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<0.1, 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). Conclusions: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Efficacy of an assistive guide tube for improved endoscopic access to gastrointestinal lesions: an in vivo study in a porcine model.

BACKGROUND/AIMS: Guide tube-assisted endoscopy for procedures that require repeated endoscopic access is safer and more effective than conventional endoscopy. However, its effectiveness has not been confirmed in animal studies. We assessed the usefulness of guide tube-assisted endoscopic procedures in an in vivo porcine model. METHODS: Five different guide tube-assisted endoscopic procedures were performed by experienced endoscopists on a pig weighing 32 kg. To evaluate the efficacy of these procedures, we compared the endoscopic approach time when a guide tube was used to that when it was not. Additional endoscopic procedures using a guide tube were performed, including multiple foreign body extractions, multiple polypectomies, and multiple submucosal dissections. To evaluate safety, we compared the insertion force into the proximal esophagus between the guide tube and conventional overtube methods. RESULTS: Using the endoscopic approach with a guide tube required a shorter average approach time to reach the three target lesions than when using the endoscopic approach without a guide tube (p<0.001). Compared to the conventional overtube method, the guide tube method produced a lower average resistance during insertion into the upper esophagus (p<0.001). CONCLUSION: Guide tube-assisted endoscopic procedures are effective and safe for repeated endoscopic access in an in vivo porcine model.

Efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for hepatitis C in Korea: a Phase 3b study.

BACKGROUND/AIMS: Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in HCV-infected Korean adults. METHODS: This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir-velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment. RESULTS: Of 53 participants receiving sofosbuvir-velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir-velpatasvir-voxilaprevir achieved SVR 12. Overall, sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported. CONCLUSION: Treatment with sofosbuvir-velpatasvir or sofosbuvir-velpatasvir-voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

Usefulness of a new polyvinyl alcohol hydrogel (PVA-H)-based simulator for endoscopic submucosal dissection training: a pilot study.

BACKGROUND/AIMS: We developed a new endoscopic submucosal dissection (ESD) simulator and evaluated its efficacy and realism for use training endoscopists. METHODS: An ESD simulator was constructed using polyvinyl alcohol hydrogel sheets and compared to a previous ESD simulator. Between March 1, 2020, and December 30, 2021, eight expert endoscopists from three different centers analyzed the procedure-related factors of the simulator. Five trainees performed gastric ESD exercises under the guidance of these experts. RESULTS: Although the two ESD simulators provided overall favorable outcomes in terms of ESD-related factors, the new simulator had several benefits, including better marking of the target lesion's limits (p<0.001) and overall handling (p<0.001). Trainees tested the usefulness of the new ESD simulator. The complete resection rate improved after 3 ESD training sessions (9 procedures), and the perforation rate decreased after 4 sessions (12 procedures). CONCLUSION: We have developed a new ESD simulator that can help beginners achieve a high level of technical experience before performing real-time ESD procedures in patients.

Inverse Propensity Score-Weighted Analysis of Entecavir and Tenofovir Disoproxil Fumarate in Patients with Chronic Hepatitis B: A Large-Scale Multicenter Study.

Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) in preventing hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients; however, it remains controversial. This study aimed to conduct comprehensive comparisons between the two antivirals. CHB patients initially treated with ETV or TDF between 2012 and 2015 at 20 referral centers in Korea were included. The primary outcome was the cumulative incidence of HCC. The secondary outcomes included death or liver transplantation, liver-related outcome, extrahepatic malignancy, development of cirrhosis, decompensation events, complete virologic response (CVR), seroconversion rate, and safety. Baseline characteristics were balanced using the inverse probability of treatment weighting (IPTW). Overall, 4210 patients were enrolled: 1019 received ETV and 3191 received TDF. During the median follow-ups of 5.6 and 5.5 years, 86 and 232 cases of HCC were confirmed in the ETV and TDF groups, respectively. There was no difference in HCC incidence between the groups both before (p = 0.36) and after IPTW was applied (p = 0.81). Although the incidence of extrahepatic malignancy was significantly higher in the ETV group than in the TDF group before weighting (p = 0.02), no difference was confirmed after IPTW (p = 0.29). The cumulative incidence rates of death or liver transplantation, liver-related outcome, new cirrhosis development, and decompensation events were also comparable in the crude population (p = 0.24-0.91) and in the IPTW-adjusted population (p = 0.39-0.80). Both groups exhibited similar rates of CVR (ETV vs. TDF: 95.1% vs. 95.8%, p = 0.38), and negative conversion of hepatitis B e antigen (41.6% vs. 37.2%, p = 0.09) or surface antigen (2.8% vs. 1.9%, p = 0.10). Compared to the ETV group, more patients in the TDF group changed initial antivirals due to side effects, including decreased kidney function (n = 17), hypophosphatemia (n = 20), and osteoporosis (n = 18). In this large-scale multicenter study, ETV and TDF demonstrated comparable effectiveness across a broad range of outcomes in patients with treatment-naïve CHB during similar follow-up periods.

