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Over many years the liver transplant community has faced innumerable challenges which have been overcome, leading to increased donor utilization and improved recipient survival[1]. The coronavirus disease (COVID-19) pandemic has generated a set of unique obstacles for organ transplantation with significant reductions in organ donation as well as critical care capacity to facilitate transplantation[2]. Whilst transplant activity internationally continues to increase, ongoing efforts to maximize donor utilization remains vital in addressing the backlog of patients awaiting liver transplantation.

Background Tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dosing based on systemic exposure. MITRA microsampling offers a convenient, minimally invasive approach for the collection of capillary blood samples from a finger prick versus conventional venous blood sampling for quantitation of tacrolimus blood concentrations. However, the suitability of MITRA microsampling for the determination of tacrolimus concentrations requires assessment in clinical settings. Methods Paired venous (2 mL) and capillary (10 μL) blood samples were collected pre-tacrolimus dose and 1 and 3 hours postdose during routine outpatient visits from stable adult liver or kidney transplant patients receiving prolonged-release tacrolimus. Tacrolimus concentrations were determined by liquid chromatography-tandem mass spectrometry, and the concentrations obtained by the 2 sampling methods were compared by linear regression and Bland-Altman agreement analyses. Results Samples were available for 82 transplant recipients (kidney, n = 41; liver, n = 41). A high correlation was observed between tacrolimus concentrations in capillary and venous blood samples (Pearson correlation coefficient, 0.97; Lin concordance coefficient, 0.87; slope of the fitted line, >1.0). Tacrolimus concentrations in capillary samples were 22.5% higher on average than in the corresponding venous blood samples (95% limits of agreement, 0.5%-44.6%). Similar results were observed in both transplant subgroups. Conclusions MITRA finger prick sampling provides a convenient alternative to venipuncture for therapeutic drug monitoring in transplant recipients maintained on prolonged-release tacrolimus. When using the finger prick MITRA method, the positive bias in tacrolimus concentrations observed with this technique, when compared with venipuncture, needs to be taken into consideration.

Introduction: Anxiety and depression in patients awaiting liver transplantation are associated with worse clinical outcomes. However, optimising patient mental health is not routinely addressed in pre-transplant care. Aims: To understand the prevalence of anxiety and depression in patients awaiting transplantation and their access to pharmacological and psychological therapies. Methods: Patients awaiting transplantation were offered screening for anxiety and depression using the Hospital Anxiety and Depression Screening (HADS) tool. Data pertaining to patient demographics and previous treatment for anxiety and depression were recorded and analysed. Findings: Over 50% of patients recorded abnormal scores for anxiety and depression. Of the 19 patients screened, 42% had received treatment for either disorder, and most found the intervention unhelpful due to lack of follow-up appointments and limited understanding of their underlying chronic liver disease. There was a significant association between female sex and screening positive for depression. Conclusion: Anxiety and depression are prevalent in patients awaiting liver transplantation. The integration of a psychologist into the transplantation multidisciplinary team may improve patient outcomes.

Background and aims Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period ("epoch") after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non-HCC recipients. Approach and results We assessed pre-LT PS using the 5-point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow-up (0-90 days and 90 days to 1 year) and in different eras of transplantation (1995-2005 and 2006-2016). 2107 HCC and 10,693 non-HCC patients were included. One-year survival decreased with worsening PS in non-HCC recipients where 1-year survival was 91.9% (95% confidence interval [CI], 88.3-94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7-80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4-93.2) and 83.1% (95% CI, 61.0-93.3), respectively. Reduction in survival in non-HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post-LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40-0.74) and non-HCC recipients (0.48; 95% CI, 0.42-0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively). Conclusions Impact on mortality of the recipient's pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non-HCC recipients and across the full range of PS.

We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease.

