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Autoimmune hepatitis (AIH) is a severe autoimmune disease, characterized by the presence of autoantibodies. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain. Here, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies in AIH. Using these results, a logistic regression classifier was able to predict which patients had AIH, indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified relative to a broad array of controls (298 patients with non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), or healthy controls). Top ranked autoreactive targets included SLA, the target of a well-recognized autoantibody in AIH, and disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a 9-amino acid stretch nearly identical to the U27 protein of HHV-6B, a virus found in the liver. In addition, antibodies against peptides derived from the leucine rich repeat N-terminal (LRRNT) domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, which is required for RXFP1 signaling. RXFP1 is a G protein-coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in the human monocytic cell line, THP1. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect. These data provide supporting evidence that HHV6 plays a role in the development of AIH and point to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention.

BackgroundSymptom-focused trials are critically needed for patients with cirrhosis. However, this work would benefit from standard processes and validated measures.MethodsA writing group was formed among hepatologists, nurses, palliative care providers, pharmacists, and clinical trial experts focused on symptom management in patients with cirrhosis to define the key (1) components of trial design, (2) symptom targets, (3) measurement, and (4) outcomes for each target. From July 2022 to January 2023, panelists participated in an iterative process of developing and arriving at a consensus for each component. The goal was to provide consensus definitions that can be operationalized in future clinical trials, including for patients with cirrhosis.ResultsThe panel reached a consensus on key reporting features for clinical trials, along with considerations for study design. Nine key symptom targets (muscle cramps, pruritus, pain, fatigue, sexual dysfunction, sleep disorders, depression and anxiety, nausea/vomiting, and dyspnea/breathlessness) were identified. The panel selected instruments that can be considered for clinical trials based on psychometric validation and previous experience. The panel identified ongoing needs, including instrument validation, safety data, evidence about non-pharmacologic interventions, and comparative effectiveness studies.ConclusionThis expert panel identified key design, reporting, and measurement elements to standardize processes and measures in future symptom-focused clinical trials in the context of cirrhosis.

Since its release as a "research preview" in November 2022, ChatGPT, the conversational interface to the Generative Pretrained Transformer 3 large language model built by OpenAI, has garnered significant publicity for its ability to generate detailed responses to a variety of questions. ChatGPT and other large language models generate sentences and paragraphs in response to word patterns in training data that they have previously seen. By allowing users to communicate with an artificial intelligence model in a human-like way, however, ChatGPT has crossed the technological adoption barrier into the mainstream. Existing examples of ChatGPT use-cases, such as negotiating bills, debugging programing code, and writing essays, indicate that ChatGPT and similar models have the potential to have profound (and yet unknown) impacts on clinical research and practice in hepatology. In this special article, we discuss the general background and potential pitfalls of ChatGPT and associated technologies-and then we explore its uses in hepatology with specific examples.

Cardiovascular disease is a leading complication after both liver and kidney transplantation. Factors associated with and rates of cardiovascular events (CVEs) after simultaneous liver-kidney transplant (SLKT) are unknown. This was a retrospective cohort study of adult SLKT recipients between 2002 and 2017 at six centers in six United Network for Organ Sharing regions in the US Multicenter SLKT Consortium. The primary outcome was a CVE defined as hospitalization due to acute coronary syndrome, arrhythmia, congestive heart failure, or other CV causes (stroke or peripheral vascular disease) within 1 year of SLKT. Among 515 SLKT subjects (mean age ± SD, 55.4 ± 10.6 years; 35.5% women; 68.1% White), 8.7% had a CVE within 1 year of SLKT. The prevalence of a CVE increased from 3.3% in 2002-2008 to 8.9% in 2009-2011 to 14.0% in 2012-2017 ( p =0.0005). SLKT recipients with a CVE were older (59.9 vs. 54.9 years, p

