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Background: Major society guidelines recommend the fibrosis‐4 index (FIB‐4) as the initial step to risk stratifying people with metabolic dysfunction‐associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD‐related hepatocellular carcinoma (HCC) and a low FIB‐4. Methods: This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD‐related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB‐4, defined as FIB‐4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis. Results: The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m2, respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB‐4 was 3.90 (IQR 2.42–6.42). A total of 78 participants (13%) had a low FIB‐4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB‐4. Participants with a low FIB‐4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha‐fetoprotein (p = 0.005), compared to participants without a low FIB‐4. Cirrhosis was associated with lower odds of low FIB‐4, but not other factors such as male sex, type 2 diabetes, or obesity. Conclusion: More than a quarter of those with MASLD‐related HCC without cirrhosis have a low FIB‐4. The proposed clinical care pathways may not identify these people for further evaluation. [ABSTRACT FROM AUTHOR]

Background: Post‐transplantation diabetes mellitus (PTDM) is common after solid organ transplantation. In the past decade, there has been increasing interest in the association between hypomagnesaemia and the development of PTDM. This systematic review aimed to investigate the current knowledge regarding the association between hypomagnesaemia and PTDM in adult liver and renal transplant recipients. Methods: A literature search of five databases, Medline, Embase, ProQuest, Scopus and Google Scholar, as well as article reference lists, was performed. Eligible studies that focused on adult liver and renal transplant recipients without pretransplantation hyperglycaemia or diabetes were included. Other eligibility criteria included quantitative studies which reported magnesium concentrations, studies with at least 6 months of follow‐up, and studies published in English. The Newcastle–Ottawa Assessment Tool was used for the quality assessment. Results: In total, 12 studies were included in the final analysis. Eleven focused on renal transplantation and one on liver transplantation. All studies were medium to high quality with eight out of 12 achieving the highest rating of nine. Eight studies found a negative association between either pretransplant or early post‐transplant serum magnesium concentration and the risk of PTDM, three studies found no association between these two variables, and one study found a positive association between the magnesium concentration at 8 weeks after transplantation and glycosylated haemoglobin A1C. Conclusions: Further large‐scale prospective studies with at least 6 months of follow‐up are needed to confirm these findings, particularly in liver transplantation, to further clarify and explore the relationship between hypomagnesaemia and PTDM. Highlights: Magnesium is critical in glucose homeostasis.Low serum magnesium concentration is independently associated with the development of post‐transplant diabetes in renal transplant recipients and is implicated in the development of post‐transplant diabetes in liver transplant recipients. [ABSTRACT FROM AUTHOR]

Background: Hypothermic Oxygenated machine PErfusion (HOPE) can reduce ischemic reperfusion injury and improve outcomes for liver transplant recipients. However, the effect of HOPE on high‐risk extended criteria donor (ECD) and donation after circulatory death determination (DCDD) grafts is incomplete, despite the expectation that this cohort benefit maximally from HOPE. Accordingly, this paper aims to characterize the effect of HOPE on ECD and DCDD grafts. Methods: This study includes all papers comparing HOPE to static cold storage for high‐risk ECD and DCDD grafts. Systematic searches of Medline, Embase, and Scopus were completed using the terms "HOPE" OR "hypothermic oxygenated machine perfusion" AND "liver transplantation". Data were extracted and analyzed using IBM SPSS to perform the meta‐analysis. Results: A total of 2286 records were identified, with 10 meeting the inclusion criteria. Overall, the quality of evidence is heterogenous with many papers relying on retrospective controls. However, pooled analysis demonstrates HOPE to significantly reduce the rate of early allograft dysfunction, 12‐month graft failure, re‐transplantation, total biliary complications, and non‐anastomotic strictures for high‐risk grafts. Conclusions: There is good evidence that HOPE improves outcomes following liver transplantation across a number of biochemical and clinical endpoints for high‐risk grafts. Of note, the reduction in biliary complications and re‐transplantation is particularly significant given the morbidity associated with these endpoints. However, further, high‐quality prospective trials with contemporary controls and clinically relevant primary endpoints are needed to better define the impact of HOPE for this cohort of grafts. [ABSTRACT FROM AUTHOR]

Background: Normothermic machine perfusion (NMP) allows for the assessment and resuscitation of ex‐vivo human livers prior to transplantation. Commercially available NMP systems are closed circuits that accumulate metabolic waste and cytokines over time, potentially limiting organ preservation times. Dialysis has been proposed as a method to remove waste and excess fluid from such systems. This study aimed to demonstrate the utility of integrating dialysis into a commercially available system by quantifying solute removal. Methods: A dialysis filter was attached in parallel to a commercially available liver perfusion system. Three livers declined for transplantation were split before undergoing long‐term NMP with blood using the modified system. During perfusion, dialysate flow rates were set in the range of 100–600 mL/h for short periods of time. At each flow rate, perfusate and spent dialysate samples were collected and analyzed for solute clearance. Results: The addition of dialysis to a commercial NMP system removed water‐soluble waste and helped regulate electrolyte concentrations. Interleukin‐6 was successfully removed from the perfusate. Solute clearance was proportional to dialysate flow rate. A guide for our perfusion setup was created for the appropriate selection of dialysis flow rates and duration based on real‐time perfusate composition. Conclusions: Dialysis circuits can efficiently remove waste and regulate perfusate composition, and can be easily incorporated to improve the performance of commercially available systems. Quantification of the effect of dialysis on perfusate composition enables refined dialysis control to optimize electrolyte profiles and avoid the over‐ or under‐correction of key solutes. [ABSTRACT FROM AUTHOR]

