High frequency and mortality of head and neck malignancy in organ transplant recipients in Ireland - A national cohort study.

BACKGROUND: Solid organ transplant recipients are recognized to carry a high burden of malignancy and frequently this cancer develops in the head and neck region. Furthermore, cancer of the head and neck post-transplant carries a significantly increased mortality. In this study, we aim to conduct a national retrospective cohort study to investigate the impact of head and neck cancer in terms of frequency and mortality in a large group of solid organ transplant recipients over a 20 year time span and compare the mortality in transplant patients to non-transplant patients with head and neck cancer. METHODS: Patients in the Republic of Ireland who underwent solid organ transplantation between 1994 and 2014 who developed post-transplant head and neck malignancy were identified from the records of two prospective, national databases (National Cancer Registry of Ireland (NCRI) and The Irish Transplant Cancer Group database) working in conjunction with each other. Incidence of head and neck malignancy post-transplant was compared with the general population by means of standardised incidence ratios (SIR). Cumulative incidence of all cause and cancer related mortality from head and neck keratinocytic was undertaken by a competing risks analysis. RESULTS: A total of 3346 solid organ transplant recipients were identified, 2382 (71.2 %) kidney, 562 (16.8 %) liver, 214 (6.4 %) cardiac and 188 (5.6 %) lung. During the period of follow up of 428 patients developed head and neck cancer, representing (12.8 %) of the population. 97 % of these patients developed keratinocytic cancers, specifically, of head and neck. The frequency of post-transplant head and neck cancer was related to the duration of immunosuppression with 14 % of patients developing cancer at 10 years and 20 % having developed at least one cancer by 15 years. 12 (3 %) patients developed non-cutaneous head and neck malignancy. 10 (0.3 %) patients died due to head and neck keratinocytic malignancy post-transplant. Competing risk analysis demonstrated that organ transplantation conferred a strong independent effect of death, compared to non-transplant patients with head and neck keratinocytes. This applied specifically for kidney (HR 4.4, 95 % CI 2.5-7.8) and heart transplants (HR 6.5, 95 % CI 2.1-19.9), and overall, across the four transplant categories (P < 0.001). The SIR of developing keratinocyte cancer varied based on primary tumor site, gender, and type of transplant organ. CONCLUSION: Transplant patients demonstrate a particularly high rate of head and neck keratinocyte cancer with a very high rate of associated mortality. Physicians should be cognizant of the increased rate of malignancy in this population and monitor for red flag signs/symptoms.

Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients.