IntroductionThe impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis.MethodsPlasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression.Resultsp-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (β = 0.75, P < .01), NfL (β = 0.32, P < .01), and t-tau (β = 0.31, P < .01), but not GFAP (β = -0.01, P = .88) or UCHL1 (β = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (β = -0.18, P < .01), NfL (β = -0.22, P < .01), GFAP (β = -0.17, P < .05), t-tau (β = -0.20, P = .02), and UCHL1 (β = -0.15, P = .09).ConclusionsElevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Background and aimsRacial/ethnic minority children have worse liver transplant (LT) outcomes. We evaluated whether neighborhood socioeconomic deprivation affected associations between race/ethnicity and wait-list mortality.Approach and resultsWe included children (age&nbsp

BACKGROUND: To implement Enhanced Recovery After Surgery (ERAS) protocols for liver transplant (LT) candidates, it is essential to identify tools that can help risk stratify patients by their risk of early adverse post-LT outcomes. OBJECTIVE: We aimed to identify pre-LT tools that assess functional capacity, frailty, and muscle mass that can best risk stratify patients by their risk of adverse post-LT outcomes. METHODS: We first conducted a systematic review following PRISMA guidelines, expert panel review and recommendations using the GRADE approach (PROSPERO ID CRD42021237434). After confirming there are no studies evaluating assessment modalities for ERAS protocols for LT recipients specifically, the approach of the review focused on pre-LT modalities that identify LT recipients at higher risk of worse early post-LT outcomes (≤90 days), considering that this is particularly pertinent when evaluating candidates for ERAS. RESULTS: Twenty-two studies were included in the review, encompassing three different types of pre-LT modalities: evaluation of physical function (including frailty and general physical scores like the Karnofsky Performance Status (KPS), assessment of cardiopulmonary capacity, and estimation of muscle mass and composition. The majority of studies evaluated frailty assessment and muscle mass. Most studies, except for liver frailty index (LFI), were retrospective and single-center. All assessment modalities could identify, in different grade, LT recipients with higher risk of early post-LT mortality, length of stay or postoperative complications. CONCLUSIONS: We identified four pre-LT assessment tools that could be used to identify patients who are suitable for ERAS protocols: (1) KPS (quality of evidence moderate, grade of recommendation strong); (2) LFI (quality of evidence moderate, grade of recommendation strong); (3) abdominal muscle mass by CT (quality of evidence moderate, grade of recommendation strong); and (4) cardiopulmonary exercise testing (CPET) (quality of evidence moderate, grade of recommendation weak). We recommend that selection of the appropriate tool depends on the specific clinical setting and available resources to administer the tool, and that use of a tool be incorporated into the routine preoperative assessment when considering implementation of ERAS protocols for LT. ispartof: CLINICAL TRANSPLANTATION vol:36 issue:10 ispartof: location:Denmark status: published

Objective inpatient frailty assessments in decompensated cirrhosis are understudied. We examined the feasibility of inpatient frailty measurements and associations with nonhome discharge, readmission, and all-cause mortality among patients admitted for cirrhosis complications. We conducted a prospective study at 3 liver transplantation (LT) centers. Frailty was assessed using the liver frailty index (LFI). Multivariable logistic and competing risk models evaluated associations between frailty and clinical outcomes. We included 211 patients with median MELD-Na score 21 (interquartile range [IQR],15-27); 96 (45%) were women, and 102 (48%) were on the LT waiting list. At a median follow-up of 8.3months, 29 patients (14%) were nonhome discharged, 144 (68%) were readmitted, 70 (33%) underwent LT, and 44 (21%) died. A total of 124 patients (59%) were frail, with a median LFI of 4.71 (IQR, 4.07-5.54). Frail patients were older (mean, 59 versus 54years) and more likely to have chronic kidney disease (40% versus 20%; P=0.002) and coronary artery disease (17% versus 7%; P=0.03). Frailty was associated with hospital-acquired infections (8% versus 1%; P=0.02). In multivariable models, LFI was associated with nonhome discharge (odds ratio, 1.81 per 1-point increase; 95% confidence interval [CI], 1.14-2.86). Frailty (LFI≥4.5) was associated with all-cause mortality in models accounting for LT as competing risk (subhazard ratio [sHR], 2.4; 95% CI, 1.13-5.11); results were similar with LFI as a continuous variable (sHR, 1.62 per 1-point increase; 95% CI, 1.15-2.28). A brief, objective inpatient frailty assessment was feasible and predicted nonhome discharge and mortality in decompensated cirrhosis. Inpatient point-of-care frailty assessment prior to hospital discharge can be useful for risk stratification and targeted interventions to improve physical fitness and reduce adverse outcomes.