Background: Surgical site infection (SSI) after liver transplant (LT) is common, but no studies have been conducted in Australia. The purpose of this study was to determine the proportion of patients who developed an SSI post‐LT in Australia's largest LT unit. Methods: This was a single‐center retrospective cohort study. We included all LT recipients who were aged 18 years or more and received their transplant between March 1, 2018 and April 1, 2023. The primary outcome was to determine the proportion of LT recipients who developed an SSI within 30 days of transplantation. Results: There were 404 LTs performed during the study period, and 375 met inclusion criteria. Of these, 8% (n = 31/375) developed an SSI and were classified as superficial (3%, n = 12/375) or deep/organ space (5%, n = 19/375). The most common antibiotics used for prophylaxis were amoxicillin/clavulanate (75%, n = 281/375), followed by piperacillin/tazobactam (17%, n = 62/375). Independent risk factors associated with the development of SSI were Roux‐en‐Y hepaticojejunostomy (aOR 3.16, 95% CI 1.17–8.28, p =.02), operative time (per 60‐min increment) (aOR 1.23, 95% CI 1.02–1.48), and re‐operation (aOR 4.16, 95% CI 1.81–9.58, p <.01). Type of antibiotic received perioperatively was not significantly associated with SSI. Conclusion: SSI occurred in 8% of LT recipients and was predominantly related to operation‐related factors rather than patient‐ or antibiotic‐related factors. [ABSTRACT FROM AUTHOR]

Frequency‐dependent nonlinear process in microresonators is widely acknowledged, but there is no theory available to calculate the conversion efficiency for each resonance of the ring, except for the phase‐matching one. Similarly for azimuth‐dependent nonlinear process in birefringent rings, there is a lack of theory to analysis the conversion efficiency for each azimuth of the ring. Consequently, it leads to old‐fashioned or ill‐considered coupling position and inefficient energy conversion in birefringent microrings. Here, the study introduces spatio‐temporal coupled‐mode equation to describe mode spatial properties in the cavity, compensating for the deficiency of temporal coupled‐mode equation in describing sophisticated responses. By this equation, it is found that over a wide frequency range, the extremely strong second‐harmonic generation of TE modes can be achieved at different azimuth under different pumps in an X‐cut lithium niobate microring, as proved by a 440 000%/W conversion efficiency in a non‐poling ring recently. This theory is important for realizing an efficient entangled quantum light source, for example. Meanwhile, it will provide new ideas and guidelines for design and applications of monolithic birefringent photonic integrated circuits with high energy efficiency. [ABSTRACT FROM AUTHOR]

Background: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. Objectives: To co‐produce information resources for patients and healthcare professionals to improve conversations about PD dementia. Methods: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. Results: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co‐develop two open‐access resources: one for people with PD and their families, and one for healthcare professionals. Conclusion: Using artistic and creative workshops, co‐learning and striving for diverse voices, we co‐produced relevant resources for a wider audience to improve conversations about PD dementia. [ABSTRACT FROM AUTHOR]

Background: Ex situ machine perfusion facilitates the assessment of livers prior to transplantation. However, currently available markers of liver function poorly predict long‐term graft function. Indocyanine green (ICG) is a liver‐specific dye which, although common in vivo, has never been comprehensively evaluated for the assessment of graft quality during ex situ machine perfusion. This study aimed to assess the utility of ICG in the ex situ setting. Methods: Using a customized long‐term perfusion system, human livers that were not suitable for transplantation were perfused using a red cell‐based perfusate. ICG was delivered into the perfusate on days 0, 1, and 4 to assess ICG clearance (spectrophotometric absorbance at 805 nm) and ICG fluorescence (near‐infrared camera). Results: Sixteen partial livers were perfused for a median duration of 172 h (7.2 days). On day 0, the median ICG perfusate disappearance rate (PDR) was 7.5%/min and the median ICG retention at 15 min was 9.9%. Grafts that survived ≥7 days had a significantly higher median ICG PDR on day 0 (14.5%/min vs. 6.5%/min, p = 0.005) but not on days 1 or 4. ICG perfusion demonstrated that long‐surviving grafts had a significantly lower median red‐value (89.8 vs. 118.6, p = 0.011) and a significantly lower median blue‐value (12.9 vs. 22.6, p = 0.045) than short‐surviving grafts. Conclusion: ICG is a novel marker for the assessment of liver function during ex situ normothermic machine perfusion. ICG PDR and quantitative ICG perfusion can distinguish between long‐ and short‐surviving grafts and demonstrate the utility of ICG in the assessment of graft quality prior to transplant. [ABSTRACT FROM AUTHOR]

Summary: Background: Reports of DILI due to herbal and dietary supplements have been increasing over time. Aims: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug‐induced liver injury (DILI) due to anabolic‐androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. Methods: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017–2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. Results: Twenty‐three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26–42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28–112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70–292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. Conclusions: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements. [ABSTRACT FROM AUTHOR]

This report identifies, for the first time, a phytochelatin compound, phytochelatin 2 [γ‐E‐C‐γ‐E‐C‐G], and related metabolites in human urine. Phytochelatins are metal‐binding peptides produced by plants. They are present in nearly all human diets, due to their ubiquity in plants. The urinary concentration of phytochelatin 2 among 143 adults was in the low micromolar range, and phytochelatin 2 and its metabolites had differential correlations with urinary selenium and toxic metals. Activities of ingested phytochelatins are largely undescribed. Observed urinary metal interactions were investigated further in cell and animal models. Selenite reacted with phytochelatin to form a phytochelatin selenotrisulfide, and the preformed selenotrisulfide showed increased selenium uptake by renal proximal tubule cells. In vivo studies further showed that oral phytochelatin increased renal selenium content and decreased lung cadmium in mice. Presence of phytochelatin in human urine combined with its function in selenium and heavy metal distribution present a new route by which diet may influence metal disposition and bioavailability. [ABSTRACT FROM AUTHOR]

Alcohol consumption is a major cause of cirrhosis and hepatocellular carcinoma (HCC). The prevalence of alcohol‐associated hepatocellular carcinoma (aHCC) varies worldwide but is highest in Eastern Europe. Alcohol is the second fastest‐growing cause of age‐standardized liver cancer mortality with tumors more often diagnosed outside surveillance protocols and at a more advanced stage. Risk factors for aHCC include greater amounts of alcohol consumption, sex, and certain genetic polymorphisms. Smoking, concomitant liver disease, obesity, and diabetes act synergistically in increasing the risk of HCC in alcohol‐associated liver disease. Alcohol‐related hepatocarcinogenesis results from the complex interactions of several mechanistic pathways. Although not completely understood, underlying mechanisms include acetaldehyde‐related hepatotoxicity, oxidative stress, activation of the innate immune system, and alterations of the host microbiome. [ABSTRACT FROM AUTHOR]

