A Modular Biosensor Design for Quantitative Measurement of Free Nedd8.

The objective of our study was to develop a genetically encoded biosensor for quantification of Nedd8, a post-translational modifier that regulates cellular signals through conjugation to other proteins. Perturbations in the balance of free (i.e., unconjugated) and conjugated Nedd8 caused by defects in Nedd8 enzymes or cellular stress are implicated in various diseases. Despite the biological and biomedical importance of Nedd8 dynamics, no method exists for direct quantification of free Nedd8, hindering the study of Nedd8 and activities of its associated enzymes. Genetically encoded biosensors are established as tools to study other dynamic systems, but limitations of current biosensor design methods make them poorly suited for free Nedd8 quantification. We have developed a modular method to design genetically encoded biosensors that employs a target binding domain and two reporter domains positioned on opposite sides of the target binding site. Target quantification is based on competition between target binding and the interaction of the reporter domains. We applied our design strategy to free Nedd8 quantification by developing a selective binder for free Nedd8 and combining it with fluorescent or split nanoluciferase reporters. Our sensors produced quantifiable and specific signals for free Nedd8 and enabled real-time monitoring of deneddylation by DEN1 with a physiological substrate. Our sensor design will be useful for high-throughput screening for deneddylation inhibitors, which have potential in treatment of cancers such as acute lymphoblastic leukemia. The modular design strategy can be extended to develop genetically encoded quantitative biosensors for other proteins of interest.

The Predictive Value of Time-Varying Noninvasive Scores on Long-Term Prognosis of NAFLD in South Korea.

Background: This study aimed to examine whether repeated measurements on noninvasive fibrosis scores during follow-up improve long-term nonalcoholic fatty liver disease (NAFLD) outcome prediction. Methods: A cohort study of 2,280 NAFLD patients diagnosed at the Seoul National University Hospital from 2001 to 2015 was conducted. Multivariable Cox regression models with baseline and designated time-point measurements of the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were used to assess the association between these scores and overall mortality, liver-related outcomes, and cardiovascular events. Results: Higher baseline NFS (high versus low probability for advanced fibrosis groups) was associated with higher risk of mortality (adjusted hazard ratio (aHR), (95% confidence interval (CI)), 2.80, [1.39-5.63]) and liver-related outcomes (3.70, [1.27-10.78]). Similar findings were observed for the association of baseline FIB-4 with mortality (2.49, [1.46-4.24]) and liver-related outcomes (11.50, [6.17-21.44]). In models considering designated time-point measurements of the scores, stronger associations were noted. For NFS, a higher time-point measurement was associated with a significantly higher risk of mortality (3.01, [1.65-5.49]) and liver-related outcomes (6.69, [2.62-17.06]). For FIB-4, higher time-point measurements were associated with significantly higher mortality (3.01, [1.88-4.82]) and liver-related outcomes (13.26, [6.89-25.53]). An annual increase in FIB-4 (2.70, [1.79-4.05]) or NFS (4.68, [1.52-14.44]) was associated with an increased risk of liver-related outcomes. No association between NFS/FIB-4 and risk of cardiovascular events was observed in both models. Conclusions: Higher aHRs describing the associations of FIB-4/NFS with overall mortality and liver-related outcomes were observed in the models that included designated time-point measurements of the scores. In addition to the baseline measurement, a routine monitoring on these scores may be important in predicting prognosis of NAFLD patients.

Correction to: Application of Schizosaccharomyces japonicus in makgeolli fermentation and its brewing characteristics.

[This corrects the article DOI: 10.1007/s10068-023-01265-6.].

SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion.

Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

Patient-centered care for mental health in patients with heart failure in the intensive care unit: A systematic review.

AIM: To assess basic data for developing appropriate interventions by examining the effects of patient-centered care (PCC) on the mental health of patients with heart failure in the intensive care unit (ICU). BACKGROUND: Patients with heart failure are frequently admitted to ICUs, and ICU stays are associated with prolonged mental health problems. METHODS: We conducted a systematic review using the CINAHL, Cochrane Library, Embase, MEDLINE, PsycINFO, and gray literature databases. Inclusion criteria were studies with participants aged ≥18 years with heart failure in the ICU who received a PCC intervention, and studies that described the outcomes for mental health problems. Data were extracted from five selected studies published after 2020 and analyzed. RESULTS: PCC is classified into three areas: comprehensive nursing, multidisciplinary disease management, and targeted motivational interviewing with conventional nursing. The two specific areas of focus for PCC regarding mental health were integrated mental healthcare and specific psychological nursing. Specific psychological nursing comprised relationship building, therapeutic communication, relaxation and motivational techniques, active therapeutic cooperation, psychological status evaluation, music therapy, and environmental management. CONCLUSIONS: This review provides a distinctive understanding of multidisciplinary and multicomponent PCC interventions for patients with heart failure in the ICU as an effective approach for improving their mental health. Future PCC intervention strategies aimed at patients with heart failure in the ICU should consider their preferences and family participation.

