Proactive case finding of alcohol-related liver disease in high-risk populations: A systematic review.

BACKGROUND: Alcohol-related liver disease (ARLD) is often diagnosed at a late stage when mortality is unacceptably high. Earlier identification of ARLD may lead to reduced alcohol intake, participation in hepatocellular carcinoma surveillance and reduction in liver-related morbidity and mortality. People with alcohol use disorder (AUD) are at highest risk of ARLD. The aim of this systematic review was to understand the yield of proactive screening for ARLD amongst high-risk groups. METHODS: Embase, Medline, Scopus and grey literature were searched for studies describing proactive assessment for alcohol-related liver disease in people with a history of alcohol excess or diagnosed AUD. Outcomes of interest were fibrosis and cirrhosis detection rates, clinical outcomes, portal hypertension evaluation, attendance at follow-up and cost-effectiveness. RESULTS: Fifteen studies were identified for inclusion from 1115 returned by the search. Four key settings for patient engagement were identified as inpatient addiction services, outpatient addiction services, general acute hospital admissions and community outreach. Of these, acute hospital admissions were the highest yield for cirrhosis at 10.8%-29.6% and community outreach the lowest was 1.2%-2.3%. CONCLUSIONS: Targeted fibrosis assessment of high-risk populations for ARLD is feasible to conduct and identifies a proportion of patients at risk of advanced liver disease. The highest yield is amongst inpatients admitted with AUD. Prospective work is needed to establish which are the most effective and acceptable screening methods and the impact on long-term outcomes.

EASL clinical practice guidelines: non-invasive liver tests for evaluation of liver disease severity and prognosis.

The European Association for the Study of the Liver has recently published updated guidelines on the use of non-invasive tests to identify and stratify chronic liver disease. Here, we provide a summary of the key recommendations from the guideline.

Evaluating future risk of NAFLD in adolescents: a prediction and decision curve analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the commonest liver condition in the western world and is directly linked to obesity and the metabolic syndrome. Elevated body mass index is regarded as a major risk factor of NAFL (steatosis) and NAFLD fibrosis. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we sought to investigate whether other variables from adolescence could improve prediction of future NAFL and NAFLD fibrosis risk at 24 years, above BMI and sex. METHODS: Aged 24 years, 4018 ALSPAC participants had transient elastography (TE) and controlled attenuation parameter (CAP) measurement using Echosens 502 Touch. 513 participants with harmful alcohol consumption were excluded. Logistic regression models examined which variables measured at 17 years were predictive of NAFL and NAFLD fibrosis in young adults. Predictors included sex, BMI, central adiposity, lipid profile, blood pressure, liver function tests, homeostatic model assessment for insulin resistance (HOMA-IR), and ultrasound defined NAFL at 17 years (when examining fibrosis outcomes). A model including all these variables was termed "routine clinical measures". Models were compared using area under the receiver operator curve (AUROC) and Bayesian Information Criterion (BIC), analysis, which penalises model complexity. Models were tested in all participants and those with overweight or obese standardised BMIs (BMI SDS) centiles at the 17-year time point. A decision curve analysis (DCA) was performed to evaluate the clinical utility of models in overweight and obese adolescents predicting NAFLD fibrosis at a threshold probability of 0.1. RESULTS: The "routine clinical measures" model had the highest AUROC for predicting NAFL in all adolescent participants (AUROC 0.79 [SD 0.00]) and those with an overweight/obese BMI SDS centile (AUROC 0.77 [SD 0.01]). According to BIC analysis, insulin resistance was the best predictor of NAFL in all adolescents, whilst central adiposity was the best predictor in those with an overweight/obese BMI SDS centile. The "routine clinical measures" model also had the highest AUROC for predicting NAFLD fibrosis in all adolescent participants (AUROC 0.78 [SD 0.02]) and participants with an overweight/obese BMI SDS centile (AUROC 0.84 [SD 0.03]). However, following BIC analysis, BMI was the best predictor of NAFLD fibrosis in all adolescents including those with an overweight/obese BMI SDS centile. A decision curve analysis examining overweight/obese adolescent participants showed the model that had the greatest net benefit for increased NAFLD fibrosis detection, above a treat all overweight and obese adolescents' assumption, was the "routine clinical measures" model. However, the net benefit was marginal (0.0054 [0.0034-0.0075]). CONCLUSION: In adolescents, routine clinical measures were not superior to central adiposity and BMI at predicting NAFL and NAFLD fibrosis respectively in young adulthood. Additional routine clinical measurements do provide incremental benefit in detecting true positive fibrosis cases, but the benefit is small. Thus, to reduce morbidity and mortality associated with NASH cirrhosis in adults, the ultimate end point of NAFLD, the focus must be on obesity management at a population level.