Background and Aim: Acute‐on‐chronic liver failure (ACLF) is distinct from acute decompensation (AD) of cirrhosis in its clinical presentation, pathophysiology, and prognosis. There are limited published Australian ACLF data. Methods: We performed a single‐center retrospective cohort study of all adults with cirrhosis admitted with a decompensating event to a liver transplantation (LT) centre between 2015 and 2020. ACLF was defined using the European Association for the Study of the Liver‐Chronic Liver Failure (EASL‐CLIF) definition while those who did not meet the definition were classified as AD. The primary outcome of interest was 90‐day LT‐free survival. Results: A total of 615 patients had 1039 admissions for a decompensating event. On their index admission, 34% (209/615) of patients were classified as ACLF. Median admission model for end‐stage liver disease (MELD) and MELD‐Na scores were higher in ACLF patients compared with AD (21 vs 17 and 25 vs 20 respectively, both P < 0.001). Both the presence and severity of ACLF (grade ≥ 2) significantly predicted worse LT‐free survival compared with patients with AD. The EASL‐CLIF ACLF score (CLIF‐C ACLF), MELD and MELD‐Na scores performed similarly in predicting 90‐day mortality. Patients with index ACLF had a higher risk of 28‐day mortality (28.1% vs 5.1%, P < 0.001) and shorter times to readmission compared with those with AD. Conclusion: ACLF complicates over a third of hospital admissions for cirrhosis with decompensating events and is associated with a high short‐term mortality. The presence and grade of ACLF predicts 90‐day mortality and should be identified as those at greatest risk of poor outcome without intervention such as LT. [ABSTRACT FROM AUTHOR]

[Color figure can be viewed at wileyonlinelibrary.com] gl GLO:FQJ/01dec22:aor14372-fig-0003.jpg PHOTO (COLOR): 3 Evidence of worsening liver function at the end of perfusion during long-term ex situ machine perfusion of human livers. Keywords: ex situ machine perfusion; long-term perfusion; split livers EN ex situ machine perfusion long-term perfusion split livers 2504 2510 7 11/17/22 20221201 NES 221201 In this case report, we preserved human livers for up to 13 days under normothermic conditions using a modified commercial perfusion system. (A and B) For all livers (A: Liver 1, B: Liver 2) and all partial grafts, perfusate glucose levels remained stable during long-term perfusion sustained on infusions of glucose and glucagon. Long-term perfusion, ex situ machine perfusion, split livers. [Extracted from the article]

When light interacts with microscopic objects at the micro‐ and nano‐scale, the momentum exchange between photons and objects can be very significant. While the optical radiation pressure at the same level is usually too weak to change the mechanical state of macro‐scale objects at millimeter scale or beyond. Suspended metasurfaces with excellent mechanical and optical properties are ideal candidates for light‐matter interactions. Here, without sound insulation conditions, the spatial optical nonreciprocity based on an optomechanical system with a 2 mm × 2 mm × 110 nm Si3N4 suspended metasurface at the telecom wavelength is demonstrated, with peak wavelength shift up to 1.1 pm, which is about 4.0 times of the full width at half maximum, together with optical bistability at only about 10 W cm−2 input intensities, which is more than 4 orders of magnitude lower than traditional nonlinear optical mechanism. This work may pave new avenues for spatially nonreciprocal devices and bistable devices, and benefit the applications such as precision sensing, cavity quantum optomechanics, and all‐optical switching. [ABSTRACT FROM AUTHOR]

The emergence of coronavirus disease 19 (COVID‐19) has significantly disrupted liver transplantation worldwide. Despite significant, collective experience in treating liver transplant recipients with COVID‐19, there remains a paucity of data to guide the management of transplant candidates with acute COVID‐19 who require urgent transplantation. We present the case of an otherwise well, 39‐year‐old female presenting for urgent liver transplantation for acute liver failure secondary to hepatitis B, with concomitant acute, mild COVID‐19 due to Omicron BA.2. COVID‐19 antivirals were not administered pre‐transplant as the potential risk of hepatotoxicity precipitating further deterioration of liver function was not felt to outweigh the small, potential benefit of antiviral therapy. No effective SARS‐CoV‐2 monoclonal antibodies were available; however, the patient was previously vaccinated against SARS‐CoV‐2 with evidence of anti‐spike antibodies at the time of COVID‐19. Transplantation surgery and recovery were uncomplicated with no progression of COVID‐19 post‐transplant, hospital discharge was at day 14. At 30 days post‐transplant the patient had recovered, with normal liver function and SARS‐CoV‐2 was not detectable on nasopharyngeal PCR. While the safety of transplantation of patients with acute COVID‐19 cannot be assured by a single case, ours highlights the complex decision‐making process undertaken and competing priorities that need to be balanced when assessing patients with acute COVID‐19 who require urgent transplantation. [ABSTRACT FROM AUTHOR]

Introduction: Split liver transplantation (SLT) enables two recipients to be transplanted using a single donor liver; typically, an adult and a child. Despite equivalent long‐term outcomes to whole grafts in selected adults, the use of these grafts in high‐risk adult recipients with high model for end‐stage liver disease (MELD) scores (≥30), a poor pre‐transplant clinical status (ICU or hospital‐bound), acute liver failure or retransplantation remains controversial. Methods: We retrospectively analyzed all deceased donor adult liver transplants performed between July 2002 and November 2019 at a single high‐volume center and performed a propensity score‐matched analysis. A subgroup analysis was performed to assess utility of these grafts for high‐risk recipients. Results: A total of 1090 adult liver transplants were performed, including 155 SLT (14%). Graft survival at 1‐, 3‐ and 5‐years were comparable between recipients of split and whole liver grafts (82%, 79% and 74% vs. 86%, 81% and 77%, respectively, log rank P =.537), as was patient survival at 1‐, 3‐ and 5‐years. Recipients of split grafts were more likely to have biliary complications and hepatic artery thrombosis, but equivalent long‐term survival. Recipients with high MELD scores or a poor pre‐transplant clinical status had similar patient and graft survival and complication profiles irrespective of whether they received split or whole grafts. Conclusions: SLT is an important method for addressing donor shortages and provides comparable long‐term outcomes in adult recipients despite an increase in short‐term complications. SLT use in high‐risk recipients should be considered to allow for sickest‐first allocation policies. [ABSTRACT FROM AUTHOR]