Background & aimsIn 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.

IntroductionAdvances in transjugular intrahepatic portosystemic shunt (TIPS) technology have led to expanded use. We sought to characterize contemporary outcomes of TIPS by common indications.MethodsThis 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).ResultsAmong 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).DiscussionMELD-Na has differing relationships with patient outcomes dependent on TIPS indication. These data provide new insights into contemporary predictors of outcomes after TIPS.

Background & aimsCirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis aetiology. We aimed to characterize the relationship between frailty and cirrhosis aetiology.MethodsIncluded were adults with cirrhosis listed for liver transplantation (LT) at 10 US centrer who underwent ambulatory testing with the Liver Frailty Index (LFI; 'frail'=LFI ≥ 4.4). We used logistic regression to associate aetiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness).ResultsOf 1,623 patients, rates of frailty differed by aetiology: 22% in chronic hepatitis C, 31% in alcohol-associated liver disease (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic and 31% in 'other' (P.05 for each). No interaction between frailty and aetiology on the association with waitlist mortality was found (P>.05 for each interaction term).ConclusionsFrailty is more common in patients with ALD, NAFLD and 'other' aetiologies. However, frailty was associated with waitlist mortality independent of cirrhosis aetiology, supporting the applicability of frailty across all cirrhosis aetiologies.

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 60years, 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.

One in 10 people die awaiting transplantation from donor shortage. Only half of Americans register as organ donors. In this cross-sectional study, we evaluated population-level associations of neighborhood socioeconomic deprivation and racial segregation on organ donor registration rates. We analyzed state identification card demographic and organ donor registration data from 5 states to estimate the association between a neighborhood socioeconomic deprivation index (range [0, 1]; higher values indicate more deprivation) and a racial index of concentration at the extreme (ICE) (range [-1, 1]; lower values indicate predominantly black neighborhoods, higher values indicate predominantly white neighborhoods) on organ donor registration rates within a specified geography (census tract or ZIP code tabulation area [ZCTA]). Among 26720738 registrants, 32% of the sample were registered organ donors. At the census tract level, with each 0.1 decrease in the deprivation index, the organ donor registration rate increased by 6.8% (95% confidence interval [CI]: 6.6%, 7.0%). With each 0.1 increase in the racial ICE, the rate increased by 1.5% (95% CI: 1.5%, 1.6%). These associations held true at the ZCTA level. Areas with less socioeconomic deprivation and a higher concentration of white residents have higher organ donor registration rates. Public health initiatives should consider neighborhood context and novel data sources in designing optimal intervention strategies.

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. Adults with cirrhosis who underwent TIPS at 9 hospitals in the United States from 2010 to 2015 were included. We defined "post-TIPS renal dysfunction" as a change in estimated glomerular filtration rate (ΔeGFR) ≤-15 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. Of the 673 patients, the median age was 57 years, 38% of the patients were female, 26% had diabetes mellitus, and the median MELD-Na was 17. After 30 days post-TIPS, 66 (10%) had renal dysfunction, of which 23 (35%) required new RRT. Patients with post-TIPS renal dysfunction, compared with those with stable renal function, were more likely to have nonalcoholic fatty liver disease (NAFLD; 33% versus 17%; P=0.01) and comorbid diabetes mellitus (42% versus 24%; P=0.001). Multivariate logistic regressions showed NAFLD (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.00-4.17; P=0.05), serum sodium (Na; OR, 1.06 per mEq/L; 95% CI, 1.01-1.12; P=0.03), and diabetes mellitus (OR, 2.04; 95% CI, 1.16-3.61; P=0.01) were associated with post-TIPS renal dysfunction. Competing risk regressions showed that those with post-TIPS renal dysfunction were at a higher subhazard of death (subhazard ratio, 1.74; 95% CI, 1.18-2.56; P=0.01). In this large, multicenter cohort, we found NAFLD, diabetes mellitus, and baseline Na associated with post-TIPS renal dysfunction. This study suggests that patients with NAFLD and diabetes mellitus undergoing TIPS evaluation may require additional attention to cardiac and renal comorbidities before proceeding with the procedure.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P&nbsp