BACKGROUND: Non-adherence to immunosuppressant therapy is a significant concern following a solid organ transplant, given its association with graft failure. Adherence to immunosuppressant therapy is a modifiable patient behaviour, and different approaches to increasing adherence have emerged, including multi-component interventions. There has been limited exploration of the effectiveness of interventions to increase adherence to immunosuppressant therapy. OBJECTIVES: This review aimed to look at the benefits and harms of using interventions for increasing adherence to immunosuppressant therapies in solid organ transplant recipients, including adults and children with a heart, lung, kidney, liver and pancreas transplant. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 14 October 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs, and cluster RCTs examining interventions to increase immunosuppressant adherence following a solid organ transplant (heart, lung, kidney, liver, pancreas) were included. There were no restrictions on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts of identified records, evaluated study quality and assessed the quality of the evidence using the GRADE approach. The risk of bias was assessed using the Cochrane tool. The ABC taxonomy for measuring medication adherence provided the analysis framework, and the primary outcomes were immunosuppressant medication initiation, implementation (taking adherence, dosing adherence, timing adherence, drug holidays) and persistence. Secondary outcomes were surrogate markers of adherence, including self-reported adherence, trough concentration levels of immunosuppressant medication, acute graft rejection, graft loss, death, hospital readmission and health-related quality of life (HRQoL). Meta-analysis was conducted where possible, and narrative synthesis was carried out for the remainder of the results. MAIN RESULTS: Forty studies involving 3896 randomised participants (3718 adults and 178 adolescents) were included. Studies were heterogeneous in terms of the type of intervention and outcomes assessed. The majority of studies (80%) were conducted in kidney transplant recipients. Two studies examined paediatric solid organ transplant recipients. The risk of bias was generally high or unclear, leading to lower certainty in the results. Initiation of immunosuppression was not measured by the included studies. There is uncertain evidence of an association between immunosuppressant medication adherence interventions and the proportion of participants classified as adherent to taking immunosuppressant medication (4 studies, 445 participants: RR 1.09, 95% CI 0.95 to 1.20; I² = 78%). There was very marked heterogeneity in treatment effects between the four studies evaluating taking adherence, which may have been due to the different types of interventions used. There was evidence of increasing dosing adherence in the intervention group (8 studies, 713 participants: RR 1.14, 95% CI 1.03 to 1.26, I² = 61%).  There was very marked heterogeneity in treatment effects between the eight studies evaluating dosing adherence, which may have been due to the different types of interventions used. It was uncertain if an intervention to increase immunosuppressant adherence had an effect on timing adherence or drug holidays. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on persistence. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on secondary outcomes. For self-reported adherence, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants classified as medically adherent to immunosuppressant therapy (9 studies, 755 participants: RR 1.21, 95% CI 0.99 to 1.49; I² = 74%; very low certainty evidence). Similarly, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the mean adherence score on self-reported adherence measures (5 studies, 471 participants: SMD 0.65, 95% CI -0.31 to 1.60; I² = 96%; very low certainty evidence). For immunosuppressant trough concentration levels, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants who reach target immunosuppressant trough concentration levels (4 studies, 348 participants: RR 0.98, 95% CI 0.68 to 1.40; I² = 40%; very low certainty evidence). It is uncertain whether an intervention to increase adherence to immunosuppressant medication may reduce hospitalisations (5 studies, 460 participants: RR 0.67, 95% CI 0.44 to 1.02; I² = 64%; low certainty evidence). There were limited, low certainty effects on patient-reported health outcomes such as HRQoL. There was no clear evidence to determine the effect of interventions on secondary outcomes, including acute graft rejection, graft loss and death. No harms from intervention participation were reported. AUTHORS' CONCLUSIONS: Interventions to increase taking and dosing adherence to immunosuppressant therapy may be effective; however, our findings suggest that current evidence in support of interventions to increase adherence to immunosuppressant therapy is overall of low methodological quality, attributable to small sample sizes, and heterogeneity identified for the types of interventions. Twenty-four studies are currently ongoing or awaiting assessment (3248 proposed participants); therefore, it is possible that findings may change with the inclusion of these large ongoing studies in future updates.

Andrew K. Burroughs: a research hepatologist extraordinaire.

Andrew K (Andy) Burroughs passed away in March 2014 at the early age of 60 years. Andy was one of the last of the great all round giants of hepatology. He was a consummate physician, clinical investigator and educator. Over a period of 35 years at the Royal Free Hospital Liver Unit he produced a prodigious quantity of original research and made major contributions in many areas of hepatology including portal hypertension, liver transplantation and chronic liver disease. His work on the methodology of clinical trials is carried on by the Baveno consensus meetings. From bedside clinical mastery to early molecular biology applications to diagnosis and pathology, his contributions left a mark in liver science and advanced medical science in general. He also was praised by his work in medical education particularly in post-graduate mentorship and, an admirable human touch with patients. We will not see his like again.

Repeatability of transient elastography in children.

BACKGROUND: Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children. METHODS: TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination. RESULTS: The normal range of TE was 2.88-6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from -0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups. CONCLUSIONS: This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements. IMPACT: The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted. TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease. This study demonstrates that TE does not have adequate precision in children. This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

Post-transplant malignancy in solid organ transplant recipients in Ireland, The Irish Transplant Cancer Group.