There is much controversy regarding enhanced recovery for recipients of liver transplants from deceased and living donors. The objectives of this Review were to summarise current knowledge on individual enhanced recovery elements on short-term outcomes, identify key components for comprehensive pathways, and create internationally accepted guidelines on enhanced recovery for liver-transplant recipients. The ERAS4OLT.org collaborative partnered by the International Liver Transplantation Society performed systematic literature reviews on the effect of 32 relevant enhanced perioperative recovery elements on short-term outcomes, and global specialists prepared expert statements on deceased and living donor liver transplantation. The Grading Recommendations, Assessment, Development and Evaluations approach was used for rating of quality of evidence and grading of recommendations. A virtual international consensus conference was held in January, 2022, in which results were presented, voted on by the audience, and discussed by an independent international jury of eight members, applying the Danish model of consensus. 273 liver transplantation specialists from 30 countries prepared expert statements on elements of enhanced recovery for liver transplantation based on the systematic literature reviews. The consensus conference yielded 80 final recommendations, covering aspects of enhanced recovery for preoperative assessment and optimisation, intraoperative surgical and anaesthetic conduct, and postoperative management for the recipients of liver transplants from both deceased and living donors, and for the living donor. The recommendations represent a comprehensive overview of the relevant elements and areas of enhanced recovery for liver transplantation. These internationally established guidelines could direct the development of enhanced recovery programmes worldwide, allowing adjustments according to local resources and practices.

IntroductionLiver transplantation (LT) remains integral to the management of end-stage chronic liver disease (CLD). However, referral thresholds and assessment pathways remain poorly defined. Distance from LT centre has been demonstrated to impact negatively on patient outcomes resulting in the development of satellite LT centres (SLTCs). We aimed to evaluate the impact of SLTCs on LT assessment in patients with CLD and hepatocellular carcinoma (HCC).MethodsA retrospective cohort study was undertaken including all patients with CLD or HCC assessed for LT at King’s College Hospital (KCH) between October 2014 and October 2019. Referral location, social, demographic, clinical and laboratory data were collected. Univariable and multivariable analyses (MVA) were performed to assess the impact of SLTCs on patients being accepted as LT candidates and contraindications being identified.Results1102 and 240 LT assessments were included for patients with CLD and HCC, respectively. MVA demonstrated significant associations with; patients living greater than 60 min from KCH/SLTCs and LT candidacy acceptance in CLD, and less deprived patients and LT candidacy acceptance in HCC. However, neither variable was associated with identification of LT contraindications. MVA demonstrated that referrals from SLTCs were more likely to result in acceptance of LT candidacy and less likely to result in a contraindication being identified in CLD. However, such associations were not demonstrated in HCC.ConclusionSLTCs improve LT assessment outcomes in CLD but not HCC reflecting the standardised HCC referral pathway. Developing a formal regional LT assessment pathway across the UK would improve equity of access to transplantation.

Liver transplantation (LT) is a life-saving treatment for patients with end-stage chronic liver disease. Given the negative impact of distance from transplant centre on patient outcomes,1 2 King’s College Hospital (KCH) developed a network of satellite liver transplant centres (SLTCs) in Plymouth and Belfast to optimise access to LT.3 These centres deliver transplant assessment and comparable post-LT care to conventional LT centres.4 However, patients are still required to complete their assessments at KCH prior to listing. The COVID-19 pandemic has caused unprecedented strain on health services globally. The UK LT programme was affected with transplantation and assessment occurring only in patients with urgent need.5 However, patients at SLTCs were also subject to travel restrictions which further disadvantaged them compared with local patients. A virtual transplant assessment (VTA) pathway was developed to allow SLTCs to assess their patients for LT locally and to discuss listing without attendance at KCH. Here, we describe our first experiences with this novel pathway. We retrospectively included all patients from both SLTCs who completed an LT assessment between April 2020 and April 2021. The decision for a VTA was made by consensus decision from the …

Background The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS). Methods All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records. Results Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure. Conclusion Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.

BACKGROUND: Rifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30-day readmissions.AIM: To examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.METHODS: Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.RESULTS: Of the 622 patients listed for transplantation, 101 had HE. Sixty-six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14-16)] rifaximin-treated and 16 [14-18] rifaximin-naïve). Patients on the waiting list treated with rifaximin had reduced all-cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 (95% CI 6-12) in the rifaximin-treated group vs 14 days (95% CI 7-21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3-140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89-0.93).CONCLUSION: Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.

Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC.LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria.346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively).LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.

Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients.In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death.Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients.Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic.European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

Background Acute liver failure (ALF) remains a rare but life-threatening condition which requires early prognostication for transplantation (LTx). Existing models such as the King’s College Criteria (KCC) lack sensitivity. We have previously demonstrated the potential for regeneration linked miRNA to perform as biomarkers in acute and chronic liver disease. The aim of this study was to develop a miRNA-based prognostic model for acetaminophen (APAP) ALF. Methods Samples were provided by the US ALF Study Group. We assessed serum miRNA expression from 193 patients (94 survivors, 89 non-survivors) with APAP-ALF at two time points (early; day 1, late; day 3–5). Transplanted patients were excluded. A panel of 24 miRNA identified from our previous studies were analysed. Multiple logistic regression was used to create early and late miRNA outcome prediction models. Clinical data were incorporated to improve prognostication. Results Early up-regulation of miR-150 and down-regulation of -16–2 were associated with mortality. The early detection of miR-20a and absence of miR-149 were associated with mortality. Late up-regulation of miR-30a and down-regulation of -122, 16–2 and -21 were significantly associated with mortality. Late detection of miR-149, -17 and -191 were associated with mortality. Prognostic models were made for early and late miRNA expression. The early model contained miRNA associated with regeneration (miR-20a, -27a, -140, -150, -191) and achieved an area under the receiver operator curve (AUC) of 0.78 (95% CI 0.71–0.84, p Conclusion We demonstrate that specific serum miRNA have prognostic value as biomarkers in ALF. Our early model utilised regeneration linked miRNA whereas our late model utilised cell-death linked miRNA; this may signify mechanistic differences at early and late time points which determine patient survival.

Background Common variable immunodeficiency (CVID) is a rare primary B-cell immunodeficiency disorder associated with multisystem complications of impaired humoral immunity. CVID is characterized by impaired adaptive responses to pathogen challenge and a paradoxical predisposition to a wide range of autoimmune and neoplastic complications. Methods We present a case series describing our experience of liver transplantation in two patients with CVID and perform a comprehensive literature review of post-transplant complications and survival outcomes detailing the global experience of 30 reported cases of adult liver transplantation for common variable immunodeficiency-related liver disease (CVIDrLD). Results Liver transplantation in CVIDrLD is frequently complicated by atypical infections, autoimmune complications and graft recurrence and is associated with suboptimal long term survival outcomes post-transplantation in comparison to established listing indications for liver transplantation; this is further compounded (median survival 3 vs. 5 years) when removing patients with concomitant chronic hepatitis C infection from the survival analysis. Conclusions Liver transplantation is associated with poor overall survival outcomes and careful consideration should be given to the phenotype and severity of immunodeficiency, the presence of chronic pathogen colonisation and the extrahepatic burden of disease at the time of assessment. At present, despite careful patient selection, survival post-transplant outcomes fall below acceptable listing thresholds, necessitating a conservative approach to consideration of single organ listing in this context with current available treatments. Patients with a secondary aetiological factor for liver disease may perform better post-transplant.

Supplemental Digital Content is available in the text., Background. The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients. Methods. We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up. Results. A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3–4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group. Conclusions. We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.

Supplemental Digital Content is available in the text., Background. Kidney and liver transplantation is the standard of care for end-stage renal or liver disease. However, long-term survival of kidney and liver grafts remain suboptimal. Our study aimed to understand the healthcare resources utilized and their associated costs in the years before graft failure. Methods. Two noninterventional, retrospective, observational studies were conducted in cohorts of kidney or liver transplant patients. Once identified, patients were followed using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics databases from the date of transplantation to the date of the first graft failure. Total healthcare costs in the year before graft failure (primary endpoint) and during years 2–5 before graft failure (secondary endpoint) were collected. Results. A total of 269 kidney and 81 liver transplant patients were analyzed. The mean total costs were highest for all resource components in the last year before graft failure, except for mean costs of immunosuppressive therapy per patient, which decreased slightly by index date (ie, graft failure). The mean total healthcare costs in the last year before graft failure were £8115 for kidney and £9988 for liver transplant patients and were significantly (P < 0.05) higher than years 2–5 before graft failure. Mean healthcare costs for years 2, 3, 4, and 5 before graft failure were £5925, £5575, £5469, and £5468, respectively, for kidney, and £6763, £7042, £6020, and £5651, respectively, for liver transplant patients. Conclusions. Total healthcare costs in the last year before graft failure are substantial and statistically significantly higher than years 2–5 before graft failure, in both kidney and liver transplant patients. Our findings show the economic burden placed on healthcare services in the years before graft failure.