Evaluating the interaction of human serum albumin (HSA) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes in different aqueous environments using anisotropy resolved multi-dimensional emission spectroscopy (ARMES).

Studying the interaction between plasma proteins and liposomes is critical, particularly for their use as drug delivery systems. Here, the efficacy of anisotropy resolved multidimensional emission spectroscopy (ARMES) for investigating the interaction of human serum albumin (HSA) with liposomes was explored and compared to conventional spectroscopic techniques. Dynamic Light Scattering (DLS) and absorbance spectroscopy (with Multivariate Curve Resolution (MCR) modeling) indicated that the highest degree of liposome rupturing, and aggregation occurred in water, with less in ammonium bicarbonate buffer (ABC) and phosphate buffered saline (PBS). Fluorescence emission spectra of HSA-liposome mixtures revealed significant hypsochromic shifts for water and ABC, but much less in PBS, where the data suggests a non-penetrating protein layer was formed. Average fluorescence lifetimes decreased upon liposome interaction in water (6.2→5.2 ns) and ABC buffer (6.3→5.6 ns) but increased slightly for PBS (5.6→5.8 ns). ARMES using polarized Total Synchronous Fluorescence Scan measurements with parallel factor (PARAFAC) analysis resolved intrinsic HSA fluorescence into two components for interactions in water and ABC buffer, but only one component for PBS. These components, in water and ABC buffer, corresponded to two different HSA populations, one blue-shifted and penetrating the liposomes (λex/em = ~ 280/320 nm) and a second, similar to free HSA in solution (λex/em = ~ 282/356 nm). PARAFAC scores for water and ABC buffer suggested that a large proportion of HSA interacted in an end on configuration. ARMES provides a new way for investigating protein-liposome interactions that exploits the full intrinsic emission space of the protein and thus avoids the use of extrinsic labels. The use of multivariate data analysis provided a comprehensive and structured framework to extract a variety of useful information (resolving different fluorescent species, quantifying their signal contribution, and extracting light scatter signals) all of which can be used to discriminate between interaction mechanisms.

Association of maternal pre-pregnancy BMI and breastfeeding with NAFLD in young adults: a parental negative control study.

BACKGROUND: The importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood. METHODS: 4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI. FINDINGS: There was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74]. INTERPRETATION: Higher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD. FUNDING: Medical Research Council UK, Alcohol Research UK, David Telling Charitable Trust.

Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues.

