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BACKGROUND AND AIMS: Racial/ethnic minority children have worse liver transplant outcomes. We evaluated whether neighborhood socioeconomic deprivation affected associations between race/ethnicity and waitlist mortality. APPROACH AND RESULTS: We included children (age

Racial/ethnic minorities experience higher rates of wait-list mortality and longer waiting times on the liver transplant wait list. We hypothesized that racial/ethnic minorities may encounter greater logistical barriers to maintaining "readiness" on the wait list, as reflected in offer nonacceptance. We identified all candidates who received an organ offer between 2009 and 2018 and investigated candidates who did not accept an organ offer using a free-text refusal reason associated with refusal code 801. We isolated patients who did not accept an organ offer due to "candidate-related logistical reasons" and evaluated their characteristics. We isolated 94,006 "no 801" patients and 677 "with 801 logistical" patients. Common reasons for offer decline among the 677 were 60% "unable to travel/distance," 22% "cannot be contacted," 13% "not ready/unspecified," and 5% "financial/insurance." Compared to "no 801," "with 801 logistical" patients were more likely to be Hispanic (19% vs. 15%, P&nbsp

A primary approach to establishing hierarchy is through contests, in which conflicts are settled using various behavioural patterns. Although dominance ranks in a hierarchy are determined by quality-related innate factors, how the inequality of competitors is assessed and triggers the formation of a hierarchy by means of behavioural interactions remains unclear. Here, we report the sequence of aggressive behaviours that mediates the onset of hierarchy formation in eusocial bumble bee workers by continuously monitoring pairwise contests. Sequential analysis characterized the dynamics of the behavioural repertoire during hierarchy formation in Bombus terrestris; this was organized in phases associated with a divergence in dominance rank and included mutual pumping (a dorsoventral abdominal movement), bilateral physical contact and unilateral strikes. Escalated bilateral aggression served as a mutual assessment strategy and caused a rapid divergence in rank in evenly matched contests. Head butting was subsequently performed by dominants, suggesting it is a badge of higher rank. The behavioural progression was also similar in two other Bombus species despite interspecific variation in behavioural patterns. Size asymmetry reduced the duration of bilateral aggression, while age advantages over callow workers eliminated bilateral aggression. These results suggested potential roles of mutual assessment by ritualized fighting in hierarchy formation in queenless bumble bee societies.

Introduction Advances in transjugular intrahepatic portosystemic shunt (TIPS) technology have led to expanded use. We sought to characterize contemporary outcomes of TIPS by common indications. Methods This was a multicenter, retrospective cohort study using data from the Advancing Liver Therapeutic Approaches study group among adults with cirrhosis who underwent TIPS for ascites/hepatic hydrothorax (ascites/HH) or variceal bleeding (2010-2015). Adjusted competing risk analysis was used to assess post-TIPS mortality or liver transplantation (LT). Results Among 1,129 TIPS recipients, 58% received TIPS for ascites/HH and 42% for variceal bleeding. In patients who underwent TIPS for ascites/HH, the subdistribution hazard ratio (sHR) for death was similar across all Model for End-Stage Liver Disease Sodium (MELD-Na) categories with an increasing sHR with rising MELD-Na. In patients with TIPS for variceal bleeding, MELD-Na ≥20 was associated with increased hazard for death, whereas MELD-Na ≥22 was associated with LT. In a multivariate analysis, serum creatinine was most significantly associated with death (sHR 1.2 per mg/dL, 95% confidence interval [CI] 1.04-1.4 and 1.37, 95% CI 1.08-1.73 in ascites/HH and variceal bleeding, respectively). Bilirubin and international normalized ratio were most associated with LT in ascites/HH (sHR 1.23, 95% CI 1.15-1.3; sHR 2.99, 95% CI 1.76-5.1, respectively) compared with only bilirubin in variceal bleeding (sHR 1.06, 95% CI 1.00-1.13). Discussion MELD-Na has differing relationships with patient outcomes dependent on TIPS indication. These data provide new insights into contemporary predictors of outcomes after TIPS.

Queries of electronic health record (EHR) data repositories allow for automated data collection. These techniques have not been used in hepatology due to the inability to capture hepatic encephalopathy (HE) grades, which are inputs for acute‐on‐chronic liver failure (ACLF) models. Here, we describe a methodology to use EHR data to calculate rolling ACLF scores. We examined 239 patient admissions with end‐stage liver disease from July 2014 to June 2019. We mapped EHR flowsheet data to determine HE grades and calculated two longitudinally updated ACLF scores. We validated HE grades and ACLF diagnoses by chart review and calculated sensitivity, specificity, and Cohen’s kappa. Of 239 patient admissions analyzed, 37% were women, 46% were non‐Hispanic white, median age was 60 years, and the median Model for End‐Stage Liver Disease–Na score at admission was 25. Of the 239, 7% were diagnosed with ACLF as defined by the North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) diagnostic criteria at admission, 27% during the hospitalization, and 9% at discharge. Forty percent were diagnosed with ACLF by the European Association for the Study of the Liver– Chronic Liver Failure Consortium (CLIF‐C) diagnostic criteria at admission, 51% during the hospitalization, and 34% at discharge. From the chart review of 51 admissions, we found sensitivities and specificities for any HE (grades 1‐4) were 92%‐97% and 76%‐95%, respectively; for severe HE (grades 3‐4), sensitivities and specificities were 100% and 78%‐98%, respectively. Cohen’s kappa between flowsheet and chart review of HE grades ranged from 0.55 to 0.72. Sensitivities and specificities for NACSELD‐ACLF diagnoses were 75%‐100% and 96%‐100%, respectively; for CLIF‐C‐ACLF diagnoses, these were 91%‐100% and 96‐100%, respectively. We generated approximately 28 unique ACLF scores per patient per admission day. Conclusion: We developed an informatics‐based methodology to calculate longitudinally updated ACLF scores. This opens new analytic potentials, such as big data methods, to develop electronic phenotypes for patients with ACLF., Queries of electronic health record (EHR) data repositories allow for automated data collection. These techniques have not been utilized in hepatology due to previous inability to capture hepatic encephalopathy (HE) grades, which are inputs for acute‐on‐chronic liver failure (ACLF) models. We describe a methodology to utilizing EHR data to calculate rolling ACLF scores.