Background & aimsTo date, studies evaluating the association between frailty and mortality in patients with cirrhosis have been limited to assessments of frailty at a single time point. We aimed to evaluate changes in frailty over time and their association with death/delisting in patients too sick for liver transplantation.MethodsAdults with cirrhosis, listed for liver transplantation at 8 US centers, underwent ambulatory longitudinal frailty testing using the liver frailty index (LFI). We used multilevel linear mixed-effects regression to model and predict changes in LFI (ΔLFI) per 3 months, based on age, gender, model for end-stage liver disease (MELD)-Na, ascites, and hepatic encephalopathy, categorizing patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted ΔLFI on death/delisting, with transplantation as the competing risk.ResultsWe analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe worsening of frailty had worse baseline LFI and were more likely to have non-alcoholic fatty liver disease, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted because of sickness. The cumulative incidence of death/delisting increased by worsening ΔLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELD-Na, and albumin, a 0.1 unit change in ΔLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI 1.35-3.09).ConclusionWorsening frailty was significantly associated with death/delisting independent of baseline frailty and MELD-Na. Notably, patients who experienced improvements in frailty had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.Lay summaryFrailty, as measured at a single time point, is predictive of death in patients with cirrhosis, but whether changes in frailty over time are associated with death is unknown. In a study of over 1,000 patients with cirrhosis who underwent frailty testing, we demonstrate that worsening frailty is strongly linked with mortality, regardless of baseline frailty and liver disease severity. Notably, patients who experienced improvements in frailty over time had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.

BackgroundA randomized trial of a pedometer-based intervention with weekly activity goals led to increased walking among dialysis patients. However, the association of participant-expressed motivations and barriers to participation and performance in such an intervention has not been determined.MethodsThirty dialysis patients were randomized to a 12-week pedometer-based intervention with weekly step goals. Participants were asked about motivations and barriers to the increasing activity via weekly semi-scripted telephone interviews. We examined the association of these motivations and barriers with achieving weekly goals, reaching overall targets and increasing steps through multivariable linear and logistic regression analyses adjusted for age, sex, body mass index, dialysis modality and baseline steps.ResultsThe most common motivations were desire to maintain/improve functional ability (30%) and activity (30%). The most common barriers were health-related (33%). Motivation to maintain/improve functional ability was associated with achieving weekly goals 17.9% more often [95% confidence interval (CI) 1.7-34.2] and with a greater increase in steps (1524 steps; 95% CI 61-2989) than those lacking this motivation. Experiencing a health-related barrier was not associated with the decreased achievement of weekly goals but was associated with lower odds of reaching overall targets (odds ratio = 0.06; 95% CI 0.01-0.53) and a smaller increase in steps (-1640 steps, 95% CI -3244 to -36). No patients who reported weather/environmental barriers or safety concerns reached overall targets.ConclusionsParticipants who express a desire to maintain/improve functional ability may be particularly suited for activity interventions. Health-related setbacks should be met with revised goals. Reporting environmental or safety concerns may merit lowering overall targets.

BackgroundWomen 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.MethodsUsing the UNOS/OPTN registry, we analysed all non-Status 1 adult deceased donor liver transplant recipients without exception points from 2008 to 2017. Poisson regression associated female gender with post-transplant LOS.ResultsOf 27294 transplant recipients, 36% were women. Women were more likely to be hospitalized pretransplant than men (44% vs 39%, P&nbsp

Long-term outcomes remain suboptimal following pediatric liver transplantation; only one third of children have normal biochemical liver function without immunosuppressant comorbidities 10years posttransplant. We examined the association between an index of neighborhood socioeconomic deprivation with graft and patient survival using the Scientific Registry of Transplant Recipients. We included children