A homo-dimeric enzyme, thymidylate synthase (TS), has been a long-standing molecular target in chemotherapy. To further elucidate properties and interactions with ligands of wild-type mouse thymidylate synthase (mTS) and its two single mutants, H190A and W103G, spectroscopic and theoretical investigations have been employed. In these mutants, histidine at position 190 and tryptophan at position 103 are substituted with alanine and glycine, respectively. Several emission-based spectroscopy methods used in the paper demonstrate an especially important role for Trp 103 in TS ligands binding. In addition, the Advanced Poisson-Boltzmann Solver (APBS) results show considerable differences in the distribution of electrostatic potential around Trp 103, as compared to distributions observed for all remaining Trp residues in the mTS family of structures. Together, spectroscopic and APBS results reveal a possible interplay between Trp 103 and His190, which contributes to a reduction in enzymatic activity in the case of H190A mutation. Comparison of electrostatic potential for mTS complexes, and their mutants, with the substrate, dUMP, and inhibitors, FdUMP and N4-OH-dCMP, suggests its weaker influence on the enzyme-ligand interactions in N4OH-dCMP-mTS compared to dUMP-mTS and FdUMP-mTS complexes. This difference may be crucial for the explanation of the "abortive reaction" inhibitory mechanism of N4OH-dCMP towards TS. In addition, based on structural analyses and the H190A mutant capacity to form a denaturation-resistant complex with N4-OH-dCMP in the mTHF-dependent reaction, His190 is apparently responsible for a strong preference of the enzyme active center for the anti rotamer of the imino inhibitor form.

Persistent Hepatitis E virus infection across England and Wales 2009-2017: Demography, virology and outcomes.

The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.

Impact of direct-acting antiviral agents on liver function in patients with chronic hepatitis C virus infection.

Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3 years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.

Modelling Förster resonance energy transfer (FRET) using anisotropy resolved multi-dimensional emission spectroscopy (ARMES).

BACKGROUND: Förster Resonance Energy Transfer (FRET) is widely used to study the structure and dynamics of biomolecular systems and also causes the non-linear fluorescence response observed in multi-fluorophore proteins. Accurate FRET analysis, in terms of measuring changes in donor and acceptor spectra and energy transfer efficiency is therefore critical. METHODS: We demonstrate a novel quantitative FRET analysis using anisotropy resolved multidimensional emission spectroscopy (ARMES) in a Human Serum Albumin (HSA) and 1,8-anilinonaphathalene sulfonate (ANS) model. ARMES combines 4D measurement of polarized excitation emission matrices (pEEM) with multivariate data analysis to spectrally resolve contributing fluorophores. Multivariate analysis (Parallel Factor, PARAFAC and restricted Tucker3) was used to resolve fluorophore contributions and for modelling the quenching of HSA emission and the HSA-ANS interactions. RESULTS: pEEM spectra were modelled using Tucker3 which accommodates non-linearities introduced by FRET and a priori chemical knowledge was used to optimise the solution, thus resolving three components: HSA emission, ANS emission from indirect FRET excitation, and ANS emission from direct excitation. Perpendicular emission measurements were more sensitive to indirectly excited acceptor emission. PARAFAC modelling of HSA, donor emission, separated ANS FRET interacting (Tryptophan) and non-interacting (Tyrosine) components. This enabled a new way of calculating quenching constants using the multi-dimensional emission of individual donor fluorophores. CONCLUSIONS: FRET efficiency could be calculated using the multi-dimensional, resolved emission of the interacting donor fluorophores only which yielded higher ET efficiencies compared to conventional methods. GENERAL SIGNIFICANCE: Shows the potential of multidimensional fluorescence measurements and data analysis for more accurate FRET modelling in proteins.

Spontaneous portomesenteric thrombosis in a non-cirrhotic patient with SARS-CoV-2 infection.

Intra-abdominal thromboses are a poorly characterised thrombotic complication of COVID-19 and are illustrated in this case. A 42-year-old man with chronic hepatitis B (undetectable viral load, FibroScan 7.4 kPa) developed fever and cough in March 2020. 14 days later, he developed right upper quadrant pain. After being discharged with reassurance, he re-presented with worsening pain on symptom day 25. Subsequent abdominal ultrasound suggested portal vein thrombosis. CT of the abdomen confirmed portal and mid-superior mesenteric vein thromboses. Concurrent CT of the chest suggested COVID-19 infection. While reverse transcription PCR was negative, subsequent antibody serology was positive. Thrombophilia screen excluded inherited and acquired thrombophilia. Having been commenced on apixaban 5 mg two times per day, he is currently asymptomatic. This is the first case of COVID-19-related portomesenteric thrombosis described in the UK. A recent meta-analysis suggests 9.2% of COVID-19 cases develop abdominal pain. Threshold for performing abdominal imaging must be lower to avoid this reversible complication.