Background and aims Transjugular intrahepatic portosystemic shunt (TIPS) is an effective intervention for portal hypertensive complications, but its effect on renal function is not well-characterized. Here, we describe renal function and characteristics associated with renal dysfunction at 30-days post-TIPS. Methods Adults with cirrhosis who underwent TIPS at nine hospitals in the US 2010-2015 were included. We defined "post-TIPS renal dysfunction" as a change in estimated glomerular filtration rate (ΔeGFR) ≤ -15ml/min/1.73m2 and eGFR ≤ 60ml/min/1.73m2 , or new renal replacement therapy (RRT) at day 30. We identified the characteristics associated with post-TIPS renal dysfunction by logistic regression and evaluated survival using adjusted competing risk regressions. Results Of 673 patients: median age 57 years, 38% female, 26% had diabetes, median MELDNa 17. Thirty days post-TIPS, 66 (10%) had renal dysfunction, of which 23 (35%) required new RRT. Patients with post-TIPS renal dysfunction, compared to those with stable renal function, were more likely to have NAFLD (33% versus 17%, p = 0.01) and comorbid diabetes (42% versus 24%, p Conclusions In this large multi-center cohort, we found NAFLD, diabetes, and baseline serum sodium associated with post-TIPS renal dysfunction. This study suggests that patients with NAFLD and diabetes undergoing TIPS evaluation may require additional attention to cardiac and renal comorbidities prior to proceeding with the procedure.

Summary: Iliac vein compression syndrome, also known as May-Thurner Syndrome, is a type of vein reflux disorders which is often ignored due to lack of efficient diagnostic methods. The traditional gold standard of diagnosis is venography, but this has been challenged and largely replaced by intravascular ultrasound (IVUS). Here we report a case that a patient suffered with iodine anaphylaxis was successfully performed iliac vein stenting guided by using IVUS alone. This case provides the evidence that IVUS can offer necessary information for physicians in the diagnosis and treatment of iliac vein compression. We also find that balloon dilatation notch cannot precisely reflect the whole lesion, indicating it may be unreliable for diagnosis. Differ from the commonly accepted opinion, we find that comparing to IVUS, the notch of balloon dilatation cannot completely reflect the extent of lesion narrowness. Thus, we think the notch should not be used as a reference for seriousness of the lesion, and the diagnosis of stenosis cannot be ruled out even if there is no presence of notch.

BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered coronavirus that has generated a worldwide outbreak of infections. Many people with coronavirus disease-2019 (COVID-19) have developed severe illness, and a significant number have died. However, little is known regarding infection by the novel virus in pregnant women. We herein present a case of COVID-19 confirmed in a woman delivering a neonate who was negative for SARS-CoV-2 and related it to a review of the literature on pregnant women and human coronavirus infections. CASE SUMMARY The patient was a 36-year-old pregnant woman in her third trimester who had developed progressive clinical symptoms when she was confirmed as infected with SARS-CoV-2. Given the potential risks for both the pregnant woman and the fetus, an emergency cesarean section was performed, and the baby and his mother were separately quarantined and cared for. As a result, the baby currently shows no signs of SARS-CoV-2 infection (his lower respiratory tract samples were negative for the virus), while the mother completely recovered from COVID-19. CONCLUSION Although we presented a single case, the successful result is of great significance for pregnant women with SARS-CoV-2 infection and with respect to fully understanding novel coronavirus pneumonia.

BACKGROUND: Women on the liver transplant waitlist are at greater risk of hospitalization compared with men, but whether this impacts length of stay (LOS) post-transplant is unknown. We aimed to evaluate gender disparities in post-transplant LOS, an important surrogate of health resource utilization post-transplant. METHODS: Using the UNOS/OPTN registry, we analyzed all non-Status 1 adult deceased donor liver transplant recipients without exception points from 2008–2017. Poisson regression associated female gender with post-transplant LOS. RESULTS: Of 27,294 transplant recipients, 36% were female. Women were more likely to be hospitalized pre-transplant than men (44% vs 39%, p

Split liver transplantation (SLT) is 1 strategy for maximizing the number of deceased donor liver transplants. Recent reports suggest that utilization of SLT in the United States remains low. We examined deceased donor offers that were ultimately split between 2010 and 2014. SLTs were categorized as "primary" and "secondary" transplants. We analyzed allocation patterns and used logistic regression to evaluate factors associated with secondary split discard. Four hundred eighteen livers were split: 54% from adult, 46% from pediatric donors. Of the 227 adult donor livers split, 61% met United Network for Organ Sharing "optimal" split criteria. A total of 770 recipients (418 primary and 352 secondary) were transplanted, indicating 16% discard. Ninety-two percent of the 418 primary recipients were children, and 47% were accepted on the first offer. Eighty-seven percent of the 352 secondary recipients were adults, and 7% were accepted on the first offer. Of the 352 pairs, 99% were transplanted in the same region, 36% at the same center. In logistic regression, shorter donor height was associated with secondary discard (odds ratio 0.97 per cm, 95% CI 0.94-1.00, P=.02). SLT volume by center was not predictive of secondary discard. Current policy proposals that incentivize SLT in the United States could increase the number of transplants to children and adults.