Background: Prisoners have substantial mental health needs. Prisoners should have access to healthcare of the same standard as non-prisoners and CBT-based self-help is recommended for anxiety and depression in non-prisoners. Living Life To The Full (LLTTF) is a CBT-based approach that has been demonstrated to reduce anxiety and depression in non-prisoners. Aims: To evaluate the feasibility of Prison Officers providing guided self-help support to adult male offenders experiencing stress. Method: Prison Officers and prisoners in HMP Shotts were invited to participate. Prison Officers completed LLTTF training and met prisoners individually for four sessions of LLTTF. Prisoners completed measures of anxiety, depression, and perceived functioning. This was supplemented by questionnaires completed by Personal Officers, work attendance, and breaches of prison rules. Feedback about LLTTF was collected from prisoners and Prison Officers. Results: Six Prison Officers (6%) attended staff training and two (33%) withdrew prior to prisoner recruitment. 6% (n=15) of prisoners invited to take part volunteered and were eligible. Seven completed LLTTF. A large effect size was associated with depression self-ratings pre- to post-treatment. Pre-treatment anxiety reduced at Week 4 and increased at post-treatment, which reflects deterioration in a minority. Feedback from Prison Officers and prisoners indicated LLTTF materials require adaptation for prison. Prison Officers highlighted practical barriers to delivery, including limited resources. Conclusions: Guided self-help in prison is worth pursuing. Revision of materials with Prison Officers and prisoners is recommended, and piloted prior to future research. Designated guided self-help workers may be better placed to deliver LLTTF due to practical barriers reported by Prison Officers.

ObjectivesNosocomial infections (NIs) can be a major cause of morbidity and mortality in cirrhosis. This study aims to define the determinants of NI development and its impact on 30-day outcomes among hospitalized patients with cirrhosis.MethodsNorth American Consortium for the Study of End-Stage Liver Disease enrolled patients with cirrhosis who were admitted nonelectively. Admission variables and 30-day outcomes were compared between patients with and without NI. These were also compared based on whether there was an isolated admission infection, NI, or both. Models were created for NI development using admission variables and for 30-day mortality.ResultsThe study included 2,864 patients; of which, 15% (n = 436) developed NI. When comparing NI vs no NI, 1,866 patients were found to be infection free, whereas 562 had admission infections only, 228 had only NI, and 208 had both infections. At admission, patients with NI were more likely to be infected and have advanced cirrhosis. NIs were associated with higher rates of acute-on-chronic liver failure, death, and transplant regardless of admission infections. Patients with NI had higher respiratory infection, urinary tract infection, Clostridium difficile infection, fungal infections, and infection with vancomycin-resistant enterococci compared with patients without NI. Risk factors for NIs were admission infections, model for end-stage liver disease (MELD) > 20, systemic inflammatory response syndrome criteria, proton pump inhibitor, rifaximin, and lactulose use, but the regression model (sensitivity, 0.67; specificity, 0.63) was not robust. Age, alcohol etiology, admission MELD score, lactulose use, acute-on-chronic liver failure, acute kidney injury, intensive care unit, and NI increased the risk of death, whereas rifaximin decreased the risk of death.DiscussionNIs are prevalent in hospitalized patients with cirrhosis and are associated with poor outcomes. Although higher MELD scores and systemic inflammatory response syndrome are associated with NI, all hospitalized patients with cirrhosis require vigilance and preventive strategies.

This paper shows that signals from the offshore Hong Kong, China spot market for the currency of the People's Republic of China (PRC), the renminbi (listed as CNH), directly affect the volatility of share prices of PRC banks and the overall risks to banking stability in the country. This is especially so amid heightened uncertainty about global trade of the PRC. Thus, CNH market volatility is a leading indicator of onshore PRC banking sector volatility. The results suggest that further offshore exchange market movements arising out of news such as increasing trade friction with the United States will generate greater volatility in the PRC's banking sector. Far from being a shock absorber for the financial system of the PRC, the CNH market appears to be a shock transmitter of risk from offshore economic policy uncertainty to the PRC's banking system.

BackgroundSarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality.MethodsWe evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3months of listing, we determined SMI and PMI expressed by cm2 /m2 . Low SMI was defined as SMI 0.7, P&nbsp

When it comes to maximizing allograft function, the recipient is just as important as the liver graft itself. Whereas the “healthiest” of liver transplant candidates are likely to gain significant benefit from a liver graft of any quality, the sickest of candidates may still die despite transplantation with even an ideal liver. However, the very sick patients are precisely the ones who have the greatest need for liver transplantation—with any liver, regardless of quality—because they are most vulnerable to pretransplant death without one. How does one balance the urgent need for liver transplantation with optimization of the allograft’s function and utility for the very sick patient?

Sarcopenia is associated with increased wait-list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end-stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross-sectional area (cm2 ) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait-list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex-specific potential cutoff values to define sarcopenia were determined with a grid search guided by log-rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2 /m2 : 50.0 in men and 42.0 in women. At a median of 8.8 months follow-up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2 /m2 ; P

BackgroundPhysical frailty, as measured by the Fried Frailty Index, is increasingly recognized as a critical determinant of outcomes in patients with cirrhosis. However, its utility is limited by the inclusion of self-reported components. We aimed to identify performance-based measures associated with frailty in patients with cirrhosis.MethodsPatients with cirrhosis, aged 50 years or older, underwent: 6-minute walk test (cardiopulmonary endurance), chair stands in 30 seconds (muscle endurance), isometric knee extension (lower extremity strength), unipedal stance time (static balance), and maximal step length (dynamic balance/coordination). Linear regression associated each physical performance test with frailty. Principal components exploratory factor analysis evaluated the interrelatedness of frailty and the 5 physical performance tests.ResultsOf 40 patients with cirrhosis, with a median age of 64 years and Model for End-stage Liver Disease (MELD) MELD of 12.10 (25%) were frail by Fried Frailty Index ≥3. Frail patients with cirrhosis had poorer performance in 6-minute walk test distance (231 vs 338 m), 30-second chair stands (7 vs 10), isometric knee extension (86 vs 122 Newton meters), and maximal step length (22 vs 27 in. (P ≤ 0.02 for each). Each physical performance test was significantly associated with frailty (P < 0.01), even after adjustment for MELD or hepatic encephalopathy. Principal component factor analysis demonstrated substantial, but unique, clustering of each physical performance test to a single factor-frailty.ConclusionsFrailty in cirrhosis is a multidimensional construct that is distinct from liver dysfunction and incorporates endurance, strength, and balance. Our data provide specific targets for prehabilitation interventions aimed at reducing frailty in patients with cirrhosis in preparation for liver transplantation.

In large-scale emergencies social media has become a key source of information for public awareness, government authorities and relief agencies. However, the sheer volume of data and the low signal-to- noise ratio limit the effectiveness and the efficiency of using social media as an intelligence resource. We describe Australian Crisis Tracker (ACT), a tool designed for agencies responding to large- scale emergency events, to facilitate the understanding of critical information in Twitter. ACT was piloted by the Australian Red Cross (ARC) during the 2013-2014 Australian bushfires season. Video is available at: https://www.youtube.com/watch?v=Y-1rtNFqQbE

Short Physical Performance Battery and all-cause Mortality: Systematic Review and Meta-analysis. eTable 1. New-Castle Ottawa Scale for quality assessment. eTable 2. Source for follow-up of all the studies included in the meta-analysis. eTable 3. Meta-regression analyses considering population characteristics of each study included in the meta-analysis. eTable 4. Assessment of publication bias. eTable 5. PRISMA checklist. eFigure 1. Funnel plot and Trim and Fill analysis. A. Relation between SPPB 0-3 vs 10-12 and all-cause mortality. B. Relation between SPPB 4-6 vs 10-12 and all-cause mortality. C. Relation between SPPB 7-9 vs 10-12 and all-cause mortality. eFigure 2. Scatter Plot of meta-regression analysis for female sex, diabetes mellitus and age and relation between SPPB 7-9 vs 10-12 and all-cause death. (DOCX 146 kb)