OBJECTIVE: Solid organ transplant recipients are at increased risk of cancer compared to the general population. To date, this risk in Ireland has not been investigated. We conducted a national registry study of cancer incidence following solid organ transplantation. METHODS: National centers for solid organ transplantation supplied their respective registry databases to cross-reference with episodes of malignancy from the National Cancer Registry Ireland (NCRI) between 1994 and 2014. Standardized incidence of cancer post-transplant was compared to the general population by means of standardized incidence ratios (SIRs), and between solid organ transplant types by incidence rate ratios. RESULTS: A total of 3346 solid organ transplant recipients were included in this study. Kidney transplant recipients constituted the majority of participants (71.2%), followed by liver (16.8%), heart (6.4%), and lung (5.6%) transplants. The most common cancers within the composite of all transplant recipients included the following (SIR [95% CI]): squamous and basal cell carcinoma (20.05 [17.97, 22.31] and 7.16 [6.43, 7.96], respectively), non-Hodgkin lymphoma (6.23 [4.26, 8.59]), and renal cell carcinoma (3.36 [1.96, 5.38]). CONCLUSIONS: This study reports the incidence of cancer following solid organ transplantation in Ireland. These results have significant national policy implications for surveillance, and early diagnosis in this patient group.

A carboxymethylcellulose-heparin combination for the prevention of surgical adhesions.

BACKGROUND: Adhesions are a major clinical problem after abdominal surgery. Despite decades of research, therapies to prevent adhesion formation are suboptimal. MATERIALS AND METHODS: We have investigated combinations of carboxymethylcellulose (CMC) and heparin at preventing surgical adhesions in two rat models of adhesion formation. The first was the well-established cecal abrasion model, and the second was a model developed in our laboratory, the avascular mesenteric knot model. This model consistently produced adhesions at the knot in 90% of experiments and causes little or no tissue injury. RESULTS: Topical administration of CMC 4% gave optimal results in the avascular knot model, but was less effective in the cecal abrasion model. This concentration of CMC was combined with a range of heparin doses between 0.5 and 160 IU/mL in the cecal abrasion model. These heparin doses, apart from the lowest (0.5 IU/mL), were effective in preventing adhesion formation in combination with CMC, as was the commercially available topical product Lipactin. The optimal dose was 30 IU/mL, that abolished adhesions, but there was little difference at doses between 2 and 160 IU. Heparin was effective in doses as low as 2 IU/mL when in combination with CMC. Heparin 160 IU/mL, but not heparin 30 IU/mL or Lipactin, significantly increased the degree of bleeding post cecal abrasion surgery. CONCLUSIONS: Topical application of tiny doses of heparin, in combination with CMC 4% gel, significantly reduces adhesion formation in experimental models. We suggest that this cheap and, as far as we know, safe intervention should be evaluated in human clinical trials.

Liver transplantation in Ireland.

The Irish National Liver Transplant program commenced in 1993 in St. Vincent's University Hospital in Dublin. It is an adult-only program and is the only liver transplant program in Ireland. Pediatric recipients are referred to King's College Hospital in the United Kingdom. To date, almost 1000 adult liver transplants have been performed. Current 1-year patient survival is 93%, and 5-year survival is 79%. The program is fully funded by the government health service. There is a close collaboration with the United Kingdom Organ Donation and Transplant Directorate, and there is an arrangement for organ sharing for super-urgent transplants. Traditionally, organ donation rates have been high in Ireland. However, demand for liver transplant has increased over the past 20 years, and waiting lists are now lengthening. Deceased cardiac death donation is now being considered, but there are no plans for living related donor liver transplant. Donor coordinators have recently been appointed to the major hospitals in Ireland, and it is hoped that this initiative will lead to an increase in organ donation rates. Liver Transplantation 22 1014-1018 2016 AASLD.

Spleen stiffness can non-invasively assess resolution of portal hypertension after liver transplantation.