Imidacloprid (IMI) and thiamethoxam (THM) are two commonly applied neonicotinoid insecticides. IMI and THM could cause negative impacts on non-target organisms like bees. However, the information about neurotoxicity of IMI and THM in fish is still scarce. Here we investigated the effects of IMI and THM on locomotor behavior, AChE activity, and transcription of genes related to synaptic transmission in zebrafish exposed to IMI and THM with concentrations of 50 ng L−1 to 50,000 ng L−1 at 14 day post fertilization (dpf), 21 dpf, 28 dpf and 35 dpf. Our results showed that IMI and THM significantly influenced the locomotor activity in larvae at 28 dpf and 35 dpf. THM elevated AChE activity at 28 dpf. The qPCR data revealed that IMI and THM affected the transcription of marker genes belonging to the synapse from 14 dpf to 35 dpf. Furthermore, IMI and THM mainly affected transcription of key genes in γ-aminobutyric acid, dopamine and serotonin pathways in larvae at 28 dpf and 35 dpf. These results demonstrated the neurotoxicity of IMI and THM in zebrafish. The findings from this study suggested that IMI and THM in the aquatic environment may pose potential risks to fish fitness and survival.

ObjectiveTo investigate the determinants of willingness and practice of physicians’ online medical services (OMS) uptake based on social ecosystem theory, so as to formulate OMS development strategies.DesignCross-sectional survey.SettingResearch was conducted in two comprehensive hospitals and two community hospitals in Jiangsu, China, and the data were gathered from 1 June to 31 June 2020.ParticipantsWith multistage sampling, 707 physicians were enrolled in this study.Outcome measureDescriptive statistics were reported for the basic characteristics. χ2 test, Mann-Whitney U test and Spearman’s correlation analysis were used to perform univariate analysis. Linear regression and logistic regression were employed to examine the determinants of physicians’ OMS uptake willingness and actual uptake, respectively.ResultsThe mean score of the physicians’ OMS uptake willingness was 17.33 (range 5–25), with an SD of 4.39, and 53.3% of them reported having conducted OMS. In the micro system, factors positively associated with willingness included holding administrative positions (b=1.03, pConclusionMultiple determinants influence physicians’ OMS application. Comprehensive OMS promotion strategies should be put forward from multidimensional perspectives including the micro, meso and macro levels.

Colorectal cancer (CRC) is recognized as a common type of human cancer, and KRAS mutations are correlated with poor CRC survival outcomes. The evaluation and prediction of CRC results remain challenging. In the present study, RNA sequencing and clinical data from The Cancer Genome Atlas were used to identify KRAS mutation-related prognostic long intergenic non-coding RNAs (lincRNAs) in CRC. Significantly dysregulated lincRNAs and independent prognostic lincRNAs with KRAS mutations in CRC were identified. Two lincRNAs with KRAS mutations, LINC00265 and AL390719.2, were selected as key prognostic lincRNAs for both 10- and 5-year survival rates. In addition, competing endogenous (ce)RNA models were constructed to comprehensively assess the oncogenic performance of the two key lincRNAs. The ceRNA models suggested that LINC00265 and AL390719.2 are critical for the cell cycle and cancer pathways. Finally, reverse transcription-quantitative PCR was used to validate the ceRNA models in 12 pairs of CRC tissue samples. These prognostic lincRNAs may provide novel biomarkers for the prognostic prediction of CRC. The ceRNA model may also demonstrate the underlying mechanism of these lincRNAs in CRC.

Androgens androstadienedione (ADD) and androstenedione (AED) are predominant steroid hormones in surface water, and can disrupt the endocrine system in fish. However, little is known about the transgenerational effects of ADD and AED in fish. In the present study, F0 generation was exposed to ADD and AED from 21 to 144 days post-fertilization (dpf) at nominal concentrations of 5 (L), 50 (M) and 500 (H) ng L−1, and F1 generation was domesticated in clear water for 144 dpf. The sex ratio, histology and transcription in F0 and F1 generations were examined. In the F0 generation, ADD and AED tended to be estrogenic in zebrafish, resulting in female biased zebrafish populations. In the F1 generation, ADD at the H level caused 63.5% females, while AED at the H level resulted in 78.7% males. In brain, ADD and AED had similar effects on circadian rhythm in the F0 and F1 generations. In the F1 eleutheroembryos, transcriptomic analysis indicated that neuromast hair cell related biological processes (BPs) were overlapped in the ADD and AED groups. Taken together, ADD and AED at environmentally relevant concentrations had transgenerational effects on sex differentiation and transcription in zebrafish.