Lack of association between early on-treatment HBeAg seroclearance and development of hepatocellular carcinoma or decompensated cirrhosis.

Background & Aims: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue (NA) treatment and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) remains unclear. Here, we aimed to investigate the association of HBeAg seroclearance during potent NA treatment with the development of HCC and decompensated cirrhosis. Methods: Using a multicenter historical cohort including 2,392 non-cirrhotic adult patients with HBeAg-positive CHB who initiated NA treatment with tenofovir or entecavir, the risk of HCC and decompensated cirrhosis was compared between patients who achieved HBeAg seroclearance within 36 months of NA treatment (the HBeAg-loss group) and those who did not (the HBeAg-maintained group), using inverse probability of treatment weighting. Results: Over a median of 6.6 years of NA treatment, 1,077 patients achieved HBeAg seroclearance (HBeAg loss rate = 6.0 per 100 person-years), 64 patients developed HCC (HCC incidence rate = 0.39 per 100 person-years), and 46 patients developed decompensated cirrhosis (decompensation incidence rate = 0.28 per 100 person-years). The HBeAg-loss and HBeAg-maintained groups had a similar risk of developing HCC (hazard ratio 0.89; 95% CI 0.47-1.68; p = 0.72) and decompensated cirrhosis (hazard ratio 0.98; 95% CI 0.48-1.81; p = 0.91). Compared with delayed HBeAg seroclearance beyond 10 years of NA treatment, the risk of HCC was comparable in those who achieved earlier HBeAg seroclearance at any time point within 10 years, regardless of baseline age and fibrotic burden. Conclusions: Early HBeAg seroclearance during NA treatment was not associated with a reduced risk of development of HCC or decompensated cirrhosis in non-cirrhotic HBeAg-positive patients with CHB. Impact and implications: The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue treatment and the risk of hepatocellular carcinoma in patients with chronic hepatitis B remains unclear. Our findings indicate that early on-treatment HBeAg seroclearance within 3 years was not associated with the development of hepatocellular carcinoma or decompensated cirrhosis. Achieving HBeAg seroclearance may not be an appropriate surrogate endpoint for preventing the development of liver-related outcomes in non-cirrhotic patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues.

Comparison of volatile compound profiles derived from various livestock protein alternatives including edible-insect, and plant-based proteins.

In this study, the distinctive chemical fingerprints that contribute to the flavor characteristics of various protein materials, such as insects, plant-based protein, and livestock, were investigated. In edible-insects (Tenebrio molitor and Protaetia brevitarsis), aldehydes and cyclic volatile compounds were the predominant volatile components and had distinct flavor characteristics such as cheesy, sharp, green, floral, and sweet. In contrast, the relatively high levels of pyrazines and furans in plant-based protein materials, such as textured vegetable and pea protein. They included unique flavor properties characterized by sweet, fatty, grassy, creamy, and roasted. The primary volatile chemical group detected in livestock protein materials, such as a pork and a beef, was ketones. The pork sample showed specific flavors, such as alcoholic, green, and fruity, while a beef presented distinctive flavor, including creamy, fruity, and alcoholic. Based on the results, this research provided the understanding of the flavor aspects of diverse protein materials.

Longitudinal Relationship Between Baseline Social Frailty and Cognitive Impairment in Older Adults: 14-Year Follow-Up Results From the Korean Longitudinal Study of Ageing.

OBJECTIVES: This study aimed to investigate the longitudinal relationship between social frailty and cognitive impairment among community-dwelling older adults. DESIGN: This retrospective cohort study is based on the first to eighth waves of the Korean Longitudinal Study of Ageing (2006-2020). SETTING AND PARTICIPANTS: The participants were 2106 community-dwelling older adults aged 65 years or older and without cognitive impairment in 2006. METHODS: Social frailty was assessed with 5 items including social support, social activity, social network, loneliness, and living alone (0 = social nonfrailty, 1 = social prefrailty, 2 or more = social frailty). Cognitive function was assessed using the Korean Mini-Mental State Examination, and scores below 24 indicated cognitive impairment. We used the generalized estimating equation to assess the longitudinal relationship between social frailty and cognitive impairment. RESULTS: Of the 2106 participants, 515 (24.4%) had social frailty, 669 (31.8%) had social prefrailty, and 922 (43.8%) were social nonfrailty based on the baseline assessments. Relative to the social nonfrailty group, the odds ratios of the social prefrailty and social frailty groups for cognitive impairment were 1.30 (95% CI 1.10-1.54) and 1.41 (95% CI 1.16-1.71), respectively, during the follow-up. Subgroup analysis showed that social inactivity and loneliness were significantly associated with cognitive impairment. CONCLUSIONS AND IMPLICATIONS: These findings highlight the need for health care providers to introduce and use available social resources for older adults with social frailty to increase the relationships between individual and social context. Social inactivity and loneliness were the major domains associated with cognitive impairment, and loneliness can be resolved by participating in social activities. Therefore, health care providers especially provide opportunities for social activities, such as group-based programs in the community, to reduce social frailty and cognitive impairment.