BACKGROUND & AIMS: Spleen stiffness can be measured by transient elastography. Recent studies have shown that spleen stiffness correlates with hepatic venous pressure gradient and can predict oesophageal varices. Elevated spleen stiffness in cirrhosis has been attributed to splenic tissue hyperplasia and fibrosis, portal hypertension and its consequent hyperdynamic circulation. The aim of this study was to investigate changes to spleen stiffness after orthotopic liver transplantation (OLT) when portal hypertension resolves. METHODS: Twenty-one patients awaiting OLT were studied prospectively, while 11 post-transplant patients were recruited as controls. Spleen and liver stiffness were measured with Fibroscan before and at 2-8 weeks after OLT. Criteria applied for spleen stiffness measurement were similar to liver stiffness (≥10 measurements; ≥60% success rate; interquartile range, IQR <30% of median). RESULTS: Spleen stiffness was significantly higher before OLT compared to post-transplant patients [75.0 (63.9-75.0) kPa vs. 28.4 (22.0-37.5) kPa; P < 0.0001]. For patients awaiting OLT, 90% (19/21) had oesophageal varices (endoscopically or radiologically). In patients who underwent liver transplantation, spleen stiffness decreased significantly from a median of 75.0 (62.0-75.0) kPa before OLT, to 41.9 (27.0-47.4) kPa at 2 weeks after transplant and 32.9 (29.1-38.0) kPa in the subsequent 4-8 weeks after OLT (P < 0.0001). As expected, liver stiffness measurements reduced from 39.3 (24.9-75.0) kPa to 8.6 (6.8-11.8) kPa in patients receiving OLT (P = 0.0004). CONCLUSIONS: Spleen stiffness can non-invasively assess changes in portal pressure after liver transplantation and decreases significantly when portal hypertension resolves.

Liver transplant associated with paracetamol overdose: results from the seven-country SALT study.

AIMS: Acute drug overdose, especially with paracetamol, may cause acute liver failure leading to registration for transplantation (ALFT). Population statistics and between-country differences for ALFT related to overdose have been poorly described. The aim of the present study was to evaluate overdose ALFT in the multi-country Study of Acute Liver Transplantation (SALT). METHODS: All adult overdose-related ALFT, with or without suicidal intent, in France, Greece, Ireland, Italy, the Netherlands, Portugal and the UK between 2005 and 2007 were identified from liver transplant registries and hospital records. These were compared with whole-country and per capita use of paracetamol. RESULTS: Six hundred cases of ALFT were identified in 52 of 57 eligible transplant centres, of which 114 involved overdose (72 intentional, 10 non-intentional, 32 uncertain). Overdose represented 20% of all-cause ALFT: Ireland 52%, UK 28%, France 18%, the Netherlands 8%, and Italy 1%. Overdose ALFT were mostly females (61%), mean age 33.6 ± 10.9 years. A total of 111 (97%) of the overdoses involved paracetamol. Event rates ranged from one ALFT for 20.7 tons of paracetamol in Ireland, to one for 1074 tons in Italy and one case in 60 million inhabitants over 3 years in Italy to one case in 286 000 inhabitants per year in Ireland. Per-country event rates for non-overdose ALFT exposed to paracetamol were between 2.5 and 4.0 per million treatment-years sold. CONCLUSIONS: Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants.

Hepatitis C in the era of direct-acting antivirals: real-world costs of untreated chronic hepatitis C; a cross-sectional study.