Effects of additive interactions among obesity, visceral adiposity, and sarcopenia on nonalcoholic fatty liver disease.

Although the association of nonalcoholic fatty liver disease (NAFLD) with obesity or sarcopenia is known, few studies have investigated the combined effect of various body composition parameters on the risk of NAFLD. Thus, the aim of this study was to evaluate effects of interactions between various body composition parameters, including obesity, visceral adiposity, and sarcopenia, on NAFLD. Data of subjects who underwent health checkups between 2010 and December 2020 were retrospectively analyzed. Body composition parameters including appendicular skeletal muscle mass (ASM) and visceral adiposity were assessed using bioelectrical impedance analysis. Sarcopenia was defined as ASM/weight beyond two standard deviations below the gender-specific mean for healthy young adults. NAFLD was diagnosed using hepatic ultrasonography. Interaction analyses, including relative excess risk due to interaction (RERI), synergy index (SI), and attributable proportion due to interaction (AP), were performed. Among a total of 17,540 subjects (mean age: 46.7 years, 49.4% males), the prevalence of NAFLD was 35.9%. The odds ratio (OR) of interaction between obesity and visceral adiposity affecting NAFLD was 9.14 (95% CI: 8.29-10.07). The RERI was 2.63 (95% CI: 1.71-3.55), SI was 1.48 (95% CI: 1.29-1.69) and AP was 29%. The OR of interaction between obesity and sarcopenia affecting NAFLD was 8.46 (95% CI: 7.01-10.21). The RERI was 2.21 (95% CI: 0.51-3.90). SI was 1.42(95% CI: 1.11-1.82) and AP was 26%. The OR of interaction between sarcopenia and visceral adiposity affecting NAFLD was 7.25 (95% CI: 6.04-8.71), however, there was no significant additive interaction with RERI = 0.87 (95% CI: -0.76 to 2.51). Obesity, visceral adiposity, and sarcopenia were found to be positively associated with NAFLD. Obesity, visceral adiposity, and sarcopenia were found to have additive interaction effects on NAFLD.

Effect of water filtration infrared-A (wIRA) sauna on inorganic ions excreted through sweat from the human body.

Sweat discharged as a result of exposure to sauna plays an important role in removing inorganic ions accumulated in the body, including heavy metals. In this study, inorganic ions (toxic and nutrient elements) excreted in the form of sweat from the body using a water-filtered infrared-A (wIRA) sauna were determined using inductively coupled plasma sector field mass spectrometry. The analyzed elements included eight toxic elements (Al, As, Be, Cd, Ni, Pb, Ti, and Hg) and 10 nutrient elements (Ca, Co, Cr, Cu, Fe, Mg, Mn, Se, V, and Zn), and their correlations were determined. Analysis of the sweat obtained from 22 people using the wIRA sauna showed a higher inorganic ion concentration than that obtained from conventional activities, such as exercise or the use of wet sauna, and the concentration of toxic elements in sweat was higher in females than in males. Correlation analysis of the ions revealed a correlation between the discharge of toxic elements, such as As, Be, Cd, and Ni, and discharge of Se and V, and Ni was only correlated with Mn. This study provides fundamental information on nutritional element supplementation when using wIRA sauna for detoxification.

Association between severe hepatic steatosis examined by Fibroscan and the risk of high-risk colorectal neoplasia.