Metabolic effects and cardiovascular disease risks of antiviral treatments in patients with chronic hepatitis B.

Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.

Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment. METHODS: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders. RESULTS: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30). CONCLUSION: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Stilbenoid derivatives as potent inhibitors of HIF-1α-centric cancer metabolism under hypoxia.

Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

High-dose proton pump inhibitor treatment is associated with a higher mortality in cirrhotic patients: A multicentre study.

BACKGROUND: Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis. AIMS: This study aimed to determine whether PPI use is associated with the prognosis of cirrhotic patients. METHODS: We conducted a multicentre retrospective cohort study involving 1485 patients who had experienced hepatic encephalopathy (HE) from 7 referral centres in Korea. The primary outcome was overall survival and secondary outcomes included the development of cirrhotic complications, including recurrent HE, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and gastrointestinal bleeding. Patients treated with PPI with a mean defined daily dose (mDDD) ≥0.5 (high-dose PPI group) were compared to those treated with PPI of an mDDD < 0.5 (No or low-dose PPI group) for each outcome. RESULTS: Among 1485 patients (median age, 61 years; male, 61%), 232 were assigned to the high-dose PPI group. High-dose PPI use was independently associated with a higher risk of death (adjusted HR [aHR] = 1.71, 95% confidence interval [CI] = 1.38-2.11, p < 0.001). This result was reproducible after propensity score-matching (PSM) (aHR = 1.90, 95% CI = 1.49-2.44, p < 0.001). High-dose PPI use was an independent risk factor of recurrent HE (before PSM: aHR = 2.04, 95% CI = 1.66-2.51, p < 0.001; after PSM: aHR = 2.16, 95% CI = 1.70-2.74, p < 0.001), SBP (before PSM: aHR = 1.87, 95% CI = 1.43-2.43, p < 0.001; after PSM: aHR = 1.76, 95% CI = 1.31-2.36, p = 0.002), HRS (before PSM: aHR = 1.48, 95% CI = 1.02-2.15, p = 0.04; after PSM: aHR = 1.47, 95% CI = 0.95-2.28, p = 0.09), and gastrointestinal bleeding (before PSM: aHR = 1.46, 95% CI = 1.12-1.90, p = 0.006; after PSM: aHR = 1.74, 95% CI = 1.28-2.37, p < 0.001). CONCLUSIONS: The use of high-dose PPI was independently associated with increased risks of mortality and cirrhotic complications.

Effect of Crude Polysaccharides from Ecklonia cava Hydrolysate on Cell Proliferation and Differentiation of Hanwoo Muscle Stem Cells for Cultured Meat Production.

Ecklonia cava, a brown seaweed native to the East Asian coast, is known for its unique composition, including polysaccharides, polyphenols, and phlorotannins. Fucoidan is a sulfated polysaccharide widely used as a functional ingredient in foods. This study obtained crude polysaccharides (ECC_CPS) from E. cava celluclast enzymatic hydrolysate using ethanol precipitation. ECC_CPS increased cell viability during the proliferation of Hanwoo muscle satellite cells (HMSCs). The effect of ECC_CPS on the expression of proliferation-related markers was confirmed as MYF5 and MYOD expression significantly increased, whereas PAX7 expression was maintained. The evaluation of cell migration activity has a major impact on cell proliferation and differentiation, and the cell migration index significantly increased with ECC_CPS treatment (p < 0.01). This was related to the HGF/MET pathway and FAK pathway. Treatment with ECC_CPS promoted differentiation at the cell differentiation stage, thereby increasing the expression of differentiation markers, such as MYH2, MYH7, and MYOG (p < 0.001 or p < 0.01). Therefore, our findings imply that crude polysaccharide obtained from E. cava can be an additive ingredient that enhances the proliferation and differentiation of muscle satellite cells used in the manufacture of cultured meat products.

The effects of different extraction methods on essential oils from orange and tangor: From the peel to the essential oil.