Liver steatosis is a risk factor for hepatotoxicity in inflammatory bowel disease patients treated with azathioprine.

BACKGROUND AND AIMS: The literature demonstrates that hepatic steatosis reduces the tolerance of immunosuppression in people with inflammatory bowel disease. It also shows that elevated methylmercaptopurine may be responsible for thiopurine-induced hepatitis. This exploratory study investigates the relationship between hepatic steatosis, methylmercaptopurine and alanine transaminase. METHODS: We performed a retrospective review of patients started on azathioprine treatment at University Hospitals Bristol NHS Foundation Trust between 2014 and 2017. There were 600 patients in total. Ninety-one patients met our inclusion criteria which were at least one ultrasound scan commenting on the appearance of the liver, liver function tests at commencement of azathioprine and liver function tests and a methylmercaptopurine level between 6 and 8 weeks after starting treatment. RESULTS: Of 91 patients included in our study, 32 patients (32%) were identified as having radiological hepatic steatosis on ultrasound imaging and 59 patients had no evidence of steatosis. We found a positive association between methylmercaptopurine levels and change in alanine transaminase in patients with hepatic steatosis (P < 0.001) but not in those with a normal liver on ultrasound imaging. CONCLUSION: We conclude that the higher levels of methylmercaptopurine may be a risk factor for hepatitis in patients with hepatic steatosis but not in those with a normal liver.

Cost effectiveness of an intervention to increase uptake of hepatitis C virus testing and treatment (HepCATT): cluster randomised controlled trial in primary care.

OBJECTIVE: To evaluate the effectiveness and cost effectiveness of a complex intervention in primary care that aims to increase uptake of hepatitis C virus (HCV) case finding and treatment. DESIGN: Pragmatic, two armed, practice level, cluster randomised controlled trial and economic evaluation. SETTING AND PARTICIPANTS: 45 general practices in South West England (22 randomised to intervention and 23 to control arm). Outcome data were collected from all intervention practices and 21/23 control practices. Total number of flagged patients was 24 473 (about 5% of practice list). INTERVENTION: Electronic algorithm and flag on practice systems identifying patients with HCV risk markers (such as history of opioid dependence or HCV tests with no evidence of referral to hepatology), staff educational training in HCV, and practice posters/leaflets to increase patients' awareness. Flagged patients were invited by letter for an HCV test (with one follow-up) and had on-screen pop-ups to encourage opportunistic testing. The intervention lasted one year, with practices recruited April to December 2016. MAIN OUTCOME MEASURES: Primary outcome: uptake of HCV testing. SECONDARY OUTCOMES: number of positive HCV tests and yield (proportion HCV positive); HCV treatment assessment at hepatology; cost effectiveness. RESULTS: Baseline HCV testing of flagged patients (six months before study start) was 608/13 097 (4.6%) in intervention practices and 380/11 376 (3.3%) in control practices. During the study 2071 (16%) of flagged patients in the intervention practices and 1163 (10%) in control practices were tested for HCV: overall intervention effect as an adjusted rate ratio of 1.59 (95% confidence interval 1.21 to 2.08; P<0.001). HCV antibodies were detected in 129 patients from intervention practices and 51 patients from control practices (adjusted rate ratio 2.24, 1.47 to 3.42) with weak evidence of an increase in yield (6.2% v 4.4%; adjusted risk ratio 1.40, 0.99 to 1.95). Referral and assessment increased in intervention practices compared with control practices (adjusted rate ratio 5.78, 1.6 to 21.6) with a risk difference of 1.3 per 1000 and a "number needed to help" of one extra HCV diagnosis, referral, and assessment per 792 (95% confidence interval 558 to 1883) patients flagged. The average cost of HCV case finding was £4.03 (95% confidence interval £2.27 to £5.80) per at risk patient and £3165 per additional patient assessed at hepatology. The incremental cost effectiveness ratio was £6212 per quality adjusted life year (QALY), with 92.5% probability of being below £20 000 per QALY. CONCLUSION: HepCATT had a modest impact but is a low cost intervention that merits optimisation and implementation as part of an NHS strategy to increase HCV testing and treatment. TRIAL REGISTRATION: ISRCTN61788850.

Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.

BACKGROUND: The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score. METHODS: In this population-based study, we invited active participants of the ALSPAC cohort to our Focus@24+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7·1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI). FINDINGS: 10 018 active ALSPAC participants were invited to our Focus@24+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24·0 years (IQR 23·0-25·0). 3768 CAP scores were eligible for analysis. 780 (20·7% [95% CI 19·4-22·0]) participants had suspected steatosis (S1-S3; ≥248 dB/m), with 377 (10·0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5·17 [95% CI 4·11-6·50], p<0·0001; obese BMI: 27·27 [20·54-36·19], p<0·0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2·7% [95% CI 2·2-3·2]) had transient elastography values equivalent to suspected fibrosis (F2-F4; ≥7·9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11·7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4·02 [1·24-13·02]; p=0·02). INTERPRETATION: One in five young people had steatosis and one in 40 had fibrosis around the age of 24 years. The risk of fibrosis appears to be greatest in young adults who have harmful drinking patterns and steatosis. A holistic approach to the UK obesity epidemic and excessive drinking patterns is required to prevent an increasing health-care burden of adults with advanced liver disease in later life. FUNDING: Medical Research Council UK, Alcohol Change UK, David Telling Charitable Trust.

Cell block processing is optimal for assessing endoscopic ultrasound fine needle aspiration specimens of pancreatic mucinous cysts.

AIMS: The cell block technique for assessing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) specimens from pancreatic mucinous cystic lesions (MCLs) was systematically evaluated for the first time, including comparisons with three traditional methods of assessing such specimens. METHODS: The prospective arm comprised EUS-FNA specimens from EUS-suspected pancreatic MCLs. The retrospective arm comprised EUS-FNA specimens from pancreatic MCLs surgically resected before the study start. For each specimen, these data points were collected: macroscopic likelihood of mucin, cyst fluid carcinoembryonic antigen (CEA) level and presence of mucin in air-dried, direct smears and in cell block preparations. RESULTS: The prospective and retrospective arms of the study comprised 80 and 30 EUS-FNA specimens, respectively. Seven prospective cases led to surgical resections during the study, and therefore, 37 EUS-FNA specimens were confirmed to have originated from MCLs. In the prospective arm, macroscopic mucin was suspected, cyst fluid CEA level exceeded 192 ng/mL, mucin was detected in direct smears and cell block preparations in 78%, 30%, 39% and 73% of cases, respectively. Of the 37 specimens confirmed to originate from MCLs, macroscopic mucin assessment, cyst fluid CEA level, direct smear mucin assessment and cell block mucin assessment had sensitivities for diagnosing MCL of 87%, 45%, 45% and 81%, respectively. CONCLUSIONS: Cell block preparations are as likely to identify mucin from pancreatic MCLs as macroscopic assessment but are twice as likely to diagnose MCL than direct smears and fluid CEA biochemistry. The cell block technique is easy for sample collection and processing especially because these are identical for solid and cystic pancreatic lesions.

Implementing user-defined atlas-based auto-segmentation for a large multi-centre organisation: the Australian Experience.