The prevalence of colorectal neoplasm in patients with non-alcoholic fatty liver disease has increased twice as high as that in the general population. FibroScan is a new modality for evaluating hepatic steatosis. This study aimed to investigate the relationship between the risk of high-risk colorectal neoplasia and hepatic steatosis examined using FibroScan. This was a cross sectional study of prospectively enrolled subjects who were scheduled to undergo index colonoscopy as a health screening between March 2018 and February 2019. The severity of steatosis was graded as normal, mild, moderate, or severe using FibroScan. A total of 140 consecutive subjects were enrolled and sequentially examined using FibroScan and colonoscopy. Subjects with hepatic steatosis had more high-risk colorectal neoplasia than those without hepatic steatosis. In addition, tumor size was larger in subjects with hepatic steatosis. In multivariable analysis, severe hepatic steatosis was an independent risk factor for high-risk colorectal neoplasia (adjusted odds ratio: 3.309, confidence interval: 1.043-10.498, p = 0.042). Alcohol consumption was also identified as a risk factor for high-risk colorectal neoplasia. In conclusion, severe hepatic steatosis on FibroScan is associated with the development of high-risk colorectal neoplasia. Thus, physicians should be aware of the association between colorectal neoplasia and hepatic steatosis assessed by FibroScan and its clinical implications.

Significance of digestive symptoms after COVID-19 vaccination: A retrospective single-center study.

OBJECTIVE: There is insufficient research on digestive symptoms and outcomes following coronavirus disease (COVID-19) vaccination. We aimed to investigate digestive symptoms and related complications among South Koreans who were administered COVID-19 vaccines. METHODS: Forty-six patients (men: 22, women: 24) with a median age of 68 years (interquartile range:55.5, 73.8 years) who experienced digestive symptoms following COVID-19 vaccination between March 1 and July 30, 2021, were included. This retrospective single-center study collected information on clinical symptoms, laboratory tests, imaging results, comorbidities, complications, treatment type, and prognosis. RESULTS: Thirty-three (71.7%), nine (19.6%), and three (6.5%) patients were administered AZD1222 (AstraZeneca), BNT162b2 (Pfizer/BioNTech), and JNJ-78436735 (Johnson and Johnson) vaccines, respectively. Patients were classified with mild (25 patients, 54.3%), moderate (five patients, 10.9%), and severe (16 patients, 34.8%) based on disease severity. Digestive symptoms included abdominal pain, diarrhea, dyspepsia, and nausea, which usually developed within 1 day (78.3%) following the first vaccination. In total, 14 (30.4%) patients experienced only gastrointestinal symptoms, whereas 32 (69.6%) experienced non-gastrointestinal symptoms. Complications included enterocolitis (76%), acute kidney injury (9%), anaphylactoid reaction (2%), and duodenal perforation (2%). CONCLUSIONS: COVID-19 vaccines caused digestive symptoms and other complications that ranged from mild to severe. While further validation is required, our results suggest that monitoring digestive symptoms following COVID-19 vaccination can help detect rather severe complications that require medical intervention.

SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition that affects nearly one billion people globally, characterized by triacylglycerol accumulation in the liver as a consequence of metabolic abnormalities (obesity and impaired glucose regulation). Low-grade inflammation, oxidative stress, mitochondrial dysfunction, and dysbiosis in gut microbiota are involved in the etiology of MAFLD, and both cardiovascular events and hepatic complications are the long-term consequences. In the absence of approved therapies for this condition, sodium-glucose cotransporter 2 inhibitors (SGLT-2 Is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have the specific advantage of lowering body weight and providing cardiovascular benefits. Here, we discuss potential roles for SGLT-2 Is and GLP-1 RAs in the prevention and treatment of intrahepatic triacylglycerol accumulation and associated inflammation and/or fibrosis.

Adverse events following COVID-19 vaccination in South Korea between February 28 and August 21, 2021: A nationwide observational study.

OBJECTIVES: To investigate the clinical characteristics of adverse events (AEs) after COVID-19 vaccination in patients in South Korea. DESIGN: Data from the Korean Disease Control and Prevention Agency on AEs from 4 COVID-19 vaccines, including AZD1222, BNT162b2, JNJ-78436735, and mRNA-1273, from February 26, 2021, to August 21, 2021, were assessed. The epidemiological characteristics, clinical symptoms, severity, complications, and mortality were descriptively analyzed. RESULTS: Overall, 36.3 million individuals who completed the COVID-19 vaccination doses during the study period were included, and 153,183 AEs were reported. Most AEs occurred after the first dose (80.6%) and within a day (63.2%) after vaccination. Of the AEs, 95.5% were nonsevere cases; however, 4.5% were severe. Most mild AEs showed a similar frequency across all age groups, but major severe AEs and mortality events increased with age. CONCLUSIONS: Although there were differences in the frequency of occurrence, various adverse reactions were confirmed in using all 4 COVID-19 vaccines, even with the BNT162b2 (Pfizer-BioNTech) vaccine. Caution is needed, and further research should be continuously conducted.