Hepatocellular cancer (HCC) is an established indication for liver transplantation. This group is often allocated a donor after cardiac death (DCD) liver as a solution for waiting times. There are concerns that this approach may oncologically disadvantage HCC recipients. The aim of this study was to determine whether DCD transplantation was associated with poorer cancer-related survival in HCC.Study population was from a single institute (2001-2014) with an HCC listing diagnosis. Variables related to recipient, tumor, and graft were analyzed to determine association with HCC death.There were 347 recipients listed for HCC of which 91 received a DCD. Donor after cardiac death and donor after brain stem death (DBD) had equivalent 1-, 3-, and 5-year overall (P = 0.115) and cancer-specific survival (P = 0.7). On univariate analysis recipient age, sex, model for end stage liver disease, viral etiology had no bearing on the risk of HCC death. Neither did the graft variables of type (DCD vs DBD), donor age, steatosis, cold ischemic time, peak aspartate transaminase, day 5 bilirubin or international normalized ratio after transplant. Only tumor variables of alpha-fetoprotein, number, total diameter, microvascular invasion, and differentiation were predictors of HCC death. On multivariate analysis, predictors of HCC death remained tumor number (P = 0.002), total diameter of tumor(s) (P0.001), microvascular invasion (P = 0.025), and poor differentiation (P = 0.021).Donor liver quality in terms of graft type (DCD) has no influence on cancer related survival in transplant for HCC (hazards ratio, 1.143; 95% confidence interval, 0.528-2.423; P = 0.752).

BackgroundLiver transplant services remain a scarce resource not reflective of geography or burden of liver disease within the UK. To address geographical concerns in the South West (SW), a devolved network model of care for liver transplantation was established in 2004 between the SW Liver Unit (SWLU) at Derriford Hospital, Plymouth and King’s College Hospital, London. The SWLU has evolved to deliver both pre-transplant and post-transplant care for patients across the SW Peninsula. We determined whether risk-adjusted survival in patients assessed and managed at the SWLU compared with existing UK transplant centres.DesignRetrospective analysis of records at National Health Service Blood and Transplant (NHSBT) for patients ≥18 years listed or undergoing first liver only deceased donor transplantation from 1 January 2006 to 31 December 2017. Data collected and used were in accordance with standard NHSBT outcome measures.ResultsWe identified 8492 patients registered for first liver only transplant and 6140 patients who subsequently underwent transplantation. Of these, 215 patients listed and 172 patients transplanted were registered at the SWLU. The 1-year, 5-year and 10-year risk-adjusted post-listing survival for patients registered at the SWLU were 86%, 75% and 67%, respectively, with 1-year and 5-year risk-adjusted post-transplant survival 94.9% and 84.4%, respectively.ConclusionsRisk-adjusted post-listing 1-year, 5-year and 10-year survival outcomes and risk-adjusted 1-year and 5-year post-transplant survival outcomes at the SWLU are good and comparable with the seven UK transplant centres. These outcomes provide assurance that care delivered by our regional programme is equivalent to well-established liver transplant programmes.

Reports of pregnancy in liver transplantation (LT) patients have largely favorable outcomes. Concerns remain with regards to maternal and graft risk, optimal immunosuppression (IS), and fetal outcomes. We review all post-LT pregnancies at our center with regard to the outcomes and safety for the patient, graft, and fetus. A total of 117 conceptions occurred in 79 patients. Median age at conception was 29 years. Maternal complications included graft loss (2%), acute cellular rejection (ACR; 15%), pre-eclampsia/eclampsia (15%), gestational diabetes (7%), and bacterial sepsis (5%). ACR was significantly more common in those women who conceived within 12 months of LT (P = 0.001). The live birth rate was 73%. Prematurity occurred in 26 (31%) neonates, and 24 (29%) neonates were of low or very low birth weight. IS choice (cyclosporine versus tacrolimus) had no significant effect on pregnancy outcomes and complications. No congenital abnormalities occurred, and only 1 child born at 24 weeks had delayed developmental milestones. In conclusion, pregnancy following LT has a favorable outcome in the majority, but severe maternal risks remain. Patients should be counseled with regard to the above information so informed decisions can be made, and pregnancy must be considered high risk with regular monitoring by transplant clinicians and specialist obstetricians.