Background and AimsIn patients with chronic liver diseases (CLD) with or without cirrhosis, existing data on the risk of adverse outcomes with SARS-CoV-2 infection have been mixed or have limited generalizability. We used the National COVID Cohort Collaborative (N3C) Data Enclave, a harmonized electronic health record (EHR) dataset of 5.9 million nationally-representative, diverse, and gender-balanced patients, to describe outcomes in patients with CLD and cirrhosis with SARS-CoV-2.MethodsWe identified all chronic liver diseases patients with and without cirrhosis who had SARS-CoV-2 testing documented in the N3C Data Enclave as of data release date 5/15/2021. The primary outcome was 30-day all-cause mortality. Survival analysis methods were used to estimate cumulative incidences of death, hospitalization, and mechanical ventilation, and to calculate the associations of SARS-CoV-2 infection, presence of cirrhosis, and demographic and clinical factors to 30-day mortality.ResultsWe isolated 217,143 patients with CLD: 129,097 (59%) without cirrhosis and SARS-CoV-2 negative, 25,844 (12%) without cirrhosis and SARS-CoV-2 positive, 54,065 (25%) with cirrhosis and SARS-CoV-2 negative, and 8,137 (4%) with cirrhosis and SARS-CoV-2 positive. Among CLD patients without cirrhosis, 30-day all-cause mortality rates were 0.4% in SARS-CoV-2 negative patients and 1.8% in positive patients. Among CLD patients with cirrhosis, 30-day all-cause mortality rates were 4.0% in SARS-CoV-2 negative patients and 9.7% in positive patients.Compared to those who tested SARS-CoV-2 negative, SARS-CoV-2 positivity was associated with more than two-fold (aHR 2.43, 95% CI 2.23-2.64) hazard of death at 30 days among patients with cirrhosis. Compared to patients without cirrhosis, the presence of cirrhosis was associated with a three-fold (aHR 3.39, 95% CI 2.96-3.89) hazard of death at 30 days among patients who tested SARS-CoV-2 positive. Age (aHR 1.03 per year, 95% CI 1.03-1.04) was associated with death at 30 days among patients with cirrhosis who were SARS-CoV-2 positive.ConclusionsIn this study of nearly 220,000 CLD patients, we found SARS-CoV-2 infection in patients with cirrhosis was associated with 2.43-times mortality hazard, and the presence of cirrhosis among CLD patients infected with SARS-CoV-2 were associated with 3.39-times mortality hazard. Compared to previous studies, our use of a nationally-representative, diverse, and gender-balanced dataset enables wide generalizability of these findings.

Background: With the continuous large-scale development of the COVID-19 vaccine, the acceptance of vaccination and its influencing factors at the individual level have become crucial to stemming the pandemic. This study aims to explore the factors that influence the acceptance of the COVID-19 vaccine among international college students. Methods: The target population constituted international students pursuing various degrees in Jiangsu Province through an online cross-sectional study. A cluster random sampling was performed using a self-administered questionnaire. The Health Belief Model and Knowledge, Attitude/Beliefs, and Practice Theory served as the underlying theories to understanding the factors that influence vaccine acceptance. Results: We received 330 responses. About 36.4% intended to accept the vaccine. The acceptance varied across respondents’ place of residence, program of study, continent of origin, knowledge, susceptibility, severity, benefits, and cues to action (p &lt, 0.05). A multivariable logistics regression revealed cues to action (p &lt, 0.001), the perception of COVID-19 vaccination benefits (p = 0.002), and the perception of barriers (p &lt, 0.001) that were associated with vaccine acceptance. Conclusions: The acceptance of the COVID-19 vaccine was low among international students. The correct and comprehensive beliefs of the target groups regarding the benefits and barriers of the vaccination must be raised. Various effective social strategies must be adopted to trigger the intention of COVID-19 vaccination. The study findings will inform the decisions of public health campaigners, aimed at reducing vaccine hesitation when the COVID-19 vaccine is widely available.

Supplemental Digital Content is available in the text., Background: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated. Methods: We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts. Results: We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice. Conclusions: ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.

Background and aims Frailty, as measured by the Liver Frailty Index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality. Approach and results Adults with cirrhosis awaiting LT without hepatocellular carcinoma at nine LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37 (3%), 82 (6%), and 135 (10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95% confidence interval [CI], 4.0-4.8) for 3-month mortality, 4.2 (95% CI, 4.1-4.4) for 6-month mortality, and 4.2 (95% CI, 4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79. Conclusions LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates.

Background and AimsQueries of electronic health record (EHR) data repositories allow for automated data collection. These techniques have not been utilized in hepatology due to previous inability to capture hepatic encephalopathy (HE) grades, which are inputs for acute-on-chronic liver failure (ACLF) models. Here, we describe a methodology to utilizing EHR data to calculate rolling ACLF scores.MethodsWe examined 239 patient-admissions with end-stage liver disease 7/2014-6/2019. We mapped EHR flowsheet data to determine HE grades and calculated two longitudinally updated ACLF scores. We validated HE grades and ACLF diagnoses via chart review; and calculated sensitivity, specificity, and Cohen’s kappa.ResultsOf 239 patient-admissions analyzed, 37% women, 46% non-Hispanic White, median age 60 years, median MELD-Na at admission. Of the 239, 7% were diagnosed with NACSELD-ACLF at admission, 27% during the hospitalization, and 9% at discharge. Forty percent diagnosed with CLIF-C-ACLF at admission, 51% during the hospitalization, and 34% at discharge.From chart review of 51 admissions, we found sensitivities and specificities for any HE (grades 1-4) were 92-97% and 76-95%, respectively; for severe HE (grades 3-4) were 100% and 78-98%, respectively. Cohen’s kappa between flowsheet and chart review HE grades ranged 0.55-0.72. Sensitivities and specificities for NACSELD-ACLF diagnoses were 75-100% and 96-100%, respectively; for CLIF-C-ACLF diagnoses were 91-100% and 96-100%, respectively. We generated approximately 28 unique ACLF scores per patient per admission-day.ConclusionIn this study, we developed an informatics-based methodology for to calculate longitudinally updated ACLF scores. This opens new analytic potentials, such big data methods to develop electronic phenotypes for ACLF patients.