Background and aim: Data are limited on whether Clostridioides difficile infection (CDI) in the first year after liver transplantation (LT) is associated with increased mortality. In an Australian setting without hypervirulent strain of C. difficile we investigated the prevalence, risk factors, and patient survival associated with CDI in LT. Methods: Consecutive patients who underwent deceased‐donor LT from 2007 to 2017 were studied retrospectively. Prevalence and long‐term outcomes of LT recipients with and without CDI were examined in the entire LT cohort. A case–control study was performed to investigate risk factors associated with CDI. Results: Six hundred and forty‐nine patients underwent LT, of which 32 (4.9%) were diagnosed with CDI within the first 12 months post‐LT. There was no difference in patient survival in the overall LT cohort on Kaplan–Meier analysis when stratified by CDI status (log‐rank test, p =.08). Furthermore, age was the only predictor of mortality on Cox regression (hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.00–1.13, p =.03). On multivariable logistic regression, rifaximin pre‐LT reduced risk (odds ratio (OR) 0.22, 95% CI 0.65–0.74, p =.01) whereas antibiotics pre‐LT (OR 7.02, 95% CI 1.26–39.01, p =.03) and length of hospital stay after LT (OR 1.03, 95% CI 1.01–1.06, p =.02) were associated with increased risk of CDI. Conclusions: Within the local setting of our study, CDI within 12 months post‐LT is of low severity, associated with pre‐LT antibiotic exposure and longer hospital stay but no survival impact after LT. Rifaximin use pre‐LT reduced the risk of CDI post‐LT. [ABSTRACT FROM AUTHOR]

Objective: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements.Design: Retrospective electronic medical record data analysis.Setting, Participants: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020.Main Outcome Measures: 90-day transplant-free survival; drugs implicated as causal agents in DILI.Results: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36).Conclusion: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Kuo et al papers. To view these articles, visit https://doi.org/10.1111/apt.17637 and https://doi.org/10.1111/apt.17742 [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is a common cancer with a poor prognosis, associated with high economic costs and a significant burden of disease. While it is often asymptomatic in the early stages, patients may experience great discomfort from advanced disease, treatment adverse effects, or decompensation of underlying cirrhosis. Palliative care has the potential to markedly improve quality of life, physical, and psychological symptoms in patients with end‐stage liver disease, and has been shown to prolong survival in some nonhepatocellular carcinoma malignancies. However, this service is underutilized in hepatocellular carcinoma, and referrals are frequently late due to factors such as stigmatization, inadequate resources, lack of education for nonpalliative care physicians and inadequate modeling for integration of palliative and supportive care within liver disease services. In the future, education workshops, population‐based awareness campaigns, increased funding and improved models of care, may improve the uptake of palliative care and subsequently optimize patient care, particularly towards the end of life. [ABSTRACT FROM AUTHOR]

Background and aims: In non‐alcoholic fatty liver disease (NAFLD), fibrosis is the strongest prognostic factor and can be assessed by non‐invasive methods. We evaluated the ability of liver stiffness measurement (LSM) to predict overall survival and liver, cardiovascular and oncologic complications. Methods: We prospectively collected data on 2251 consecutive NAFLD patients (mean age 59 years, male 53%, mean body mass index 28 kg/m2) in two centres. At inclusion, all patients had LSM, clinical and biological evaluation. During follow‐up, we recorded cardiovascular events, cancers, liver complications, liver transplantation and death. The primary endpoint was overall survival. Survival curves according to LSM were first performed using Kaplan‐Meier method for the primary endpoint, and Aalen‐Johansen method for secondary outcomes to take into account competitive risks. In a second step, a Cox proportional hazard model analysis was done to identify independent predictors of overall survival. Results: Median follow‐up was 27 months [IQR: 25‐38]. Fifty‐five patients died and three patients had liver transplantation. Overall survival significantly decreased as baseline LSM increased. Twenty‐one patients (0.9%) had a liver event, 142 (6.3%) developed cancer (excluding HCC) and 151 (6.7%) had a cardiovascular event during follow‐up. By multivariable analysis, independent predictors of overall survival were as follows: baseline LSM (adjusted HR (aHR) = 2.85 [1.65‐4.92], P =.0002), age (aHR = 1.11 [1.08‐1.13], P <.0001) and male sex (aHR = 2.05 [1.17‐3.57], P =.012). Patients with elevated LSM were also more likely to develop cardiovascular, and liver events but not other cancers. Conclusion: LSM can be used to predict survival, cardiovascular and liver complications in NAFLD patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Lamivudine and entecavir reduce hepatic events and death in chronic hepatitis B (CHB) patients with cirrhosis, but the impact of tenofovir disoproxil fumarate (TDF) is less well studied. Aim: To investigate the effectiveness of TDF therapy in CHB patients with cirrhosis. Methods: We studied TDF‐treated and untreated CHB patients with cirrhosis from three tertiary centres. TDF cohort included consecutive patients who received TDF for ≥12 months while the untreated cohort were historical controls receiving routine clinical care prior to the availability of anti‐viral therapy. The primary outcome was 5‐year cumulative probability of hepatocellular carcinoma (HCC) with secondary outcomes being hepatic decompensation and death or liver transplantation (LT). Results: A total of 1088 (291 untreated and 797 TDF‐treated) patients were included in the study. Five‐year cumulative probabilities in untreated vs TDF‐treated cohorts were 14.9% vs 9.8% for HCC (P = .07), 22.3% vs 5.9% for decompensation (P < .01) and 13.1% vs 1.1% for death or LT (P < .01) respectively. On multivariable Cox regression, TDF treatment was independently associated with reduced risks of HCC (adjusted hazard ratio [aHR] 0.46, P < .01), decompensating events (aHR 0.28, P = .01) and death or LT (aHR 0.06, P < .01). On sensitivity analyses, these risk reductions with TDF treatment were consistently demonstrated regardless of severity of liver disease and prior anti‐viral treatment. TDF treatment led to sustained improvements in most validated prognostic scores for predicting HCC, decompensation and death. Conclusions: Compared to untreated patients, TDF treatment reduces the risks of HCC, hepatic decompensation and death in CHB patients with cirrhosis at 5 years. [ABSTRACT FROM AUTHOR]