Efficacy and Safety of Pregabalin for Muscle Cramps in Liver Cirrhosis: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Muscle cramp is possibly related to peripheral nerve hyperexcitability (PNH), and one of the most debilitating symptoms frequently encountered in patients with liver cirrhosis. We investigated whether pregabalin, a gamma-aminobutyric acid analogue, can suppress neuronal excitability and reduce muscle cramps in cirrhotic patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in which study participants with cirrhosis from a single tertiary center were enrolled. Primary endpoint was the relative change in cramp frequency from the run-in to standard dose treatment phase (4 weeks per each). Secondary endpoints included the responder rate, and the changes in cramp frequency during sleep, pain intensity, health-related quality of life (Liver Disease Quality of Life Instrument, Short Form-36) and electrophysiological measures of PNH. RESULTS: This study was terminated early because of insufficient accrual. 80% (n = 56) of the target number of participants (n = 70) were randomized to pregabalin (n = 29) or placebo (n = 27). Median baseline frequency of muscle cramps (interquartile range) was 5.8 (3.5-10) per week in the pregabalin group and 6.5 (4.0-10) in the placebo group (P = 0.970). The primary analysis showed a significant reduction in cramp frequency with pregabalin compared to placebo (-36% vs. 4.5% for the percentage change, P = 0.010). Secondary outcomes did not differ significantly between the two groups. Adverse effects with pregabalin were mainly dizziness and lethargy. CONCLUSION: With multiple problems emerging from premature termination in mind, the results suggested an acceptable safety profile and favorable effect of pregabalin in reducing muscle cramps compared to placebo in cirrhotic patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01271660.

Helicobacter pylori infection is not associated with portal hypertension-related gastrointestinal complications: A meta-analysis.

Despite the importance of Helicobacter pylori infection and portal hypertension (PH)-associated gastrointestinal (GI) diseases, such as esophageal varices and portal hypertensive gastropathy (PHG), the impact of H. pylori infection on PH-related GI complications has not yet been elucidated. This meta-analysis investigated the association between H. pylori infection and the risk of PH-related GI complications. An electronic search for original articles published before May 2020 was performed using PubMed, EMBASE, and the Cochrane Library. Independent reviewers conducted the article screening and data extraction. We used the generic inverse variance method for the meta-analysis, and Begg's rank correlation test and Egger's regression test to assess publication bias. A total of 1,148 cases of H. pylori infection and 1,231 uninfected controls were included from 13 studies. H. pylori infection had no significant association with esophageal varices [relative risk (RR) = 0.96, 95% confidence interval (CI) = 0.87-1.06 for all selected studies; RR = 0.95, 95% CI = 0.84-1.07 for cohort studies; odds ratio (OR) = 0.96, 95% CI = 0.60-1.54 for case-control studies]. Although H. pylori infection was significantly associated with PHG in case-control studies [OR = 1.86, 95% CI = 1.17-2.96], no significant differences were found in the cohort studies [RR = 0.98, 95% CI = 0.91-1.05] or all studies combined [RR = 1.18, 95% CI = 0.93-1.52]. In conclusion, H. pylori infection was not associated with the risk of PH-related GI complications. Clinicians should carefully treat cirrhotic patients with PH-related GI complications, regardless of H. pylori infection.

Role of radiotherapy in Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIM: This study aimed to investigate the clinical benefits of locoregional radiation therapy (RT) before, after, and concurrent with sorafenib therapy for Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) patients. METHODS: Patients treated with sorafenib for BCLC stage C HCC between January 2015 and December 2017 were retrospectively reviewed. In this study, only RT to locoregional sites, including the primary HCC, tumor thrombosis, or lymph node metastasis, was analyzed. Propensity score matching was used to adjust important baseline characteristics between groups. RESULTS: Among 398 patients treated with sorafenib, 68 (17.1%) patients were treated with locoregional RT. Median progression-free survival and overall survival (OS) were 2.2 and 9.5 months, respectively. In the multivariate analysis, locoregional RT (P < 0.001) was associated with a favorable OS. After 1:1 propensity score matching, patients who did not receive locoregional RT showed a worse OS than those who received RT (median 9.6 vs 15.7 months, P = 0.017). Whereas locoregional RT before/concurrent with sorafenib did not result in prolonged OS, locoregional RT after sorafenib showed significantly prolonged OS compared with sorafenib without locoregional RT (P = 0.003). Moreover, patients treated with ≥ 12 weeks of sorafenib significantly benefited from locoregional RT (15.3 vs 23.6 months, P = 0.046). CONCLUSION: Locoregional RT was associated with significantly longer survival in BCLC stage C HCC patients who were treated with sorafenib. Therefore, incorporating locoregional RT could improve the dismal prognosis for these patients.

