Ken Stein

Does Participating in Physical Activity in Outdoor Natural Environments Have a Greater Effect on Physical and Mental Wellbeing than Physical Activity Indoors? A Systematic Review

Our objective was to compare the effects on mental and physical wellbeing, health related quality of life and long-term adherence to physical activity, of participation in physical activity in natural environments compared with physical activity indoors. We conducted a systematic review using the following data sources: Medline, Embase, Psychinfo, GreenFILE, SportDISCUS, The Cochrane Library, Science Citation Index Expanded, Social Sciences Citation Index, Arts and Humanities Citation Index, Conference Proceedings Citation Index--Science and BIOSIS from inception to June 2010. Internet searches of relevant Web sites, hand searches of relevant journals, and the reference lists of included papers and other review papers identified in the search were also searched for relevant information. Controlled trials (randomized and nonrandomized) were included. To be eligible trials had to compare the effects of outdoor exercise initiatives with those conducted indoors and report on at least one physical or mental wellbeing outcome in adults or children. Screening of articles for inclusion, data extraction, and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. Due to the heterogeneity of identified studies a narrative synthesis was performed. Eleven trials (833 adults) were included. Most participants (6 trials; 523 adults) were young students. Study entry criteria and methods were sparsely reported. All interventions consisted of a single episode of walking or running indoors with the same activity at a similar level conducted outdoors on a separate occasion. A total of 13 different outcome measures were used to evaluate the effects of exercise on mental wellbeing, and 4 outcome measures were used to assess attitude to exercise. Most trials (n = 9) showed some improvement in mental wellbeing on one or other of the outcome measures. Compared with exercising indoors, exercising in natural environments was associated with greater feelings of revitalization and positive engagement, decreases in tension, confusion, anger, and depression, and increased energy. However, the results suggested that feelings of calmness may be decreased following outdoor exercise. Participants reported greater enjoyment and satisfaction with outdoor activity and declared a greater intent to repeat the activity at a later date. None of the identified studies measured the effects of physical activity on physical wellbeing or the effect of natural environments on exercise adherence. The hypothesis that there are added beneficial effects to be gained from performing physical activity outdoors in natural environments is very appealing and has generated considerable interest. This review has shown some promising effects on self-reported mental wellbeing immediately following exercise in nature which are not seen following the same exercise indoors. However, the interpretation and extrapolation of these findings is hampered by the poor methodological quality of the available evidence and the heterogeneity of outcome measures employed. The review demonstrates the paucity of high quality evidence on which to base recommendations and reveals an undoubted need for further research in this area. Large, well designed, longer term trials in populations who might benefit most from the potential advantages of outdoor exercise are needed to fully elucidate the effects on mental and physical wellbeing. The influence of these effects on the sustainability of physical activity initiatives also awaits investigation.

A multidimensional conceptual framework for analysing public involvement in health services research

Objective To describe the development of a multidimensional conceptual framework capable of drawing out the implications for policy and practice of what is known about public involvement in research agenda setting.