Objective: This study explored underlying metabolism-related dysfunction by examining metabolomic profiles in adults categorized as lean, as having normal weight obesity (NWO), or as having overweight/obesity.Methods: Participants (N = 179) had fasting plasma analyzed by liquid chromatography and high-resolution mass spectrometry for high-resolution metabolomics. Body composition was assessed by dual-energy x-ray absorptiometry. NWO was defined as BMI < 25 and body fat > 30% for women and > 23% for men. Differentiating metabolomic features were determined by using linear regression models and likelihood ratio tests with false discovery rate correction. Mummichog was used for pathway and network analyses.Results: A total of 222 metabolites significantly differed between the groups at a false discovery rate of q = 0.2. Linoleic acid, β-alanine, histidine, and aspartate/asparagine metabolism pathways were significantly enriched (all P < 0.01) by metabolites that were similarly upregulated in the NWO and overweight/obesity groups compared with the lean group. A module analysis linked branched-chain amino acids and amino acid metabolites as elevated in the NWO and overweight/obesity groups compared with the lean group (all P < 0.05).Conclusions: Metabolomic profiles of individuals with NWO reflected similar metabolic disruption as those of individuals with overweight/obesity. High-resolution metabolomics may help identify people at risk for developing obesity-related disease, despite normal BMI. [ABSTRACT FROM AUTHOR]

Background: A significant number of patients have liver stiffness measurements in the grey zone where liver biopsy is recommended. Aims: To study chronic hepatitis B patients with initial liver stiffness measurements in the grey zone with regards to rates of liver biopsy, repeat liver stiffness measurements and outcomes. Methods: Consecutive chronic hepatitis B patients who underwent transient elastography from August 2006 to July 2017 were retrospectively studied. Liver‐related events were defined as hepatocellular carcinoma or cirrhotic complications. Grey zone was defined as liver stiffness measurements: 6.1‐9.0 kPa (normal ALT) or 7.6‐12.0 kPa (ALT 1‐5 × upper limit of normal) on M‐probe and 6.9‐10.0 kPa on XL‐probe. Results: Of the 3212 patients analysed, 837 (26%) had initial liver stiffness measurements in grey zone. Only 3.6% of grey zone patients proceeded to liver biopsy within 6 months of transient elastography, of which 33% had METAVIR F3‐4 fibrosis. Repeat liver stiffness measurements was performed in 44% of grey zone patients. Liver biopsy and repeat liver stiffness measurements prompted change in management in 47% and 31% of patients respectively. Independent predictors for liver‐related events in grey zone patients included increased age, low albumin and low platelet count. Liver‐related events rates were increased (9%‐17%) in patients with METAVIR > F2 fibrosis on biopsy or repeat liver stiffness measurements which did not improve. Conclusions: Chronic hepatitis B patients with initial liver stiffness measurements in the grey zone rarely proceed to a clarifying liver biopsy which would reveal advanced fibrosis or cirrhosis in one‐third of patients. Both liver biopsy and repeat liver stiffness measurements in grey zone patients have clinical utility in prompting changes in management and providing prognostic information. [ABSTRACT FROM AUTHOR]

We describe an unusual endoscopic finding, caused by a dominant ovarian follicle compressing a low‐lying ascending colon just inferior to a patulous retroverted cecum. Endoscopically detected extra‐colonic lesions represent a diverse group of pathologies, and it is important the endoscopist has an appreciation of the varied number of benign and malignant causes—including those of gynecological origin. [ABSTRACT FROM AUTHOR]

Prognostication of patients with cirrhosis is complex, depending on more than just the severity of liver disease. Scores such as the model for end‐stage liver disease (MELD) and Child Pugh can assist with prognostication, yet by focusing on physiological parameters they fail to completely capture the elements contributing to a patient's clinical status. Evidence is increasing to support an important role for physical functioning in patient outcomes. Frailty has been increasingly recognised in medical literature over recent years, including in hepatology where it is identified in nearly half of cirrhosis patients. It is a complex construct consisting of multisystemic physiological decline and increased vulnerability to stressors. Diagnosis is complicated by lack of a consensus definition and measurement tool for frailty in cirrhosis. Frailty heralds a poor prognosis, predicting increased morbidity and mortality both pre‐ and postliver transplant, independent of MELD score. It is thought to be reversible, with promising data supporting prehabilitation and lifestyle intervention programs. In the future, assessment of patients with cirrhosis is likely to incorporate a measure of frailty, however, further research is required. [ABSTRACT FROM AUTHOR]

Background: To study the epidemiology of chronic hepatitis C virus infection in Hong Kong and to estimate the service gap for achieving the WHO hepatitis elimination targets of attaining a diagnosis rate of 90%, treatment rate of 80% and 65% reduction in mortality rate by 2030. Methods: From January 2005 to March 2017, patients who were tested positive for anti‐HCV were retrospectively retrieved from all public hospitals in Hong Kong. The epidemiological data of 15 participating hospitals were analysed. Results: A total of 11 309 anti‐HCV+ patients were identified and the estimated diagnosis rate was 50.9%. Our HCV‐infected patients were ageing (median age 59). The all‐cause mortality rate increased from 26.2 to 54.8 per 1000 person‐years over the last decade. Our estimated treatment rate was 12.4%. Among the treated patients, 93.6% had received pegylated interferon/ribavirin (Peg‐IFN/RBV) but only 10.8% had received interferon‐free direct‐acting antivirals (DAAs). In a cohort of 1533 patients, 39% already had advanced liver fibrosis or cirrhosis. The sustained virological response rate for Peg‐IFN/RBV and DAAs were 74.8% and 97.2% respectively. However, more than 70% of patients were not subjected to interferon treatment for various reasons. Patients who achieved SVR were associated with a significantly lower risk of HCC (4.7% vs 9.6%, P = 0.005) and death (1.7% vs 23.8%, P < 0.001). Conclusion: Our diagnosis rate, treatment rate and mortality rate reduction were still low, particularly the Peg‐IFN outcomes, making it difficult to meet the WHO hepatitis elimination targets. A more generalized use of DAAs is urgently needed to improve the situation. See Editorial on Page 1902 [ABSTRACT FROM AUTHOR]