Backgrounds Recurrent hepatitis C virus (HCV) infection is universal post-transplantation. Fibrosis (F) stage ≥2 at 12 months identifies patients with rapid fibrosis progression. Antiviral therapy (AVT) remains the only option to attenuate fibrosis progression. We hypothesized that CXCL10 levels can distinguish between slow and fast fibrosis progression at 12 months, development of F ≥ 4 post-transplantation, and help predict treatment response in patients undergoing AVT. Methods All patients that had undergone primary liver transplantation at King's College Hospital, London, between 2000 and 2011 were identified. Quantification of CXCL10 was performed using an ELISA-based assay on stored plasma at six months post-transplant and pre-treatment. Comparison was made with liver biopsies performed at 12 months and in the post-transplant period where available. Results One hundred and thirty-three patients were included. CXCL10 levels were lower in the slow fibrosis group compared to the rapid fibrosis group (p

Objective Delivering excellent healthcare depends on accurate communication between professionals who may be in different locations. Frequently, the first point of contact with the liver unit at King9s College Hospital (KCH) is through a telephone call to a specialist registrar or liver fellow, for whom no case notes are available in which to record information. The aim of this study was to improve the clinical governance of telephone referrals and to generate contemporaneous records that could be easily retrieved and audited. Design An electronic database for telephone referrals and advice was designed and made securely available to registrars in our unit. Setting Service development in a tertiary liver centre that receives referrals from across the UK and Europe. Main outcome measures Demographic and clinical data were recorded prospectively and analysed retrospectively. Results Data from 350 calls were entered during 5 months. The information included the nature and origin of the call (200 from 75 different institutions), disease burden and severity of disease among the patients discussed with KCH, and outcome of the call. The majority of cases were discussed with consultants or arrangements were made for formal review at KCH. Conclusions A telephone referrals and advice database provides clinical governance, serves as a quality indicator and forms a contemporaneous record at the referral centre. Activity data and knowledge of disease burden help to tailor services to the needs of referrers and commissioners. We recommend implementation of similar models in other centres that give extramural verbal advice.

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.

Recurrent hepatitis C virus (HCV) infection is associated with accelerated fibrosis rates after liver transplantation (LT) and is the leading cause of graft failure. Furthermore, distinguishing recurrent HCV from acute cellular rejection (ACR) can be problematic, and this can lead to inappropriate treatments and adverse outcomes. We hypothesized that intragraft microRNA (miRNA) expression profiles could distinguish the severity of recurrent HCV and differentiate recurrent HCV from ACR. We established meticulously matched post-LT patient cohorts in order to derive robust global miRNA expression profiles and minimize the impact of variables known to influence HCV recurrence. These cohorts consisted of patients with slow HCV fibrosis progression (Ishak stage

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Disclosure and contributions: This supplement collects a number of the sessions from the meeting 'Advancing Transplantation: New Questions, New Possibilities'. The meeting was sponsored by Astellas Pharma Europe Ltd; the agenda was developed by Astellas in collaboration with the meeting's scientific committee: J Wadström, BG Ericzon, WO Bechstein, D Serón and PF Halloran. The event was approved by the Federation of the Royal Colleges of Physicians of the United Kingdom for 12 category 1 (external) CPD credits. The scientific committee and faculty developed their own content for the meeting with editorial support from iS Health Group. Editorial support for the meeting was funded by Astellas Pharma Europe Ltd. Previously unpublished data that could not be included, due to existing embargo policies or to protect intellectual property, have been excluded from this report. The unpublished data in this report were included at the discretion of the authors as personal communications. Based on the presentations given at the meeting and under the direction of the authors, iS LifeScience provided editorial support throughout the development of this supplement. Editorial support was funded by Astellas Pharma Europe Ltd. A.L., in his role as the Guest Editor, reviewed this supplement and advised on the content throughout the development process. The authors had final authority over the editorial content and approved the final version of this supplement before submission. Astellas Pharma and associated companies developed, manufacture and supply tacrolimus (tacrolimus hard capsules (Prograf), tacrolimus prolonged-release hard capsules (Advagraf)). Prescribing information and adverse event reporting information can be found on pages S40-S41. J.W. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. B-G.E reports nonfinancial support from Astellas, during the development of this supplement; honoraria and consultancy fees from Astellas, Pfizer and Novartis and clinical trial support from Novartis and Astellas, outside of the submitted work. P.H. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work shares in TSI, a university company with an interest in molecular diagnostics. W.B. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. G.O. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work D.S. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work J.G. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. A.L. reports nonfinancial support from Astellas, during the development of this supplement; nonfinancial support and personal fees from Astellas, outside of the submitted work. 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M.G. reports nonfinancial support from Astellas during the development of this supplement; nonfinancial support from Astellas and personal fees from Astellas, outside the submitted work. ispartof: Transplantation vol:101 issue:2 ispartof: location:United States status: published