Approximately 600 million people worldwide practise the carcinogenic habit of betel nut/quid chewing. Carcinogenic N-nitroso compounds have been identified in saliva or urine of betel chewers and the betel alkaloid arecoline in hair from habitual betel quid chewers. However, the pharmacokinetic parameters of these compounds have been little explored. Assessment of betel use by biomarkers is urgently needed to evaluate the effectiveness of cessation programmes aimed at reducing betel consumption to decrease the burden of cancers in regions of high betel consumption. In the search for biomarkers of betel consumption, we measured by liquid chromatography-mass spectrometry (LC-MS) the appearance and disappearance of betel alkaloids (characteristic for betel nuts), N-nitroso compounds, and chavibetol (characteristic for Piper Betle leaves) in saliva (n=4), hair (n=2), and urine (n=1) of occasional betel nut/quid chewers. The betel alkaloids arecoline, guvacoline, guvacine, and arecaidine were detected in saliva of all four participants and peaked within the first 2 h post-chewing before returning to baseline levels after 8 h. Salivary chavibetol was detected in participants consuming Piper Betle leaves in their quid and peaked ~1 h post-chewing. Urinary arecoline, guvacoline, and arecaidine excretion paralleled saliva almost exactly while chavibetol glucuronide excretion paralleled salivary chavibetol. No betel nut related compounds were detected in the tested hair samples using various extraction methods. From these preliminary results, we conclude that betel exposure can only be followed on a short-term basis (≤8 h post-chewing) using the applied biomarkers from urine and saliva while the feasibility of using hair has yet to be validated. Copyright © 2015 John WileySons, Ltd.

BackgroundWhether chronic HCV, a disease characterized by systemic inflammation, impacts bone mineral density (BMD) independent of cirrhosis is unknown.AimWe aimed to evaluate the association between BMD, systemic inflammation, and markers of bone turnover in chronic HCV without cirrhosis.MethodsNon-cirrhotics, 40-60 years old, with chronic HCV underwent measurement of: (1) BMD by dual-energy X-ray absorptiometry scan and (2) serum markers of systemic inflammation and bone turnover. By Chi-squared or t test, we compared those with normal versus low BMD.ResultsOf the 60 non-cirrhotics, 53 % were female and 53 % Caucasian. Mean (SD) age was 53.3 years (5.7), total bilirubin 0.7 mg/dL (0.3), creatinine 0.8 mg/dL (0.2), and body mass index 28.4 kg/m(2) (6.5). Low BMD was observed in 42 %: 30 % had osteopenia, 12 % had osteoporosis. Elevated tumor necrosis factor α, interleukin-6, and C-reactive protein levels were found in 26, 32, and 5 %, respectively, but did not differ by BMD group (p > 0.05). Patients with low BMD had higher serum phosphorus (4.1 vs. 3.5 mg/dL) and pro-peptide of type 1 collagen (P1NP; 73.1 vs. 47.5 ng/mL) [p < 0.05], but similar bone-specific alkaline phosphatase, serum C-telopeptide, and parathyroid hormone levels.ConclusionsLow BMD is prevalent in 40- to 60-year-old non-cirrhotics with chronic HCV, but not associated with systemic inflammatory markers. Elevated P1NP levels may help to identify those at increased risk of bone complications in this population. Chronic HCV should be considered a risk factor for bone loss, prompting earlier BMD assessments in both men and women.

BackgroundIn nontransplant patients with chronic hepatitis C virus (HCV), HCV genotype has been linked with a differential response to antiviral therapy, risk of steatosis and fibrosis, as well as all-cause mortality, but the role of HCV genotypes in posttransplant disease progression is less clear.MethodsUsing the multicenter CRUSH-C cohort, genotype-specific rates of advanced fibrosis, HCV-specific graft loss and response of antiviral therapy were examined.ResultsAmong 745 recipients (605 [81%] genotype 1, 53 [7%] genotype 2, and 87 [12%] genotype 3), followed for a median of 3.1 years (range, 2.0-8.0), the unadjusted cumulative rate of advanced fibrosis at 3 years was 31%, 19%, and 19% for genotypes 1, 2, and 3 (P = 0.008). After multivariable adjustment, genotype remained a significant predictor, with genotype 2 having a 66% lower risk (P = 0.02) and genotype 3 having a 41% lower risk (P = 0.07) of advanced fibrosis compared to genotype 1 patients. The cumulative 5-year rates of HCV-specific graft survival were 84%, 90%, and 94% for genotypes 1, 2, and 3 (P = 0.10). A total of 37% received antiviral therapy, with higher rates of sustained virologic response in patients with genotype 2 (hazard ratios, 5.10; P = 0.003) and genotype 3 (hazard ratios, 3.27; P = 0.006) compared to patients with genotype 1.ConclusionRisk of advanced fibrosis and response to therapy are strongly influenced by genotype. Liver transplantation recipients with HCV genotype 1 have the highest risk of advanced fibrosis and lowest sustained virologic response rate. These findings highlight the need for genotype-specific management strategies.