Abstract: Crohn's disease is a heterogeneous, inflammatory condition that can affect any location of the gastrointestinal tract. Proximal gastrointestinal involvement occurs in 0.5–16% of patients, and it is usually diagnosed after recognition of intestinal disease. Symptoms are often mild and nonspecific; however, upper gastrointestinal disease predicts a more severe Crohn's phenotype with a greater frequency of complications such as obstruction and perforation. Gastroscopy and biopsy is the most sensitive diagnostic investigation. There is a paucity of data examining the treatment of this condition. Management principles are similar to those for intestinal disease, commencing with topical therapy where appropriate, progressing to systemic therapy such as glucocorticoids, 5‐aminosalicylic acid, immunomodulators, and biologics. Acid suppression therapy has symptomatic but no anti‐inflammatory benefit for gastroduodenal and esophageal involvement. Surgical intervention with bypass, strictureplasty, or less frequently, endoscopic balloon dilation may be required for complications or failed medical therapy. [ABSTRACT FROM AUTHOR]

Background and Aim Endoscopic retrograde cholangiopancreatography ( ERCP) in patients with roux-en-Y anastomosis ( REYA) is challenging. Use of double balloon enteroscope-assisted ERCP ( DBE- ERCP) has been successful. We aim to determine predictors of successful biliary cannulation with DBE- ERCP in patients with REYA. Methods We retrospectively studied patients with REYA who had DBE- ERCP between 2009 and 2015. Results 86 DBE- ERCP were done on 52 patients. Patients had REYA for liver transplant ( n = 26), gastrojejunostomy ( n = 9), previous bile duct injury ( n = 9), biliary atresia ( n = 2) and other ( n = 6). The biliary-enteric anastomosis was reached in 76% and cholangiogram was successful in 70%. Highest success rates were in patients with previous bile duct injury (94%) or gastrojejunostomy (89%). Post-transplant patients had intermediate success (64%). Patients with redo surgery (46%) and childhood surgery (38%), especially Kasai procedure (20%), had low success. Patients with previous bile duct injury were more likely to succeed (94% vs 63%, P = 0.010). Those more likely to fail were patients with childhood surgery (38% vs 73%, P = 0.037), biliary atresia (20% vs 73%, P = 0.013) and second operation post-transplant (25% vs 70%, P = 0.046). Conclusion Indication for REYA impacts on successful biliary cannulation in patients undergoing DBE- ERCP. The procedure is most successful in non-liver transplant adult surgery and post-transplant patients without a second operation. It is least successful in patients with surgically corrected biliary atresia and post-transplant patients with second operation. Alternative methods of biliary access should be considered in these patients. [ABSTRACT FROM AUTHOR]

Background & Aims Epidemiological data on primary sclerosing cholangitis ( PSC) outside the Northern hemisphere are limited. Similarly, the impact of inflammatory bowel disease ( IBD) on PSC outcomes remains unclear. We aimed to study the epidemiology and outcomes of PSC patients with and without IBD in an Australian cohort. Methods We retrospectively studied PSC patients attending two tertiary referral hospitals over 20 years. Diagnosis of PSC was made according to international guidelines by positive cholangiography and/or liver biopsy (for small duct PSC) with supporting clinical and laboratory evidence. Results Of 208 PSC patients (61% male) were studied (2271patient-years follow-up). The median age of PSC diagnosis was similar for PSC- IBD and PSC-only patients (40 years vs 42 years, P = .35). All 33 deaths occurred in PSC- IBD patients while there were no deaths in PSC-only patients (21% vs 0%, P < .01). However, there were no significant differences in liver transplantation ( PSC-only 25% vs PSC- IBD 31%, P = .45) and transplant-free survival between PSC-only and PSC- IBD patients ( P = .43). On multivariate Cox regression, only elevated international normalized ratio ( INR) was associated with a greater risk of death or liver transplant ( HR 2.0, 95% CI 1.1-3.6, P = .02). Development of gastrointestinal malignancy was higher in the PSC- IBD group compared to PSC-only group (22% vs 2%, P < .01). Conclusion Australian PSC patients have similar characteristics compared to European and North American cohorts. IBD is a significant predictor of gastrointestinal malignancies. Deaths were more common in PSC- IBD but overall transplant-free survival remained similar in PSC- IBD and PSC-only groups. An elevated INR was an independent predictor of death or liver transplantation. [ABSTRACT FROM AUTHOR]

The subsidence history of the Soutpansberg Basin was reconstructed by a tectonic subsidence analysis coupled with backstripping calculations based on data of newly interpreted sequence boundaries. Furthermore, burial and time plots were constructed in order to understand the burial and thermal history of the basin. Input data were based on facies, lithostratigraphic models and tectonic interpretations. The studied succession is up to 1000 m and is underlain by the Achaean Limpopo Mobile Belt. The subsidence within the basin supports the primary graben system which must have been centred within the present basins, and later became a region of faulting. The subsidence and burial history curves suggests two phases of rapid subsidence during the Early-Late Permian (300-230 Ma) and Middle Triassic (215-230 Ma). The areas of greater extension subsided more rapidly during these intervals. Two slow subsidence phases are observed during the Late Triassic (215-198 Ma) and Early Jurassic (198-100 Ma). These intervals represent the post-rift thermal subsidence and are interpreted as slow flexural subsidence. Based on these observations on the subsidence curves, it is possible to infer that the first stage of positive inflexion (300 Ma) is therefore recognised as the first stage of the Soutpansberg Basin formation. [ABSTRACT FROM AUTHOR]