AIM To identify objective predictive factors for donor after cardiac death (DCD) graft loss and using those factors, develop a donor recipient stratification risk predictive model that could be used to calculate a DCD risk index (DCD-RI) to help in prospective decision making on organ use. METHODS The model included objective data from a single institute DCD database (2005-2013, n = 261). Univariate survival analysis was followed by adjusted Cox-regressional hazard model. Covariates selected via univariate regression were added to the model via forward selection, significance level P = 0.3. The warm ischemic threshold was clinically set at 30 min. Points were given to each predictor in proportion to their hazard ratio. Using this model, the DCD-RI was calculated. The cohort was stratified to predict graft loss risk and respective graft survival calculated. RESULTS DCD graft survival predictors were primary indication for transplant (P = 0.066), retransplantation (P = 0.176), MELD > 25 (P = 0.05), cold ischemia > 10 h (P = 0.292) and donor hepatectomy time > 60 min (P = 0.028). According to the calculated DCD-RI score three risk classes could be defined of low (DCD-RI < 1), standard (DCD-RI 2-4) and high risk (DCD-RI > 5) with a 5 years graft survival of 86%, 78% and 34%, respectively. CONCLUSION The DCD-RI score independently predicted graft loss (P < 0.001) and the DCD-RI class predicted graft survival (P < 0.001).

Background An association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognized. However, the disease course of IBD following liver transplantation (LT) for PSC remains ill-defined. Aims and methods We aimed to assess the impact of IBD in patients that had undergone LT for PSC to help identify risk factors for flare and to assess the impact of IBD on graft survival. Results 110 patients underwent LT for PSC (Oct 1990-Aug 2009) at King's College Hospital. 74 (67%) patients had concurrent IBD and 36 had PSC alone prior to transplant. 39 patients developed IBD (flare of IBD and de-novo) post transplant. Cumulative risk for IBD at 1-, 2-, 5- and 10-years was 16%, 24%, 38% and 72% respectively. Flare of IBD occurred in 33 patients with a mean time to flare of 30 ± 28 months. De-novo IBD occurred in 6 patients (all UC). Mean time to diagnosis was 29 ± 25 months. Multivariate cox-regression analysis identified active IBD at time of LT as a significant predictor of graft failure post LT (HR 10, CI 3-39, P = 0.001) and smoking at time of transplantation and subsequent cessation predictive of recurrent IBD post transplantation (HR 17, 2-180, P = 0.02). Conclusion In conclusion, smoking at time of LT was predictive of flare of IBD and active IBD at time of transplantation had a significant effect on graft survival. Medical therapy needs to be maximised in the pre-LT period. Patients with poorly controlled IBD refractory to medical therapy should be considered for colectomy at time of transplantation.

Pregnancy constitutes a major challenge to the maternal immune system, as it has to tolerate the persistence of paternal alloantigen. Although localized mechanisms contribute to fetal evasion from immune attack, maternal alloreactive lymphocytes persist. We demonstrate here an alloantigen-independent, systemic expansion of the maternal CD25+ T cell pool during pregnancy and show that this population contains dominant regulatory T cell activity. In addition to their function in suppressing autoimmune responses, maternal regulatory T cells suppressed an aggressive allogeneic response directed against the fetus. Their absence led to a failure of gestation due to immunological rejection of the fetus.