BACKGROUND: Recent advances in Hepatitis C therapeutics offer the possibility of cure but will be expensive. The cost of treatment may be partially offset by the avoidance of advanced liver disease. We performed a micro-costing study of the ambulatory healthcare utilisation of patients with Hepatitis C supplemented with inpatient diagnosis related group costs. METHODS: The staff utilisation costs associated with a Hepatitis C ambulatory visit were measured and combined with the costs of investigations to establish a mean cost per consultation. An annualised estimate of cost was produced by multiplying this by the number of consultations accessed, stratified by degree of liver impairment. Inpatient costs were established by identifying the number of inpatient episodes and multiplying by Irish diagnosis related group costs. Non-parametric bootstrapping was performed to derive mean and 95%CI values. RESULTS: Two hundred and twenty-five patients were identified. The cost of an outpatient medical review was €136 (€3.60 SD). The cost of a Hepatitis C nursing review was €128 (€7.30 SD). The annual mean costs of care were as follows (95%CI): Mild €398 (€336, €482), Moderate €417(€335, €503), Compensated cirrhosis €1790 (€990, €3164), Decompensated cirrhosis €8302 (€3945, €14,637), Transplantation Year 1 €137,176 (€136,024, €138,306), Transplantation after Year 1 €5337 (€4942, €5799), Hepatocellular carcinoma €21,992 (€15,222, €29,467), Sustained virological response €44 (€16, €73). CONCLUSIONS: The direct medical cost associated with Hepatitis C care in Ireland is substantial and increases exponentially with progression of liver disease. The follow-up costs of patients with a sustained virological response in this cohort were low in comparison to patients with chronic infection.

Hepatitis C community prevalence is over-estimated: a prospective, birth cohort study.

BACKGROUND: Hepatitis C virus infection is often asymptomatic, and many patients may be unaware they are infected. Community-based, birth cohort screening has been advocated to identify these patients. It has been estimated that 0.7-1% of individuals born between 1965 and 1985 in Ireland are infected. The cost-effectiveness of screening is critically dependent on the population prevalence. AIMS: The aim is to determine the community prevalence of hepatitis C virus infection in the birth cohort 1965-1985. METHODS: Residual serum samples from blood tests ordered by community general practitioners were anonymised and analysed for the presence of hepatitis C antibody ± antigen. Twelve large general hospitals throughout the country participated. RESULTS: A total of 14,320 samples were tested, 9347 of which were from the birth cohort 1965-1985. Seventy-two samples were positive for hepatitis C antibody of which 12 were positive for hepatitis C antigen (17%). The overall prevalence of hepatitis C antigen in the birth cohort was 0.09%. A higher prevalence (0.39%) was identified in males in two urban areas of Dublin. CONCLUSIONS: Hepatitis C virus seroprevalence was much lower than previously estimated. The proportion of antibody positive patients with hepatitis C antigen was also lower than expected suggesting the effects of treatment and/or high spontaneous viral clearance. Universal birth cohort screening is unlikely to be cost-effective. Targeted birth cohort screening in high prevalence areas could be considered.

Recurrent sclerosing cholangitis post-transplant: increased recurrence rates following re-transplantation.

Sclerosing cholangitis recurs in some patients following liver transplantation. These high-risk patients may provide clues to the pathogenesis of this disease. AIMS: In this single-center study, from a high prevalence area, we investigated the incidence of recurrent sclerosing cholangitis following liver transplantation and re-transplantation. METHODS: A retrospective cohort study of all patients with primary sclerosing cholangitis transplanted in the Irish National Liver Transplant program between 1993 and 2019. RESULTS: Recurrent sclerosing cholangitis occurred in 23/112 patients (20.7%). Overall patient survival was similar in the recurrence and non-recurrence groups. Nine patients were re-transplanted for recurrent disease. Patients with recurrence were significantly younger (42.7 + - 2.5 years vs. 49.3 + - 1.3 p < 0.05), and colectomy post-transplant was performed more frequently in the recurrence group (6/21 vs. 9/81 p < 0.05). Further recurrence after re-transplantation was identified in 6/9 patients and was identified a shorter time after transplant than the first recurrence (median 41.5 months; range 26-53 vs. median 65.5; range 38: p < 0.05). DISCUSSION/CONCLUSION: Recurrent PSC following liver transplantation is common, particularly in younger patients. It occurs earlier and is more frequent following a second transplant.