Citrus fruits are largely consumed due to their unique and pleasant aromas. Citrus hybrids have been developed to enhance their flavors and bioactivities. Citrus aroma depends on the composition of the volatile compounds in citrus essential oils (CEOs), which are mostly located in the peels. During the extraction of CEOs, a specific series of chemical reactions occurred depending on the extraction methods (CP, cold pressing; HD, hydrodistillation), leading to variations in the composition of volatile compounds. In this study, the orange and the tangor which is a hybrid between C. reticulata × C. sinensis were investigated to compare the changes in volatile compounds based on the extraction methods. Results showed that the CP-specific volatile compounds were sesquiterpenes, oxygenated monoterpenes, and fatty acid derivatives, while the HD-specific volatile compounds were terpinyl cation derivatives, limonene, and 4-vinylguaiacol. On the other hand, the contents of some volatile compounds ((E)-ocimene, α-terpinene, and α-terpinolene) were affected by the Citrus species rather than by the extraction methods. In particular, during HD, terpinene-4-ol and 4-vinylguiacol, known as off-flavor compounds in citrus juice, were formed more abundantly in the orange than in the tangor. In conclusion, these results provide comprehensive data on essential oils, especially those derived from oranges and tangors, for selecting the appropriate extraction method for obtaining a higher yield and quality of citrus flavor.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Effects of Natural Extract Mixtures on the Quality Characteristics of Sausages during Refrigerated Storage.

Owing to the residual toxicity and adverse health effects of chemical preservatives, there is an increasing demand for using natural preservatives in food. Although many natural extracts have been evaluated, research on their antibacterial effects remains insufficient. Therefore, this study aimed to explore the possibility of developing Psidium guajava, Ecklonia cava, and Paeonia japonica (Makino) Miyabe & Takeda extracts as natural food preservatives. Further, the effect of mixing these extracts on microbial growth and quality was evaluated during the refrigeration of sausages. Optimal mixing ratios were determined based on the minimum inhibitory and bactericidal concentrations of each mixed extract against the Listeria monocytogenes, Salmonella spp. and Escherichia coli. D-optimal mixing design optimization tool was further used to obtain an optimum mixing ratio of Formulation 1 (F1). The antibacterial activity of F1 increased with increasing concentration, with similar activities at 0.5% and 1%. The sausages with synthetic or natural preservatives showed significantly lower lipid oxidation than those of the control and grapefruit extract-treated sausages after 4 wk of refrigeration. Total plate counts were observed only in the control and treatment groups stored for 3 wk, and no significant effect of ascorbic acid was observed. Compared to the other samples, sausages with added natural extracts showed the highest overall acceptability scores initially and after 4 wk. Therefore, similar amounts of grapefruit seed and natural extracts had the same effect on microbiological analysis and lipid rancidity during sausage storage. Hence, this mixture can serve as a potential natural preservative in meat products.

Extrahepatic malignancies in metabolic dysfunction-associated fatty liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.

New Horizons: Translational Aspects of Osteomorphs.

Osteomorphs are a newly described osteoclast lineage cell in mice, which are suggested to play a significant role in the maintenance of bone resorption. Preclinical investigations revealed that osteomorphs are generated through the fission of multinucleated bone-resorbing osteoclasts and can also re-fuse with existing osteoclasts. Modifications to RANKL signaling have been shown to alter cycles of fission and re-fusion of osteomorphs in mice. These novel findings were also shown to contribute to the rebound phenomenon after cessation of anti-RANKL therapy in mice. Moreover, the absence of osteomorph-specific genes in mice exhibits bone structural and quality phenotypes. Given these insights, it could be speculated that osteomorphs play a significant role in bone homeostasis, bone metabolic diseases, and response to therapeutics. In this review, we discuss these potential translational roles for osteomorphs. Importantly, we highlight the need for future preclinical and clinical studies to verify the presence of osteomorphs in humans and explore further the translational implications of this discovery.

Application of the Nagoya Protocol to veterinary pathogens: concerns for the control of foot-and-mouth disease.

The Nagoya Protocol is an international agreement adopted in 2010 (and entered into force in 2014) which governs access to genetic resources and the fair and equitable sharing of benefits from their utilisation. The agreement aims to prevent misappropriation of genetic resources and, through benefit sharing, create incentives for the conservation and sustainable use of biological diversity. While the equitable sharing of the benefits arising from the utilisation of genetic resources is a widely accepted concept, the way in which the provisions of the Nagoya Protocol are currently being implemented through national access and benefit-sharing legislation places significant logistical challenges on the control of transboundary livestock diseases such as foot-and-mouth disease (FMD). Delays to access FMD virus isolates from the field disrupt the production of new FMD vaccines and other tailored tools for research, surveillance and outbreak control. These concerns were raised within the FMD Reference Laboratory Network and were explored at a recent multistakeholder meeting hosted by the European Commission for the Control of FMD. The aim of this paper is to promote wider awareness of the Nagoya Protocol, and to highlight its impacts on the regular exchange and utilisation of biological materials collected from clinical cases which underpin FMD research activities, and work to develop new epidemiologically relevant vaccines and other diagnostic tools to control the disease.