To explore the utility of three-dimensional (3D) visualization technology in liver resection for patients with complex liver cancer. In this retrospective cohort study, we collected and analyzed clinic pathological data from 105 patients who underwent complicated liver cancer resection at the authors’ unit between January 2014 and June 2019. Observation indicators included general demographic information, operative time, intraoperative blood loss, blood transfusion volume, postoperative liver function, complication rate, hospital stay, and in-hospital mortality. Compared with the complex liver cancer control group, operative time (257.1 ± 63.4 min versus [vs] 326.6 ± 78.3 min; P

The green cocoon shell of a novel variety of silkworm, Bombyx mori, is rich in two types of quercetin and kaempferol flavonoids. The aim of this study was to identify these flavonoids in the ethanolic extract (EE) from green cocoons and develop EE applications in healthy foods. The experimental results indicated that the amount of total amino acids in EE was 27.06%. The flavonoids in EE are presented in quercetin and kaempferol glycosides. The total amount of the two aglycones was 33.42 ± 0.08 mg/g. The IC50 values of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 1,2’-azino-bis (3-ethylbenzthiazoline-6-sulphonicacid) (ABTS), and hydroxyl radical scavenging abilities were 296.95 ± 13.24 μg/mL, 94.31 ± 9.13 μg/mL, and 9.21 ± 0.15 mg/mL, respectively. The IC50 values of the inhibitory activities of α-amylase and α-glucosidase were 37.57 ± 6.45 μg/mL and 212.69 ± 22.94 μg/mL, respectively. EE also reduced the level of reactive oxygen species (ROS) and oxidative stress in L02 cells induced by high glucose levels. It also effectively decreased the content of 8-hydroxyl deoxyguanosine (8-OHdG), nuclear factor κB (NF-κB), and tumour necrosis factor alpha (TNF-α) in cells with a good dose effect. These results clearly indicated that the flavonoid-rich EE with excellent antioxidant and glucosidase inhibition abilities significantly reduced the damage to cells caused by oxidative stress and inflammatory reactions. It is suggested that EE might serve as useful functional foods for the treatment of related diseases induced by oxidative stress such as diabetes mellitus.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers’ opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient’s HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 U.S. medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient’s HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; p

The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10F/F mice (cFat10−/−). Compared with their wild-type littermates, cFat10−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

Outbreak of COVID-19 is ongoing all over the world. Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production. Patients with unstable spine fractures or continuous deterioration of neurological function require emergency surgery. The COVID-19 epidemic has brought tremendous challenges to the diagnosis and treatment of such patients. To coordinate the diagnosis and treatment of infectious disease prevention and spine trauma so as to formulate a rigorous diagnosis and treatment plan and to reduce the disability and mortality of the disease, multidisciplinary collaboration is needed. This expert consensus is formulated in order to (1) prevent and control the epidemic, (2) diagnose and treat patients with spine trauma reasonably, and (3) reduce the risk of cross-infection between patients and medical personnel during the treatment.

Protein arginine methyltransferases (PRMTs) have been implicated in the development of various cancers. PRMT2, a member of the type I PRMT family, is overexpressed in multiple tumors. However, the expression and role of PRMT2 in hepatocellular carcinoma (HCC) have not been studied. Here, we discovered that PRMT2 expression is elevated in HCC tissues compared to the corresponding non-tumor tissues, and PRMT2 overexpression is an independent predictor of poor prognosis in HCC patients. Depletion of PRMT2 in HCC cell lines inhibited their cell growth and induced apoptosis. Mechanistic investigations showed that PRMT2 is responsible for H3R8 asymmetric methylation (H3R8me2a). H3R8me2a enrichment at the Bcl2 promoter increases its accessibility to STAT3, promoting Bcl2 gene expression. In addition, our results confirmed that the catalytically inactive mutant of PRMT2 or the type I PRMT inhibitor MS023 impaired the pro-tumorigenic functions of PRMT2 in HCC cells. Overall, our findings showed that PRMT2 functions as an oncogenic gene in HCC, revealing its potential as a novel therapeutic target in HCC.

In order to explore a novel and potential method using carbon nanotubes (CNTs) for controlling blue-green algal blooms efficiently in future, effects of single-walled carbon nanotubes (SWCNTs) on Microcystis aeruginosa growth control were investigated under lab cultured conditions. Related physiological changes were tested involving several important enzyme of antioxidant defense system (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), malondiadehyde (MDA), photosynthetic pigments, protein, soluble sugar and extracellular microcystin toxins (MC-LR)). Algal cell density was significantly inhibited by SWCNTs at high concentration (>5.00 mg/L), and the inhibition rate was dose-dependent. For treatment with 100 mg/L SWCNTs, the inhibitory rates even reached above 90%. 96 h IC50 was determined as 22 mg/L. Antioxidant enzyme activities were dramatically dropped with increasing lipid peroxidation at higher SWCNTs concentration, indicating intracellular generation of reactive oxygen species (ROS) and oxidative stress damage in algae. Reduction of photosynthetic pigments, soluble sugar and protein contents suggested that SWCNTs may severely ruin algal photosynthesis system, destroy the metabolism-related structure of cell, and thus lead to negative physiological status in M. aeruginosa. Besides, SWCNTs can effectively decrease the amount of extracellular microcystins in culture medium.

