR, up to 10.6; all P 0.05). In addition, FIB-4 was calculated to be a significantly high relative risk of HCC development (HR, up to 20.1; adjusted HR, up to 7.3; all P 0.05), whereas APRI was not (P = 0.168). The cumulative incidence of HCC development was significantly different among three risk groups (P 0.001, log-rank test).This study suggests that GPR can be used as a noninvasive marker to assess the risk of HCC development in CHB patients.

BACKGROUND AND AIM We aimed to subclassify hepatocellular carcinoma (HCC) using Barcelona Clinic Liver Cancer intermediate and advanced stages, which include a highly heterogeneous population. METHODS From two registries ("random" and "voluntary" cohorts in the Korean Liver Cancer Study Group), patients who were newly diagnosed as HCC with intermediate or advanced stage between 2003 and 2005 were considered eligible. Overall survival (OS) was analyzed using Kaplan-Meier method with comparison by log-rank test. RESULTS Patients with intermediate-stage HCC (n = 994) were subclassified according to tumor size and Child-Pugh class. Patients with tumor size

Background: Recently, a novel model predicting 5-year survival after gastrectomy was developed, the Yonsei Gastric Cancer Prognosis Prediction Model, to overcome limitations of the tumor-node-metastases (TNM)staging system. This study aimed to validate this model in a European cohort. Methods: All patients who underwent gastrectomy for gastric cancer were selected from the Netherlands Cancer Registry (2005–2015). Patients with 30-day mortality, co-existing cancer, neoadjuvant therapy, or missing data were excluded. The prediction model included gender, age, resection type, pT-stage, pM-stage, number of retrieved lymph nodes, number of metastatic lymph nodes, and tumor histology. The model was validated and compared to the 7th TNM staging system using calibration plots and the concordance index (c-statistic with 95% confidence interval (CI)). Results: From the 5748 patients who underwent gastrectomy, 2253 were included in this study. Mean age was 72.1 years, most patients had advanced gastric cancer (88%), and in 1102 patients (49%)no proper TNM staging could be performed since

We compared the risk of hepatocellular carcinoma (HCC) development between patients with chronic hepatitis B (CHB) who achieved virological response (VR; HBV-DNA 2000 IU/mL) with nucleos(t)ide analogues (NUCs) treatment (NUC-VR group) and patients with inactive CHB phase (ICHBP group).To adjust for imbalances between NUC-VR and ICHBP groups, propensity score matching (PSM) models with 1:1 ratios were performed.This study included 2032 patients (n = 1291 in NUC-VR group and n = 741 in ICHBP group). Before PSM, NUC-VR group was at higher risk of HCC development than ICHBP group at 7 years (9.4% in NUC-VR group vs 3.3% in ICHBP group; P 0.001). However, after PSM, the cumulative HCC development rates at 7 years were similar in NUC-VR and ICHBP groups using the three PSM models [2.0% vs 4.3%, PSM model-1 (612 pairs); 3.7% vs 4.4%, PSM model-2 (618 pairs); and 2.4% vs 4.3%, PSM model-3 (610 pairs)] (all P 0.05).After adjusting heavier hepatic fibrosis burden in NUC-VR group, overall clinical outcomes between 2 groups had become comparable. Therefore, if appropriate, NUCs to prevent viral replication and hepatic inflammation are required for achieving better prognosis.

Several risk prediction models have been created to predict hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurrence, with promising results. However, their prognostic performances need to be validated in the era of antiviral therapy. From 2006 to 2011, patients with chronic HBV infection were recruited and those with a history of HCC or hepatic decompensation were excluded. At enrollment, liver stiffness (LS) was measured using transient elastography. We assessed the performances of conventional HCC prediction models (CU-HCC, GAG-HCC, REACH-B, and LSM-HCC scores) and the modified REACH-B (mREACH-B) score where LS values were incorporated into REACH-B score instead of serum HBV-DNA levels. Of 1,308 subjects analyzed, the median age was 50.0 years (883 men). During the follow-up (median, 75.3 months), HCC developed in 125 (9.6%) patients. mREACH-B score had the highest areas under the receiver operating characteristic curves (AUROCs) for the prediction of HCC development at 3/5 years (0.828/0.806), compared with LSM-HCC (0.777/0.759), GAG-HCC (0.751/0.757), REACH-B (0.717/0.699), and CU-HCC (0.698/0.700) scores, respectively, with statistical significances (all P values

We performed a propensity-score matched analysis to investigate whether entecavir, compared with lamivudine, can reduce risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B after adjusting for level of fibrosis.We performed a retrospective study of 1079 patients with chronic hepatitis B who received first-line therapy with lamivudine (n = 435) or entecavir (n = 644) from 2006 through 2013. Only patients with available liver stiffness value measured by transient elastography were recruited. Liver cirrhosis was diagnosed by ultrasonography. To adjust for the imbalance of patients treated with lamivudine versus entecavir, we performed propensity-score matching (PSM), at a ratio of 1:1, using 7 factors (age, sex, hepatitis B e antigen, alanine aminotransferase, serum albumin, platelet count, and liver stiffness; PSM1) or 8 factors (variables of PSM1 plus ultrasonography measurements of cirrhosis; PSM2). Patients with virologic breakthrough or resistance mutations received rescue therapy.Over the 7-year period, 91 patients developed HCC and 104 had liver-related events in the entire cohort. In multivariate analyses, level of fibrosis, but not antiviral regimen, was independently associated with risk of HCC (P.05). The PSM1 group included 342 pairs of patients and the PSM2 group included 338 pairs. Similar proportions of patients given lamivudine versus entecavir developed HCC in each model (10.5% given lamivudine vs 9.9% given entecavir in PSM1 and 11.9% vs 12.6% in PSM2; all P.05). When PSM was applied to patients with liver stiffness value ≤13 kPa or13 kPa, patients given lamivudine versus entecavir still had similar cumulative rates of HCC development (all P.05).In a PSM analysis, we associated level of fibrosis, rather than antiviral regimen, with risk of HCC, when patients received appropriate rescue therapy in case of virologic breakthrough or resistance mutations.