An artificial intelligence model to predict hepatocellular carcinoma risk in Korean and Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk. METHODS: Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development. RESULTS: In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up. CONCLUSIONS: This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir. LAY SUMMARY: Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.

Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus.

BACKGROUND AND AIMS: Bile acid (BA) dysregulation is related to not only metabolic diseases but also nonalcoholic fatty liver disease (NAFLD). We investigated whether circulating BA levels are altered according to the histological severity of NAFLD independent of metabolic derangements. METHODS: Global metabolic profiling and targeted BA analysis using sera collected from biopsy-proven no-NAFLD (n = 67), nonalcoholic fatty liver (NAFL) (n = 99), and nonalcoholic steatohepatitis (NASH, n = 75) subjects were performed sequentially. Circulating metabolome analysis integrated with the hepatic transcriptome was performed to elucidate the mechanistic basis of altered circulating BA profiles after stratification by obesity (body mass index ≤ 25 kg/m2 ). Circulating BA alterations were also validated in an independent validation cohort (29 no-NAFLD, 70 NAFL and 37 NASH). RESULTS: Global profiling analysis showed that BA was the metabolite significantly altered in NASH compared to NAFL. Targeted BA analysis demonstrated that glyco-/tauro-conjugated primary BAs were commonly increased in nonobese and obese NASH, while unconjugated primary BAs increased only in nonobese NASH. These characteristic primary BA level changes were maintained even after stratification according to diabetes status and were replicated in the independent validation cohort. Compared to nonobese NAFL patients, nonobese NASH patients exhibited upregulated hepatic expression of CYP8B1. CONCLUSIONS: BA metabolism is dysregulated as the histological severity of NAFLD worsens, independent of obesity and diabetes status; dysregulation is more prominent in nonobese NAFLD patients. Metabolome-driven omics approach provides new insight into our understanding of altered BA metabolism associated with individual phenotypes of NAFLD.

Evaluation of a multiplex PCR method for the detection of porcine parvovirus types 1 through 7 using various field samples.

Porcine parvoviruses (PPVs) are small, nonenveloped DNA viruses that are widespread in the global pig population. PPV type 1 (PPV1) is a major causative agent of reproductive failure and has been recognized since the 1960s. In recent decades, novel PPVs have been identified and designated as PPVs 2 through 7 (PPV2~PPV7). Although the epidemiological impacts of these newly recognized parvoviruses on pigs are largely unknown, continuous surveillance of these PPVs is needed. The aim of this study was to develop an improved and efficient detection tool for these PPVs and to assess the developed method with field samples. Using 7 sets of newly designed primers, a multiplex polymerase chain reaction (mPCR) protocol was developed for the simultaneous detection of the seven genotypes of PPV (PPV1~PPV7). The sensitivity of the mPCR assay was analyzed, and the detection limit was determined to be 3×103 viral copies. The assay was highly specific in detecting one or more of the viruses in various combinations in specimens. The mPCR method was evaluated with 80 serum samples, 40 lung or lymph node samples and 40 intestine or fecal samples. When applied to these samples, the mPCR method could detect the 7 viruses simultaneously, providing rapid results regarding infection and coinfection status. In conclusion, the developed mPCR assay can be utilized as an effective and accurate diagnostic tool for rapid differential detection and epidemiological surveillance of various PPVs in numerous types of field samples.