ABSTRACT Photovoltaic performance of cross-linkable Ru(2,2′-bipyridine-4,4′-bicarboxylic acid)(4,4′-bis((4-vinyl benzyloxy)methyl)-2,2′-bipyridine)(NCS)2 (denoted as RuS dye) adsorbing on TiO2 mesoporous film was enhanced by polymerizing with either ionic liquid monomer, 1-(2-acryloyloxy-ethyl)-3-methyl-imidazol-1-ium iodide (AMImI), to form RuS-cross-AMImI or di-functional acrylic monomer with ether linkage, triethyleneglycodimethacrylate (TGDMA), to form RuS-cross-TGDMA. Their cross-linking properties were investigated by UV-vis spectroscopy by rinsing with 0.1 N NaOH aqueous solution. The power conversion efficiencies (PCEs) of dye-sensitized solar cells (DSSCs) with RuS-cross-AMImI and RuS-cross-TGDMA both reached over 8% under standard global air mass 1.5 full sunlight. The increased PCE for DSSCs with RuS-cross-AMImI comparing with cross-linked RuS was attributed to the I− counterion of AMImI increasing the charge regeneration rate of RuS dye, whereas that with RuS-cross-TGDMA was attributed to the Li+ coordination property of TGDMA. The photovoltaic performance of RuS-cross-TGDMA was also slightly better than that of RuS-cross-AMImI because of higher open-circuit photovoltage ( Voc) and short-circuit photocurrent ( Jsc). Its higher Voc was supported by the Bode plot of impedance under illumination and Nyquist plots at dark, whereas higher Jsc was supported by the incident monochromatic photon-to-current conversion efficiency spectra and charge extraction experiments. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

R2142 --> 699.10 --> High resolution mass spectrometry (HRMS) detects tens of thousands of unknown features in human plasma. Many of these features could be indicative of xenobiotic exposure, but identifying candidates poses a challenge due to low abundance and lack of authentic standards. Here we propose using co‐occurrence of metabolites as a criterion to aid identification of undocumented xenobiotic exposures and co‐exposures in humans. Plasma from 49 volunteer Emory University/Georgia Tech employees in a longitudinal study were analyzed with HRMS, and aligned features were arranged as nodes in networks connected according to feature co‐occurrence and common biotransformation mass differences, marking possible xenobiotic pathways. These networks were compared against curated metabolic profiles of xenobiotic reference material generated on an enzyme‐based biotransformation system (liver S9 fractions). Profile matches, coupled with available MS/MS, suggest confident exposure identification of zolpidem, dextromethorphan, nicotine, citalopram, caffeine and tramadol within the cohort. Further investigation of co‐occurrence networks also facilitated suggestion of possible xenobiotic co‐exposures beyond biotransformation pathways. In this cohort, Zolpidem metabolites co‐occurred with high abundance features having the the masses of melatonin and its metabolites, suggesting co‐exposure due to polypharmacy for a single condition. [ABSTRACT FROM AUTHOR]

Background and Aim: Colorectal cancer (CRC) screening improves survival and requires appropriate recommendation by general practitioners (GPs). Screening practises may be influenced by barriers related to ethnicity and training. Methods: A mail survey assessed GPs' practises and the barriers towards CRC screening. The association of screening practises and demography, including GP ethnicity, medical training and practise characteristics, were evaluated. Results: Of 212 GPs (median age 54 years, 73% men, 27% Caucasian, 38% foreign graduates), 87% agreed that fecal occult blood test (FOBT) screening improved survival in the average-risk patient. Considerable variations existed in the starting age (40-49 years: 31%; 50 years: 65%) and frequency (1-2 years: 77%; 3-5 years: 22%) of screening. FOBT was used for indications other than screening: anemia (59%), altered bowel habits (54%), abdominal pain (24%), and rectal bleeding (23%), and these were significantly more frequent in Asian GPs independent of medical training. GPs were less likely to recommend screening to immigrants, and most reported that immigrants were less likely to participate. More Asian and Middle Eastern GPs reported a major barrier with FOBT inaccuracy compared with Caucasian GPs (22% vs 9%, P = 0.03; and 27% vs 9%, P = 0.03, respectively). Conclusions: Considerable differences existed in GPs' CRC screening practises. Indications for use of FOBT and the subsequent investigation of a positive FOBT also varied according to GPs' ethnicity, independent of medical training. Patient's ethnicity and associated language and cultural barriers may affect screening uptake, which may negatively affect the health of immigrants. Resources and culture-specific interventions are recommended to improve overall screening participation. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is an opportunistic fungal pathogen and an important cause of morbidity and mortality in immunocompromised patients. We report a case of osteomyelitis caused by C. neoformans in a liver transplant recipient who presented with a headache and scalp lump after sustaining mild head trauma. There was no evidence of central nervous system involvement or dissemination. This is the first known case report of isolated cryptococcal osteomyelitis in a liver transplant recipient. [ABSTRACT FROM AUTHOR]

See Article on Page 1595 [ABSTRACT FROM AUTHOR]

Proof-of-concept in clinical trials has traditionally focused on the identification of a maximum tolerated dose with the assumption that the higher doses provide better efficacy. However, adverse events associated with a maximum tolerated dose may have a negative effect on efficacy. We present an efficient adaptive dose-finding strategy that concentrates patient assignments at and around the dose which has the best efficacy/tolerability profile based on a utility function. The strategy is applied within the setting of a crossover design. While the strategy may also be applied to parallel studies, a crossover design provides more power for a given sample size for comparisons between the optimal dose versus placebo and/or active control when it is reasonable to assume no carryover effects. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