Agreement analysis is conducted to assess reliability among rating results performed repeatedly on the same subjects by one or more raters. The kappa statistic is commonly used when rating scales are categorical. The simple and weighted kappa statistics are used to measure the degree of agreement between two raters, and the generalized kappa statistics to measure the degree of agreement among more than two raters. In this paper, we compare the performance of four different generalized kappa statistics proposed by Fleiss (1971), Conger (1980), Randolph (2005), and Gwet (2008a). We also examine how sensitive each of four generalized kappa statistics can be to the marginal probability distribution as to whether marginal balancedness and/or homogeneity hold or not. The performance of the four methods is compared in terms of the relative bias and coverage rate through simulation studies in various scenarios with different numbers of raters, subjects, and categories. A real data example is also presented to illustrate the four methods.

Background The objective of this retrospective study was to determine if there are any differences in grafted kidney function in recipients of kidney transplantation (KT) when donors and recipients were anesthetized with sevoflurane compared to desflurane. Methods Seventy-three pairs of donors-recipients were anesthetized with sevoflurane (Sevo group) and 71 pairs were anesthetized with desflurane (Des group). We retrospectively investigated the blood urea nitrogen (BUN) levels, creatinine (Cr) levels, and estimated glomerular filtration rates (eGFR) of the recipients in both groups for 1 year postoperatively. We tested non-inferiority for serum creatinine at discharge and 1 year after KT. Short-term (1 year) outcomes of KT were assessed by the incidence of delayed graft function (DGF), acute rejection episodes (ARE), and graft failure. Results There were no differences in BUN, Cr, eGFR, or outcomes of KT at 1 year postoperatively. Specifically, the 95% confidence interval for the difference in creatinine levels between the Sevo and Des groups was less than the margin of equivalence at the time of discharge and 1 year after surgery. The occurrences of DGF, ARE, and graft failure were comparable between the groups. Conclusions Compared to desflurane, sevoflurane had no adverse effects on grafted renal function or on the short-term outcome of renal transplantation.

Computed tomography (CT) has become the predominant test for diagnosing acute appendicitis in adults. In children and young adults, exposure to CT radiation is of particular concern. We evaluated the rate of negative (unnecessary) appendectomy after low-dose versus standard-dose abdominal CT in young adults with suspected appendicitis.In this single-institution, single-blind, noninferiority trial, we randomly assigned 891 patients with suspected appendicitis to either low-dose CT (444 patients) or standard-dose CT (447 patients). The median radiation dose in terms of dose-length product was 116 mGy·cm in the low-dose group and 521 mGy·cm in the standard-dose group. The primary end point was the percentage of negative appendectomies among all nonincidental appendectomies, with a noninferiority margin of 5.5 percentage points. Secondary end points included the appendiceal perforation rate and the proportion of patients with suspected appendicitis who required additional imaging.The negative appendectomy rate was 3.5% (6 of 172 patients) in the low-dose CT group and 3.2% (6 of 186 patients) in the standard-dose CT group (difference, 0.3 percentage points; 95% confidence interval, -3.8 to 4.6). The two groups did not differ significantly in terms of the appendiceal perforation rate (26.5% with low-dose CT and 23.3% with standard-dose CT, P=0.46) or the proportion of patients who needed additional imaging tests (3.2% and 1.6%, respectively; P=0.09).Low-dose CT was noninferior to standard-dose CT with respect to negative appendectomy rates in young adults with suspected appendicitis. (Funded by GE Healthcare Medical Diagnostics and others; ClinicalTrials.gov number, NCT00913380.).

Background and Aim: Liver stiffness (LS) measurement can distinguish individuals with potential liver disease (LD) from the general population. However, if LS is sex-sensitive, prevalence of LD may be incorrectly estimated when the same reference LS value is applied irrespective of sex. Here, we evaluated whether normal ranges of LS differ between healthy men and women. Methods: LS was measured in a cohort of healthy living liver and kidney donors, none of whom suffered from diabetes mellitus, hypertension, hepatitis B or C virus infection, heart or liver dysfunction, or metabolic syndrome. Patients with abnormal laboratory findings related to potential LD (platelet count 40 IU/L; alanine aminotransferase [ALT] > 40 IU/L; albumin 1.2 mg/dL; gamma-glutamyl transpeptidase > 54 IU/L; alkaline phosphatase > 115 IU/L) were excluded. Results: Among 242 patients analyzed, the mean age was 34.1 for men (n = 121) and 40.5 years for women (n = 121) (P