In liver transplantation, adults with small stature have a greater susceptibility to waitlist mortality. This may explain the persistent waitlist mortality disparity that exists for women. We hypothesized that women who receive early offers of pediatric donor livers have improved waitlist survival, and that preferentially offering these organs to women mitigates this sex-based disparity. We analyzed donor liver offers from 2010 to 2014. Adult candidates who received a first offer that ranked within the first three match run positions from the donors’ perspective were classified based on gender and whether they received a pediatric versus adult offer. We used competing risks regression to associate first offer type and waitlist mortality. A total of 8,101 waitlist candidates received a first offer that was ranked within the first three match run positions: 5.6% (293/5,202) men and 6.2% (179/2,899) women received a pediatric donor liver as their first offer. In multivariable analyses, compared with adult-first men, adult-first women (subhazard ratio [sHR] 1.33, 95% confidence interval 1.17–1.51, P < 0.01) had an increased pretransplant mortality risk while pediatric-first men and pediatric-first women had noninferior risks of morality. Pediatric-to-adult and adult-to-adult recipients had similar risks of graft failure and posttransplant mortality. Conclusion: Our study examines allograft selection by donor age, recipient sex, and in effect size as a means to address disparities in waitlist mortality. We found that women who received a pediatric donor liver as the first offer had a lower risk of waitlist mortality compared with those who receive adult offers. Our data provides a simple approach to mitigating the increased waitlist mortality experienced by women by incorporating donor and recipient size as variables into organ allocation. (HEPATOLOGY 2018; 68:1101–1110).

Background & Aims In patients with chronic liver disease (CLD) with or without cirrhosis, existing studies on the outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have limited generalizability. We used the National COVID Cohort Collaborative (N3C), a harmonized electronic health record dataset of 6.4 million, to describe SARS-CoV-2 outcomes in patients with CLD and cirrhosis. Methods We identified all patients with CLD with or without cirrhosis who had SARS-CoV-2 testing in the N3C Data Enclave as of July 1, 2021. We used survival analyses to associate SARS-CoV-2 infection, presence of cirrhosis, and clinical factors with the primary outcome of 30-day mortality. Results We isolated 220,727 patients with CLD and SARS-CoV-2 test status: 128,864 (58%) were noncirrhosis/negative, 29,446 (13%) were noncirrhosis/positive, 53,476 (24%) were cirrhosis/negative, and 8941 (4%) were cirrhosis/positive patients. Thirty-day all-cause mortality rates were 3.9% in cirrhosis/negative and 8.9% in cirrhosis/positive patients. Compared to cirrhosis/negative patients, cirrhosis/positive patients had 2.38 times adjusted hazard of death at 30 days. Compared to noncirrhosis/positive patients, cirrhosis/positive patients had 3.31 times adjusted hazard of death at 30 days. In stratified analyses among patients with cirrhosis with increased age, obesity, and comorbid conditions (ie, diabetes, heart failure, and pulmonary disease), SARS-CoV-2 infection was associated with increased adjusted hazard of death. Conclusions In this study of approximately 221,000 nationally representative, diverse, and sex-balanced patients with CLD; we found SARS-CoV-2 infection in patients with cirrhosis was associated with 2.38 times mortality hazard, and the presence of cirrhosis among patients with CLD infected with SARS-CoV-2 was associated with 3.31 times mortality hazard. These results provide an additional impetus for increasing vaccination uptake and further research regarding immune responses to vaccines in patients with severe liver disease.

Levonorgestrel (LNG) and dydrogesterone (DDG) are two commonly used synthetic progestins that have been detected in aquatic environments. They could affect fish sex differentiation, but the underlying mechanisms remain unknown. Here we investigated the effects of LNG (5 ng L-1 and 50 ng L-1), DDG (100 ng L-1) and their mixtures on gonadal differentiation and sex determination in zebrafish at transcriptomic and histological levels from 2 hours post-fertilization (eleutheroembryos) to 144 days post-fertilization (sexual maturity). Germ cell development and oogenesis pathways were significantly enriched in LNG and the mixture of LNG and DDG treatments, while insulin and apoptosis pathways in the DDG treatment. LNG and the mixture of LNG and DDG strongly decreased transcripts of germ cell development and oogenesis related genes, while DDG increased the transcripts of insulin and apoptosis related genes at 28 days post fertilization (dpf) and 35 dpf. Furthermore, DDG caused ∼ 90% males, and LNG and the mixture of LNG and DDG resulted in 100% males on all sampling dates. Specifically, most males in LNG and the mixture of LNG and DDG treatments were "Type I" males without juvenile oocytes at 28 dpf and 35 dpf, while those in DDG treatment were "Type II" and "Type III" males with a few juvenile oocytes. These results indicated that LNG and DDG promoted testicular differentiation via different pathways to cause male bias. LNG and DDG mixtures have similar effect on testicular differentiation to LNG alone. The findings from this study could have significant ecological implications to fish populations.