This paper tries to model the time series characteristics of capital flows to China over the period 1999-2008, namely bond flows (BF), equity flows (EF), bank credit (BC), and foreign direct investment (FDI). By utilizing the state space model and using Kalman filtering algorithm with maximum likelihood estimation, we try to gauge the relative importance of permanent and temporary components of each series. And by incorporating intervention and explanatory variables, we also try to detect if capital control measure imposed by the Chinese government and market sentiment of RMB foreign exchange rate appreciation expectation have any effect upon those flows. The empirical result shows that: all four flows are dominated by transitory component, among which BC flows have a relatively large permanent component and are the only series that are sensitive to market sentiment measure. In addition, capital control measures successfully skewed flows to come in through FDI and bond flow channels instead of equity flows. And our extended model with intervention and explanatory variables for those flows have better prediction performance compared to Sarno and Taylor (1999a) and the benchmark models.

A better educated workforce contributes to a more informed and tolerant society with higher economic output, and this is also associated with higher levels of personal health, interpersonal trust and civic and social engagement. Against this backdrop, the role of universities has expanded, as university learning has moved beyond providing an education to preparing students for leadership positions within society. This article examines the effectiveness of final-year learning experiences from the perception of recent graduates. The aim is to improve undergraduate curriculum to facilitate the transition to professional employment. An online quantitative and qualitative survey instrument was developed to investigate graduates’ perceptions of their different learning experiences and assessment types in their senior year. Four hundred and twelve alumni from five universities completed the survey. Our results indicate that graduates value case studies, group work and oral presentations, and that graduates rate lectures and guest lectures from practitioners as the least important in their transition to work. The results validate the use of graduate capability frameworks and mapping the development of the skills over the curriculum. These results are useful for curriculum designers to assist with designing programmes on the transition to professional work.

Alginate lyase enzymes represent prospective biotherapeutic agents for treating bacterial infections, particularly in the cystic fibrosis airway. To effectively deimmunize one therapeutic candidate while maintaining high level catalytic proficiency, a combined genetic engineering-PEGylation strategy was implemented. Rationally designed, site-specific PEGylation variants were constructed by orthogonal maleimide-thiol coupling chemistry. In contrast to random PEGylation of the enzyme by NHS-ester mediated chemistry, controlled mono-PEGylation of A1-III alginate lyase produced a conjugate that maintained wild type levels of activity towards a model substrate. Significantly, the PEGylated variant exhibited enhanced solution phase kinetics with bacterial alginate, the ultimate therapeutic target. The immunoreactivity of the PEGylated enzyme was compared to a wild type control using in vitro binding studies with both enzyme-specific antibodies, from immunized New Zealand white rabbits, and a single chain antibody library, derived from a human volunteer. In both cases, the PEGylated enzyme was found to be substantially less immunoreactive. Underscoring the enzyme's potential for practical utility, >90% of adherent, mucoid, Pseudomonas aeruginosa biofilms were removed from abiotic surfaces following a one hour treatment with the PEGylated variant, whereas the wild type enzyme removed only 75% of biofilms in parallel studies. In aggregate, these results demonstrate that site-specific mono-PEGylation of genetically engineered A1-III alginate lyase yielded an enzyme with enhanced performance relative to therapeutically relevant metrics., Cystic Fibrosis Foundation (Research Development Program), National Center for Research Resources (U.S.) (P20RR018787-06)