Non-cirrhotic portal hypertension (obliterative portal venopathy) is the predominant form of chronic liver disease in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF)-associated liver disease commonly manifests as portal hypertension and its complications. We investigated the proposal that the pathophysiology is of non-cirrhotic rather than cirrhotic portal hypertension. This distinction may have important implications for treatment. METHODS: We compared liver transplant explants from cystic fibrosis patients with explants from patients with classical cholestatic diseases, primary biliary cholangitis and primary sclerosing cholangitis. Presence of cirrhosis, fibrosis, nodular regenerative hyperplasia, biliary and portal venous pathology were recorded. Quantitation of portal venules in representative section was performed. RESULTS: Nine patients with cystic fibrosis liver disease, 7 primary biliary cholangitis (PBC) and 7 primary sclerosing cholangitis (PSC) were evaluated. Cirrhosis was present in 0/9 of CF patients and 11/14 of the PBC and PSC controls (p < 0.01). Nodular regenerative hyperplasia was present in 8/9 of the CF patients but none of the controls (p < 0.01). Portal venule numbers per 15 mm2 section were significantly lower in the CF patients 52 (20-72) compared to the primary biliary cholangitis 78 (47-110) and primary sclerosing cholangitis patients, 79 (41-134) (p < 0.05). Portal sclerotic nodules were found in all the CF patients but in only one of the controls (9/9 vs 1/14 p < 0.01). CONCLUSIONS: This study demonstrates that non-cirrhotic portal hypertension or obliterative portal venopathy is the predominant hepatic pathophysiology in adult CF patients requiring liver transplantation. It suggests that treatments directed at the hepatic portal venous system may be more effective than current treatment directed at the biliary system in cystic fibrosis.

The natural history of cystic fibrosis liver disease a prospective cohort study.

BACKGROUND: Our understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. AIM: to determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). METHODS: The Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) RESULTS: 480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99-10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD. During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59-12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44-3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77-1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. CONCLUSION: The incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children.

It's a man's world: does orthotopic liver transplantation in the elderly male confer an additional risk on survival?

BACKGROUND: Orthotopic liver transplantation (OLT) in a well-selected population is a highly successful procedure, with one-year survival rates reported to be as high as 90%. Advanced age is considered to be a contraindication. Survival rates in patients >60 years of age appear to be comparable with those of younger patients. However, little objective data exist on the outcomes of patients >65 years of age undergoing OLT. OBJECTIVE: To review the outcomes of OLT in the Irish National Transplant Unit in patients >65 years of age and to compare outcomes with patients ≤65 years of age. Second, to identify any factors that may provide valuable prognostic information regarding outcomes. METHOD: Patients >65 years of age who underwent OLT since the inception of the National Liver Unit in 1993 were identified from a prospectively maintained database. Medical records were reviewed. Survival was compared with the overall cohort using the Kaplan-Meier technique. Independent variables between the two groups were assessed using logistic regression analysis. RESULTS: Between January 1993 and December 2009, 551 patients underwent 639 transplants in the Irish National Liver Transplant Unit. Forty-three transplants were performed in 40 patients >65 years of age. Unadjusted one- and three-year survival rates for the elderly cohort were 77.8% and 64.5%, respectively. This compared with 93% and 85%, respectively, in the unselected cohort. Using Kaplan-Meier analysis, a significant benefit in survival was observed in patients ≤65 years of age (P=0.017). Similarly, when adjusted for sex, a significant difference was noted between the groups. Male patients >65 years of age had poorer survival compared with their female counterparts >65 years of age and all patients ≤65 years of age (P=0.02). There was no significant difference between the groups with respect to preoperative variables such as bilirubin, creatinine and sodium levels, and Model for End-stage Liver Disease score. A significant difference was seen in male patients >65 years of age with more than one comorbidity, compared with female patients and male patients ≤65 years of age. CONCLUSION: Male sex was associated with poorer survival in patients >65 years of age undergoing OLT. Multiple comorbidities in elderly male patients should be considered a relative contraindication in patients being assessed for OLT.

Milestones in the discovery of hepatitis C.