Bromodomain 4 (BRD4) proteins play an important role in histone post-translational modifications and facilitate several important physiological and pathological processes, including cancers. The inhibition of BRD4 by small molecule inhibitors shows promise as a therapeutic strategy for cancer treatment. However, their clinical applications were limited, which is largely hampered by off-target effects-induced toxicity. We herein report the design, synthesis, and cellular imaging of a set of tumor-anchored and BRD4-targeted fluorescent ligands by introducing selective and potent BRD4 inhibitor into different fluorophores via variable linkers. One of the fluorescent conjugates (compound 6) was demonstrated to be cell-permeable and low cytotoxic, preferentially accumulated in cancer cells, and display pronounced fluorescent signal. More importantly, 6 was identified to show specific BRD4 engagement in the cellular content. Collectively, this study provides a pathway for developing labeled BRD4 ligands and highlights that compound 6 may represent a valuable tool for explorative learning and target delivery study of BRD4.

The extracellular matrix has drawn considerable interest in tissue engineering not only acts as a bioactive three-dimensional scaffold but also regulates cell behaviors through providing biochemical signals. Extracellular matrix-based biomaterials, mainly derived from xenogeneic tissues, have shown positive outcomes in promoting cutaneous wound healing. However, such extracellular matrices only contain low doses of growth factors, which limit their therapeutic efficiency. Recent reports demonstrated that cell sheets made from mesenchymal stem cell can accelerate wound repair through enhanced re-epithelialization and angiogenesis, but its clinical translation is hindered by several limitations, such as the risk of aberrant immune responses and cost implications. In this study, acellular extracellular matrices were prepared from CuCl2-conditioned mesenchymal stem cell sheets and their in vivo wound healing properties were evaluated in a mouse model of full-thickness skin defect. We found that extracellular ...

// Ma Jun 1 , Guan Xue-Qiang 1 , Li Jia 1 , Xue Yang-Jing 1 , Zheng Cheng 1 and Jin Ge 1 1 The Department of Cardiology, 2nd Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China Correspondence to: Jin Ge, email: gejinjjnn63@163.com Keywords: coronary heart disease, Interleukin-6, vitamin D receptor, single nucleotide polymorphisms, smoking Received: March 09, 2017 Accepted: June 12, 2017 Published: July 22, 2017 ABSTRACT Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within Interleukin-6 ( IL- 6 ) and vitamin D receptor ( VDR ) gene, and additional gene- gene and gene- smoking interaction with coronary heart disease (CHD) risk in a Chinese population. Methods: Hardy-Weinberg equilibrium (HWE) examination was used by SNPstats ( http://bioinfo.iconcologia.net/SNPstats ). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Stratified analysis for gene- smoking interaction was investigated by logistic regression. Results: CHD risk was significantly higher in carriers with the C allele of rs1800796 within IL-6 gene than those with GG genotype (GC+ CC versus GG), adjusted OR (95%CI) =1.62 (1.19-2.23); CHD risk was also higher in carriers with the T allele of rs2228570 within VDR gene than those with CC genotype (CT+ TT versus CC), adjusted OR (95%CI) = 1.68 (1.26-2.17). However, we did not find any direct associations of the others SNPs in IL- 6 and VDR gene with CHD risk. We also found a significant interaction between rs1800796 and smoking, the cross-validation consistency of this two- locus model was 10/ 10, and the testing accuracy was 60.11%. Current smokers with rs1800796- GC or CC genotype have the highest CHD risk, compared to never- smokers with rs1800796- GG genotype within IL- 6 gene, OR (95%CI) = 2.57 (1.74 -3.46). Conclusions: We found that the C allele of rs1800796 within IL-6 and T allele of rs2228570 within VDR gene, interaction between rs1800796 and smoking were all associated with increased CHD risk.

Objectives We investigated the effects of CD100 on naïve CD8+ T cells during hepatitis C virus (HCV) infection after interferon-α (IFN-α) therapy to clarify the mechanism underlying the effect of IFN-α in enhancing the antiviral response. Methods The CD100 molecules on subsets of CD8+ T cells were analysed with flow cytometry. The effects of CD100-overexpressing naïve CD8+ T cells were determined with ELISAs and an MTT cytotoxicity assay. The role of CD100–CD72 signal transduction was analysed with a neutralization and transwell assays. Results HCV infection reduced CD100 expression on CD8+ T cells, whereas IFN-α treatment significantly increased CD100 expression on naïve CD8+ T cells. The increased CD100 interacted with the CD72 receptor and enhanced PBMC cytokine secretion (IFN-γ and tumour necrosis factor-α) and cytotoxicity. Conclusions IFN-α-induced CD100 on naïve CD8+ T cells promotes PBMC cytokine secretion and cytotoxicity through CD100–CD72 signalling during HCV infection.