INTRODUCTION: Contouring has become an increasingly important aspect of radiation therapy due to inverse planning, and yet is extremely time-consuming. To improve contouring efficiency and reduce potential inter-observer variation, the atlas-based auto-segmentation (ABAS) function in Velocity was introduced to ICON cancer centres (ICC) throughout Australia as a solution for automatic contouring. METHODS: This paper described the implementation process of the ABAS function and the construction of user-defined atlas sets and compared the contouring efficiency before and after the introduction of ABAS. RESULTS: The results indicate that the main limitation to the ABAS performance was Velocity's sub-optimal atlas selection method. Three user-defined atlas sets were constructed. Results suggested that the introduction of the ABAS saved at least 5 minutes of manual contouring time (P < 0.05), although further verification was required due to limitations in the data collection method. The pilot rollout adopting a 'champion' approach was successful and provided an opportunity to improve the user-defined atlases prior to the national implementation. CONCLUSION: The implementation of user-defined ABAS for head and neck (H&N) and female thorax patients at ICCs was successful, which achieved at least 5 minutes of efficiency gain.

Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial.

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).

Integration of palliative and supportive care in the management of advanced liver disease: development and evaluation of a prognostic screening tool and supportive care intervention.

BACKGROUND AND OBJECTIVES: Patients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life-limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention. DESIGN: Clinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. 'Plan-Do-Study-Act' (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention. RESULTS: 73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poor-prognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with decompensated cirrhosis, with the supportive care intervention (developed simultaneously) instigated for appropriate patients. CONCLUSIONS: We describe a model of care which identifies inpatients with cirrhosis at significant risk of dying over the coming year, and describe development of a supportive care intervention, which can be offered to suitable patients in parallel to ongoing active management.

Hepatitis C - Assessment to Treatment Trial (HepCATT) in primary care: study protocol for a cluster randomised controlled trial.

BACKGROUND: Public Health England (PHE) estimates that there are upwards of 160,000 individuals in England and Wales with chronic hepatitis C virus (HCV) infection, but until now only around 100,000 laboratory diagnoses have been reported to PHE and of these 28,000 have been treated. Targeted case-finding in primary care is estimated to be cost-effective; however, there has been no robust randomised controlled trial evidence available of specific interventions. Therefore, this study aims to develop and conduct a complex intervention within primary care and to evaluate this approach using a cluster randomised controlled trial. METHODS/DESIGN: A total of 46 general practices in South West England will be randomised in a 1:1 ratio to receive either a complex intervention comprising: educational training on HCV for the practice; poster and leaflet display in the practice waiting rooms to raise awareness and encourage opportunistic testing; a HCV risk prediction algorithm based on information on possible risk markers in the electronic patient record run using Audit + software (BMJ Informatica). The audit will then be used to recall and offer patients a HCV test. Control practices will follow usual care. The effectiveness of the intervention will be measured by comparing number and rates of HCV testing, the number and proportion of patients testing positive, onward referral, rates of specialist assessment and treatment in control and intervention practices. Intervention costs and health service utilisation will be recorded to estimate the NHS cost per new HCV diagnosis and new HCV patient initiating treatment. Longer-term cost-effectiveness of the intervention in improving quality-adjusted life years (QALYs) will be extrapolated using a pre-existing dynamic health economic model. Patients' and health care workers' experiences and acceptability of the intervention will be explored through semi-structured qualitative interviews. DISCUSSION: This trial has the potential to make an important impact on patient care and will provide high-quality evidence to help general practitioners make important decisions on HCV testing and onward referral. If found to be effective and cost-effective the intervention is readily scalable and can be used to support the implementation of NICE recommendations on HCV case-finding. TRIAL REGISTRATION: ISRCTN61788850 . Registered on 24 April 2015; Protocol Version: 2.0, 22 May 2015.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

BACKGROUND & AIMS: Rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-α on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-α. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between £4858 and £6607 per year. Taking into account drug costs of £3379 for 1-year treatment with rifaximin-α, there was an estimated annual mean saving of £1480-£3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-α for hepatic encephalopathy was generally cost saving.