The discovery of hepatitis C has been a landmark in public health as it brought the opportunity to save millions of lives through the diagnosis, prevention and cure of the disease. The combined work of three researchers, Alter H, Houghton M and Rice C, which set the basis for the diagnosis, treatment and prevention of hepatitis C apart from laying the ground work for a new approach to study infections in general and developing new antiviral agents. This is a story of a transfusion-associated infection. A series of clinical studies demonstrated the existence of an infectious agent associated with hepatitis. That was followed by the identification of what was later known to be the hepatitis C virus (HCV) and the development of diagnostic tests. It all preceded the full molecular identification and demonstration of a causal effect. Finally it ended up with the development and discovery of a new class of therapeutic drugs, the direct acting antivirals, which are now used not only to cure the disease but most probably, to eliminate the problem. This work started with Dr Alter H who demonstrated that a new virus was responsible for the majority of post-transfusion hepatitis followed by Houghton M who cloned the virus and developed the blood test to identify those cases that carried the virus. Finally, the work of Rice C demonstrated that a cloned HCV produced after applying molecular biology techniques could cause long-standing infection and cause the same disease as the one observed in humans.

Increasing radiation exposure from computed tomography in liver transplant recipients over time.

OBJECTIVES: To evaluate changes in radiation exposure from computed tomography (CT) among patients undergoing liver transplantation in our unit over a 10-year period. METHODS: We evaluated 134 elective patients, without hepatocellular carcinoma or cholangiocarcinoma who underwent transplantation in 2007-2008 and 2017-2018. CT scans performed in our hospital up to 2 years pre transplant and 1 year post transplant were evaluated. RESULTS: There was an increase in mean estimated effective radiation dose per patient in 2017-2018 compared to 2007-2008 (77.8 mSv ± 6.2 vs 56.7 mSv ± 5.9, p < 0.05). This change was mainly due to an increased number of pre-transplant CT scans per patient (2.9 ± 0.3 vs 1.4 ± 0.14, p = 0.0001). High radiation dose scan protocols were more frequently used in 2017-2018, with 4-phase liver CT accounting for a larger proportion of scans both pre-transplant (61% vs 43%, p = 0.004) and post-transplant (29% vs 13%, p = 0.002). A greater proportion of patients were exposed to > 100 mSv of ionising radiation in the 2017-2018 patients (29% vs 11%, p < 0.01). These figures are likely to be a significant under-estimate as they exclude other imaging modalities and CT scans performed at other institutions. CONCLUSION: Radiation exposure from diagnostic imaging has increased among liver transplant recipients at our institution over the last decade. This appears to be due to an increase in the number of CT scans performed, and a shift towards higher dose scan protocols.

Both α1B- and α1A-adrenoceptor subtypes are involved in contractions of rat spleen.

BACKGROUND: The spleen is a reservoir for circulating blood cells, and can contract to expel them. METHODS: We have investigated the adrenoceptors involved in isometric contractions of rat spleen produced by noradrenaline (NA) and the α1-adrenoceptor agonist phenylephrine (Phe). RESULTS: Contractions to NA were antagonized by both the α1-adrenoceptor antagonist prazosin (10-8 M) and the α2-adrenoceptor antagonist yohimbine (10-6M), and the combination produced further shifts in NA potency. Contractions to Phe were antagonized by prazosin (10-8 M) which caused a marked parallel shift in the concentration-response curve. High non-selective concentrations of the α1D-adrenoceptor antagonist BMY7378 (10-6 M), the α1A-adrenoceptor antagonist RS100329 ((3 × 10-8 M), and the putative α1B-adrenoceptor antagonist cyclazosin (10-8 M) also produced parallel shifts in the Phe concentration-response curve. BMY7378 at the selective concentration of 3 × 10-8 M had no effect on responses to Phe, but RS100329 in the selective concentration of 3 × 10-9 M produced a marked shift in the effects of high concentrations of Phe. Hence, antagonists in concentrations that block both α1A- and α1B-adrenoceptors produce approximately parallel shifts in Phe potency. CONCLUSIONS: Contractions of rat spleen to adrenergic agonists involve α2- and α1B-adrenoceptors, with a lesser role for α1A-adrenoceptors. This confirms the suggestion that smooth muscle contractions commonly involve multiple subtypes.