Background Diabetic nephropathy (DN) is one of the major complications of diabetes. Sericin and flavonoids are two bioactive substances which have been demonstrated to have some therapeutical effect on diabetic nephropathy. The aim of this paper is to investigate the effect of ethanolic extract (EE) rich in quercetin and kaempferol and their glucosides from the green cocoon of silkworm Bombyx mori on DN in type 2 diabetic (T2D) mice induced by high-fat and streptozotocin (STZ). Methods Ethanolic extract from the green cocoon shell of silkworm Bombyx mori was used as material. Diabetic mice were orally treated with three doses (150, 250 and 350 mg/kg) of the extract for 7 weeks, then the levels of oxidases and related inflammatory factors were measured in kidneys. Results Compared with the negative control, EE administration resulted in an evident reduction in blood glucose levels and an improvement of the body weight in diabetic mice. Oral EE could inhibit the expressions of renal tumour necrosis factor TNF-α, monocyte chemoattractant protein-1 (MCP-1), fibronectin (FN) and P38 mitogen-activated protein kinase (p38 MAPK) in T2D mice. Moreover, the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) were significantly elevated in T2D mice treated with EE. Conclusions The activities of anti-fibrosis and anti-inflammation contributed to the renal protective effects by reducing oxidative stress, which might be mediated by the inhibition of the TNF-α-p38 MAP kinase signalling pathway. It is suggested that the ethanolic extract from silkworm green cocoon might be potential as an herbal medicine for DN.

Transforming growth factor-β-activated kinase 1 (TAK1)-binding protein 3 (TAB3) and the proviral integration site for Moloney murine leukaemia virus 1 (PIM1) are implicated in cancer development. In this study, we investigated the relationship between TAB3 and PIM1 in colorectal cancer (CRC) and determined the potential role and molecular mechanism of TAB3 in PIM1-mediated CRC growth. We found that TAB3 and PIM1 expression levels were positively correlated in CRC tissues. The knockdown of TAB3 significantly decreased PIM1 expression and inhibited CRC proliferation in vitro and in vivo. The upregulation of PIM1 rescued the decreased cell proliferation induced by TAB3 knockdown, whereas PIM1 knockdown decreased TAB3-enhanced CRC proliferation. Additionally, TAB3 regulates PIM1 expression through the STAT3 signalling pathway and confirmed a positive correlation between TAB3 and phosphorylated-STAT3 expression in CRC tissues. Patients with high expression of TAB3 and phosphorylated-STAT3 had the worst prognosis. Mechanistically, TAB3 regulates PIM1 expression by promoting STAT3 phosphorylation and activation through the formation of the TAB3-TAK1-STAT3 complex. Overall, a novel CRC regulatory circuit involving the TAB3-TAK1-STAT3 complex and PIM1 was identified, the dysfunction of which may contribute to CRC tumorigenesis.

Height explains a substantial proportion of gender-based disparity in waitlist mortality among liver transplant candidates. We sought to identify a clinically relevant height cutoff below which waitlist mortality increases significantly. We examined all nonstatus one adult liver transplant candidates from 2010 to 2014. We used a recursive application of the minimum P value approach with univariate competing risk regressions (deceased donor liver transplantation as the competing risk) to detect differences in waitlist mortality with regards to height. Of 69 883 candidates, 36% (24 819) were women and 64% (45 064) were men. Median height for all was 173 cm: 163 cm in women, 178 cm in men. The optimal search method of recursively evaluating smaller height intervals yielded 166 cm as the optimal height cutoff. Using height

Each year, approximately 60 children, representing 12% of waitlist candidates, die awaiting liver transplantation. The current allocation algorithm for pediatric donor livers prioritizes local/regional adults over national children. We attempted to better understand the impact of the present algorithm on pediatric candidates. We analyzed pediatric donor liver offers from 2010 to 2014. Donors and recipients were classified based on age. We mapped allocation and acceptance patterns and used subgroup analyses to explore the significance of donor service areas (DSAs) with low pediatric transplant volumes. We used Cox proportional hazard regressions to evaluate posttransplantation outcomes: 3,318 pediatric donor livers were transplanted into 3,482 recipients, and 45% (1,569) were adults. Of the 1,569 adults, 25% (390) received a pediatric organ that was never offered to children; 52% (204) of these 390 pediatric organs originated in the 37 DSAs, with ≤25 pediatric liver transplantations; 278 children died or were delisted due to illness during the same time, with higher mortality rates in the 37 DSAs (10% versus 6%, P < 0.01). Compared to adults, pediatric recipients aged 15 before being offered to local/regional + circle non-status 1A adults.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that leads to severe hepatotoxicity at excessive doses. Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. However, the impacts of fucoidan on APAP-induced liver injury have not been sufficiently addressed. In the present study, male Institute of Cancer Research (ICR) mice aged 6 weeks were subjected to a single APAP (500 mg/kg) intraperitoneal injection after 7 days of fucoidan (100 or 200 mg/kg/day) or bicyclol intragastric administration. The mice continued to be administered fucoidan or bicyclol once per day, and were sacrificed at an indicated time. The indexes evaluated included liver pathological changes, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum, levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in the liver, and related proteins levels (CYP2E1, pJNK and Bax). Furthermore, human hepatocyte HL-7702 cell line was used to elucidate the potential molecular mechanism of fucoidan. The mitochondrial membrane potential (MMP) and nuclear factor-erythroid 2-related factor (Nrf2) translocation in HL-7702 cells were determined. The results showed that fucoidan pretreatment reduced the levels of ALT, AST, ROS, and MDA, while it enhanced the levels of GSH, SOD, and CAT activities. Additionally, oxidative stress-induced phosphorylated c-Jun N-terminal protein kinase (JNK) and decreased MMP were attenuated by fucoidan. Although the nuclear Nrf2 was induced after APAP incubation, fucoidan further enhanced Nrf2 in cell nuclei and total expression of Nrf2. These results indicated that fucoidan ameliorated APAP hepatotoxicity, and the mechanism might be related to Nrf2-mediated oxidative stress.