Clinical outcomes, dose changes, and dose-equalized tacrolimus concentrations were examined sequentially in 129 liver transplantation (LT) recipients after successful conversion to once daily modified-release tacrolimus either early (within 1 month) or late (>1 month) after LT. The data were compared with data for a group of 60 patients maintained on twice daily conventional-release tacrolimus. Formulation- and time-dependent changes in dose requirements for once and twice daily tacrolimus differed after transplantation. A 1.7-fold initial increase in the median daily dose was required to achieve target tacrolimus concentrations in the early-conversion cohort (P = 0.006), whereas a 1.25-fold increase was required for those converted later (P = 0.013 and P < 0.001 for the difference). In the subsequent 2 months, the median daily dose fell by 20% in the early-conversion cohort, remained stable for the late-conversion cohort, but rose by 33% with conventional therapy. Lower median dose-equalized concentrations persisted for up to 3 months after the conversion to modified-release therapy. Sex, ethnicity, and the underlying liver disease did not significantly affect these variables. The frequency of treated biopsy-proven acute rejection episodes fell approximately 4-fold after the conversion to modified-release tacrolimus, most notably in the late-conversion cohort, which experienced a high incidence of rejection before conversion. Posttransplant increases in serum creatinine concentrations were smaller after the introduction of modified-release tacrolimus in the late-conversion group (0.7 versus 4 mg/mL for twice daily tacrolimus over 6 months). Reduced interpatient variability in tacrolimus concentrations was evident in the early-conversion cohort versus the twice daily cohort. A decline in intrapatient variability accompanied the reduction in acute rejection in the late-conversion cohort. Our data highlight potential benefits for the rejection rate and renal function on conversion to once daily modified-release tacrolimus late after LT. Liver Transpl 21:29-37, 2015. © 2014 AASLD.

Gene expression profiling was used to explore the role of Nef in HIV. Nef induces a transcriptional program in T cells that is 97% identical to that of anti-CD3 T cell activation. This program is inhibited in the presence of cyclosporin. A requirement for TCRζ and ZAP-70 is demonstrated for formation of the complete profile. Among eight factors particular to the anti-CD3 activation profile are IL16 and YY1, negative regulators of HIV transcription. In contrast, Nef exclusively upregulates factors positively regulating HIV, including Tat-SF1, U1 SNRNP, and IRF-2. New genes associated with Nef include CDK9, the induction of which enhances Tat function. Thus, Nef acts as a master switch early in the viral life cycle, forcing an environment conducive to dynamic viral production.

A consumer-oriented approach to the delivery of health care and an understanding of the processes that influence clinical management decisions require the measurement of what patients seek when they consult their doctor. The present study completed the development of an instrument (the Patient Requests Form) that can quantify the intentions of patients attending their general practitioner. The Patient Requests Form was completed by 410 patients attending two general practices: one in an inner city area, the other in a small town. Principal components analysis revealed that the responses from each sample yielded identical components that described three distinct types of request: (i) for explanation and reassurance, (ii) for emotional support, and (iii) for investigation and treatment. Scales constructed to measure each type of request have high internal consistency while being sufficiently brief to be acceptable to general practice patients. The Patient Requests Form is a novel, convenient method to quantify the intentions of patients when they consult a general practitioner. It permits research into neglected aspects of consultation behaviour, including the factors that influence patients' intentions to seek different kinds of help and GPs' perceptions of these intentions.

Summary Introduction Sun exposure is a major risk factor for the development of skin cancer. This is particularly relevant in immunosuppressed liver-transplant recipients (LTRs). Preventative strategies may help minimize the skin-cancer risk in this patient group. Methods We assessed 670 patients in our post-transplant clinic, using questionnaires. Patient data were collected, and we assessed whether patients had received education (such as formal talks or information from transplant coordinators or from hepatologists) on skin, sun exposure and skin cancer. In a subset of 280 of the LTRs who responded, we recorded their recall of sun-protection advice and assessed the level of patient adherence to such advice. Results The response rate was 57.5% (349/607), with a mean responder age of 51.1 years (range 19–84) and an average post-transplant time of 7.1 years (range 0–27). In the recall assessment, 37.2% reported that they were given advice about their skin, while 18.1% were seen by a dermatologist, and education on sun exposure and the risks of skin cancer was given to 65.6% and 47.9%, respectively. Over three-quarters (78%; 185/280) of the patients used mechanical sun protection (i.e. hats/clothing), while 66% reported using sunscreen; 31.8% of these used a sunscreen of the recommended sun protection factor (SPF) of > 30. Twelve patients had developed squamous cell carcinoma after a mean of 10.9 years (1–23) post-transplant; half of these had used either no sunscreen or one with an SPF of < 15. Conclusions Despite the fact that LTRs are given information on sun-exposure and SC before and after transplantation, recall of such advice and use of sun-protection methods was only moderate, indicating that regular reinforcement of SC education is needed.