Empirical Treatment With Carbapenem vs Third-generation Cephalosporin for Treatment of Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Third-generation cephalosporins (TGCs) are recommended as first-line antibiotics for treatment of spontaneous bacterial peritonitis (SBP). However, antibiotics against multidrug-resistant organisms (such as carbapenems) might be necessary. We aimed to evaluate whether carbapenems are superior to TGC for treatment of SBP. METHODS: We performed a retrospective study of 865 consecutive patients with a first presentation of SBP (275 culture positive; 103 with TGC-resistant bacterial infections) treated at 7 referral centers in Korea, from September 2013 through January 2018. The primary outcome was in-hospital mortality. We made all comparisons using data from patients whose baseline characteristics were balanced by inverse probability of treatment weighting. RESULTS: Of patients who initially received empirical treatment with antibiotics, 95 (11.0%) received carbapenems and 655 (75.7%) received TGCs. Among the entire study cohort, there was no significant difference in in-hospital mortality between the carbapenem (25.8%) and TGC (25.3%) groups (adjusted odds ratio [aOR], 0.97; 95% CI, 0.85-1.11; P = .66). In the subgroup of patients with high chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores (score of 7 or greater, n = 314), carbapenem treatment was associated with lower in-hospital mortality (23.1%) than in the TGC group (38.8%) (aOR, 0.84; 95% CI, 0.75-0.94; P=.002). In contrast, among patients with lower CLIF-SOFA scores (n = 436), in-hospital mortality did not differ significantly between the carbapenem group (24.7%) and the TGC group (16.0%) (aOR, 1.06; 95% CI, 0.85-1.32; P = .58). CONCLUSIONS: For patients with a first presentation of SBP, empirical treatment with carbapenem does not reduce in-hospital mortality compared to treatment with TGCs. However, among critically ill patients (CLIF-SOFA scores ≥7), empirical carbapenem treatment was significantly associated with lower in-hospital mortality than TGCs.

Circulating lipidomic alterations in obese and non-obese subjects with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects obese and non-obese individuals. However, mechanisms underlying non-obese non-alcoholic steatohepatitis (NASH) remain unclear. AIMS: To attempt to identify metabolic perturbations associated with non-obese and obese NAFLD using a lipidomics approach. METHODS: A cross-sectional analysis of 361 subjects with biopsy-proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non-obese based on the Asian cut-off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). RESULTS: Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non-obese NAFLD (SM d38:0; P < 0.001) but not in obese NAFLD. Additionally, SM levels were significantly associated with systemic and adipose tissue insulin resistance (SM d38:0; P = 0.002 and <0.001, respectively). Five potential lipid metabolites for non-obese subjects and seven potential lipids for obese subjects were selected to predict NAFLD and NASH. These lipid combinations showed good diagnostic performance for non-obese (area under the curve [AUC] for NAFLD/NASH = 0.916/0.813) and obese (AUC for NAFLD/NASH = 0.967/0.812) subjects. Moreover, distinctly altered patterns of diacylglycerol (DAG), triacylglycerol (TAG) and SM levels were confirmed in the validation set depending on the histological severity of NAFLD. CONCLUSION: Non-obese and obese NAFLD subjects exhibit unique circulating lipidomic signatures, including DAGs, TAGs and SMs. These lipid combinations may be useful biomarkers for non-obese and obese NAFLD patients.

Pulmonary function is associated with fibrosis severity in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND & AIMS: The association between nonalcoholic fatty liver disease (NAFLD) and pulmonary function remains elusive because of the heterogeneous spectrum and inaccurate diagnostic methods of NAFLD, and insufficient pulmonary function data. We conducted this study to identify the association between histological severity of NAFLD and pulmonary function. METHODS: This study included patients ≥18 years old with baseline pulmonary function data between August 2014 and July 2019 within a biopsy-evaluated prospective NAFLD cohort. Cross-sectionally, pre-/post-bronchodilator spirometric data with diffusing capacity (DLCO ) were compared according to histological severity of NAFLD in the various demographic and metabolic subgroups. Multivariable-adjusted analysis revealed specific histological features associated with reduced pulmonary function. RESULTS: In a total of 420 patients with biopsy-proven NAFLD, pre-/post-bronchodilator forced vital capacities (FVCs; a percentage of the predictive value) were inversely correlated with histological severity of NAFLD. Conversely, pre-bronchodilator forced expiratory volume in 1 second (FEV1 )/FVC was positively correlated with NAFLD severity. Post-bronchodilator FVC (%) decreased and DLCO /alveolar volume (VA ) increased linearly with worsening histological severity of NAFLD in multivariable analysis. In particular, fibrosis stage remained a significant independent predictor of decreased post-bronchodilator FVC (%) (ß-coefficient, 4.41; 95% confidence interval [-8.39, -0.43]; P = .031) even after adjusted for clinical variables, exclusively in age <65 years, female, never-smoker and nonchronic obstructive pulmonary disease subgroups. CONCLUSIONS: Pulmonary function deteriorates with worsening histological severity of NAFLD, especially at the fibrosis stage. The common pathogenesis of reduced pulmonary function and NAFLD fibrosis progression should be further explored.