R4277 --> Background: The diversity of chemicals detectable in human samples by high‐resolution mass spectrometry (HRMS) exceeds the number of readily available chemical standards, limiting our ability to identify minor metabolites of drugs and other xenobiotics in vivo. Standard workflows for identification of unknown metabolites typically begin by interpretation of ion dissociation spectra (MS/MS) and comparison with library spectra and/or authentic standards – many of which are not available and do not incorporate enzymatic precursor‐product relationships as identification criteria. Objective: To develop a high‐throughput strategy to generate human biotransformation products from diverse xenobiotic and drugs for analysis with LC‐HRMS. Hypothesis: We hypothesize that unidentified metabolites are generated from enzymatic reactions of known metabolites. Therefore, strategies to generate and characterize metabolic products for diverse arrays of xenobiotics will facilitate identification of metabolites in vivo. Methods: Here, we adopt a strategy to generate human biotransformation products of diverse xenobiotics in a high‐throughput 96‐well plate format using incubations with human liver S9 fractions. Extracts from these reactions were collected at 0 and 24 hour time points and analyzed using LC‐HRMS (Thermo Scientific Fusion/High‐Field Q‐Exactive) to characterize metabolic products generated in a time‐dependent manner. Data‐dependent MS/MS was performed to collect MS/MS spectra. Expected biotransformation products were characterized by retention time, accurate mass m/z (MS1), MS/MS, and an increase in signal intensity for predicted or previously unreported biotransformation products. Incubations with stable‐isotope precursors aided the identification of previously unreported biotransformation products. Results: Our data show that known and previously unidentified Phase 1 and Phase 2 metabolites were produced from a range of xenobiotics in a 96‐well format using human liver S9 fractions. S9 reaction extracts of 138 drug or xenobiotic precursors were analyzed generating a total of 502 validated metabolites. Selected metabolites were used to support their identification in mouse and human samples based on matched accurate mass MS1, retention time, and co‐occurrence with the parent xenobiotic and/or related metabolites in the samples. Conclusion: We have developed a scalable tool to generate metabolites from thousands of xenobiotics to facilitate identification of drug and other xenobiotic metabolites in human samples. [ABSTRACT FROM AUTHOR]

R4160 --> As an approach to identify unknown mass spectral features corresponding to xenobiotic metabolites and simultaneously identify the enzyme(s) responsible, we developed a panel of lentivirally transduced human hepatoma cell lines (Huh7) that express xenobiotic metabolizing enzymes. However, screening thousands of chemicals individually against 40‐50 different cell lines each would require immense analytical resources. We hypothesized that pooling samples can improve analytical efficiency and throughput without significantly affecting metabolite generation or detection, and designed two pooling strategies to generate and detect metabolites from 36 different chemicals (including a number of drugs whose metabolism is well characterized) and 8 cytochrome P450‐expressing HuH7 cell lines. In the pre‐pooling strategy, 36 chemicals were grouped into 12 pools of 6 randomized compounds, with each compound present in two separate pools. The 12 pools were each incubated with 8 different cell lines for 0 and 2h resulting in 192 samples for analyses. In the post‐pooling strategy, 36 chemicals were incubated individually with 8 different cell lines. After incubation, the 36 chemicals were pooled by the same system as the pre‐pooling strategy. 10 μL aliquots of sample extracts were analyzed using liquid chromatography (Dionex Ultimate 3000) and Fourier‐transform high‐resolution mass spectrometry (Thermo Scientific Fusion) in both HILIC+ and C18‐ modes. Expression of the P450 proteins was verified by immunoblotting. Results from the pre‐pooled samples showed that the anti‐cancer drug pazopanib was metabolized by the CYP3A4‐ and CYP2C8‐expressing cell lines. Bupropion and β‐naphthoflavone were metabolized mainly by CYP2B6 and CYP1A2, verifying that the cell lines express functional P450s. Next, we compared the metabolomic profiles of the xenobiotics from the two different pooling strategies. The post‐pooling strategy generally showed more metabolite generation, although it required 3 times as many biological sample incubations. Hydroxybupropion and β‐naphthoflavone dihydrodiol generation were similar between the two pooling strategies. Qualitatively, the generation of hydroxy trifluralin, a possible metabolite of the commonly used herbicide, showed no significant differences between the two pooling strategies, although the signal levels using pre‐pooling were 13 times higher than in post‐pooling samples. Thus, either pooling strategy can be used as screens to identify enzyme‐compound pair reactions and to guide subsequent metabolite generation and characterization. The presence of each xenobiotic in two pools increases stringency for qualifying a feature as a metabolite, while achieving the same confirmation as technical replicates. While the pre‐pooling strategy may be vulnerable to confounding effects of potential interactions among xenobiotics in a given pool, the presence of each substrate in two different pools mitigated this concern. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Most patients with cirrhosis have compensated disease and are cared for in primary care; however, the exact epidemiology within Australia remains largely unknown. The aim of this study was to assess cirrhosis care in an Australian primary care setting by evaluating rates of cirrhosis diagnosis, appropriate hepatocellular carcinoma (HCC) surveillance and specialist communication.Electronic medical records in consenting general practices were reviewed using the “Liver Toolkit” to identify patients with an existing cirrhosis diagnosis. Individual cases were reviewed to identify outcomes of interest.One hundred seventy‐one patients with confirmed cirrhosis across nine general practices were identified (74% male, mean age: 61.2 years). There was significant variation in the rate of cirrhosis diagnosis between practices (range 31.7–637.9 per 100 000 patients, P < 0.0001). Patients with cirrhosis had predominately compensated disease (75% Child–Pugh A) and common etiologies of cirrhosis were alcohol (49%), hepatitis C (47%), and metabolic dysfunction‐associated steatotic liver disease (29%). Forty‐two patients (25%) had received appropriate HCC surveillance. Predictors of inadequate HCC surveillance were time from last specialist correspondence (odds ratio [OR] = 1.06 per month increase, 95% confidence interval [CI]: 1.02–1.10, P = 0.002) and hepatitis B (OR = 0.24, 95% CI: 0.06–0.98, P = 0.047). Specialist correspondence with primary care was older than 2 years or absent in 37% of cases.There was a 20‐fold difference in the rate of cirrhosis diagnosis between general practices within Sydney, suggesting a large proportion of patients remain undiagnosed. Three quarters of patients with diagnosed cirrhosis are not receiving appropriate HCC surveillance. [ABSTRACT FROM AUTHOR]

The article discusses the importance of hepatitis B virus (HBV) screening in surface antigen negative hepatitis B infection prior to the implementation of B cell-depleting therapy to avoid potential fatal reactivation of chronic hepatitis B.