The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model

OBJECTIVES To investigate whether it is clinically effective and cost-effective to provide (i) a unilateral cochlear implant for severely to profoundly deaf people (using or not using hearing aids), and (ii) a bilateral cochlear implant for severely to profoundly deaf people with a single cochlear implant (unilateral or unilateral plus hearing aid). DATA SOURCES Main electronic databases [MEDLINE; EMBASE; Cochrane Database of Systematic Reviews; CENTRAL; NHS EED; DARE; HTA (NHS-CRD); EconLit; National Research Register; and ClinicalTrials.gov] searched in October 2006, updated July 2007. REVIEW METHODS A systematic review of the literature was undertaken according to standard methods. A state-transition (Markov) model of the main care pathways deaf people might follow and the main complications and device failures was developed. RESULTS The clinical effectiveness review included 33 papers, of which only two were RCTs. They used 62 different outcome measures and overall were of moderate to poor quality. All studies in children comparing one cochlear implant with non-technological support or an acoustic hearing aid reported gains on all outcome measures, some demonstrating greater gain from earlier implantation. The strongest evidence for an advantage from bilateral over unilateral implantation was for understanding speech in noisy conditions (mean improvement 13.2%, p < 0.0001); those receiving their second implant earlier made greater gains. Comparison of bilateral with unilateral cochlear implants plus an acoustic hearing aid was compromised by small sample sizes and poor reporting, but benefits were seen with bilateral implants. Cochlear implants improved childrens quality of life, and those who were implanted before attending school were more likely to do well academically and attend mainstream education than those implanted later. In adults, there was a greater benefit from cochlear implants than from non-technological support in terms of speech perception. Increased age at implantation may reduce effectiveness and there is a negative correlation between duration of deafness and effectiveness. Speech perception measures all showed benefits for cochlear implants over acoustic hearing aids [e.g. mean increase in score of 37 points in noisy conditions (p < 0.001) with BKB sentences]; however, prelingually deafened adults benefited less than those postlingually deafened (mean change scores 20% versus 62%). For unilateral versus bilateral implantation, benefits in speech perception were significant in noisy conditions on all measures [e.g. 76% for HINT sentences (p < 0.0001)]. Quality of life measured with generic and disease-specific instruments or by interview mostly showed significant gains or positive trends from using cochlear implants. The Markov model base-case analysis estimated that, for prelingually profoundly deaf children, the incremental cost-effectiveness ratio (ICER) for unilateral implantation compared with no implantation was 13,413 pounds per quality-adjusted life-year (QALY). Assuming the utility gain for bilateral implantation is the same for adults and children, the ICERs for simultaneous and sequential bilateral implantation versus unilateral implantation were 40,410 pounds and 54,098 pounds per QALY respectively. For postlingually sensorineurally profoundly deaf adults, the corresponding ICERs were 14,163 pounds, 49,559 pounds and 60,301 pounds per QALY respectively. Probabilistic threshold analyses suggest that unilateral implants are highly likely to be cost-effective for adults and children at willingness to pay thresholds of 20,000 pounds or 30,000 pounds per QALY. There are likely to be overall additional benefits from bilateral implantation, enabling children and adults to hold conversations more easily in social situations. CONCLUSIONS Unilateral cochlear implantation is safe and effective for adults and children and likely to be cost-effective in profoundly deaf adults and profoundly and prelingually deaf children. However, decisions on the cost-effectiveness of bilateral cochlear implants should take into account the high degree of uncertainty within the model regarding the probable utility gain.

Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems

BACKGROUND Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations. OBJECTIVES To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS. DATA SOURCES A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion. REVIEW METHODS CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated. RESULTS Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (639 euros) in each of the intervention clinics compared with a 2% (208 euros) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from 41.8 euros per patient per annum to 47.2 euros after implementation of the system. LIMITATIONS The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA. CONCLUSIONS If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs. STUDY REGISTRATION Study registration 61.

Effectiveness of mindfulness-based stress reduction and mindfulness based cognitive therapy in vascular disease: A systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE To determine the effectiveness of mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) on psychological and physical outcomes for people with vascular disease. DESIGN Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES AMED, CINAHL, EMBASE, British Nursing Index, Medline, Web of Science, PsycINFO, Cochrane Database of Systematic Reviews, Central, Social Sciences Citation Index, Social Policy and Practice, and HMIC from inception to January 2013. REVIEW METHODS Articles were screened for inclusion independently by two reviewers. Data extraction and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. Random-effects meta-analyses were performed. RESULTS Nine articles (from eight original randomised controlled trials) met eligibility criteria and were included in the final review. In total, 578 participants were enrolled across the trials, with participants presenting with prehypertension/hypertension (n=3 trials), type 1 or 2 diabetes (n=2), heart disease (n=2) and stroke (n=1). Meta-analyses, using standardised mean differences, showed evidence of reductions in stress (-0.36; 95% CI -0.67 to -0.09; p=0.01), depression (-0.35; 95% CI -0.53 to -0.16; p=0.003) and anxiety (-0.50; 95% CI -0.70 to -0.29; p<0.001). Effects on physical outcomes (blood pressure, albuminuria, stress hormones) were mixed. CONCLUSION Whilst populations with vascular disease appear to derive a range of psychological benefits from MBSR/MBCT intervention, the effects on physical parameters of disease are not yet established. More robust studies, with longer term follow-up, are required to ascertain full effectiveness of such intervention.

Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study

Objective To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes. Design Meta-epidemiological study. Data sources All randomised clinical trials published in 2005 and 2006 in six high impact medical journals: Annals of Internal Medicine, BMJ, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and PLoS Medicine. Study selection Two independent reviewers selected trials. Data extraction Trial characteristics, risk of bias, and outcomes were recorded according to a predefined form. Two reviewers independently checked data extraction. The ratio of odds ratios was used to quantify the degree of difference in treatment effects between the trials using surrogate outcomes and those using patient relevant outcomes, also adjusted for trial characteristics. A ratio of odds ratios >1.0 implies that trials with surrogate outcomes report larger intervention effects than trials with patient relevant outcomes. Results 84 trials using surrogate outcomes and 101 using patient relevant outcomes were considered for analyses. Study characteristics of trials using surrogate outcomes and those using patient relevant outcomes were well balanced, except for median sample size (371 v 741) and single centre status (23% v 9%). Their risk of bias did not differ. Primary analysis showed trials reporting surrogate endpoints to have larger treatment effects (odds ratio 0.51, 95% confidence interval 0.42 to 0.60) than trials reporting patient relevant outcomes (0.76, 0.70 to 0.82), with an unadjusted ratio of odds ratios of 1.47 (1.07 to 2.01) and adjusted ratio of odds ratios of 1.46 (1.05 to 2.04). This result was consistent across sensitivity and secondary analyses. Conclusions Trials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. This finding was not explained by differences in the risk of bias or characteristics of the two groups of trials.

Dasatinib and Nilotinib for Imatinib-Resistant or -Intolerant Chronic Myeloid Leukaemia: A Systematic Review and Economic Evaluation

BACKGROUND Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

Endoscopic Sinus Surgery for the Excision of Nasal Polyps: A Systematic Review of Safety and Effectiveness:

Background Functional endoscopic sinus surgery (FESS) has been used for >20 years for the management of sinus disease including the excision of nasal polyps. Our objective was to perform a systematic review of safety and effectiveness of FESS for the removal of nasal polyps. Methods The Cochrane Library, MEDLINE, Embase, Science Citation Index, other databases, and websites were searched in January and December 2005 using key words for nasal polyps and endoscopic surgery. All randomized controlled trials, nonrandomized comparative studies, and case series studies that described outcomes associated with FESS for the excision of nasal polyps were included. Forty-two publications were included from the 632 (6.6%) articles initially identified. Two reviewers assessed validity of included studies and extracted relevant data. Results Three randomized controlled trials, 4 nonrandomized comparative studies, and 35 case series studies were included in the review. FESS was compared with endoscopic polypectomy, Caldwell-Luc, radical nasalization, and intranasal ethmoidectomy. In general, studies were of poor quality and lacked description of important variables influencing surgical outcome. Overall complications for FESS from case series studies ranged from 0.3 to 22.4% (median, 7.0%). Major complications ranged from 0 to 1.5% (median, 0%) and minor complications ranged from 1.1 to 20.8% (median, 7.5%). The potentially most serious complications were cerebrospinal fluid leaks, injury to the internal carotid artery, dural exposure, meningitis, bleeding requiring transfusion, periorbital/orbital fat exposure, and orbital penetration. Symptomatic improvement ranged from 78 to 88% for FESS compared with 43 to 84% for comparative procedures. From case series, symptomatic improvement ranged from 40 to 98% (median, 88%). Conclusion FESS may offer some advantages in safety and effectiveness over comparative techniques, but wide variation in reported results and methodological shortcomings of studies limit the certainty of these conclusions. Wide variation in complication rates suggests the need for audit of existing practice. Additional high-quality studies with a fuller description of potential confounding factors and effect modifiers will help to define the effectiveness of FESS more clearly.

The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders.

OBJECTIVES To determine natural history and estimate effectiveness and cost of enzyme replacement therapy (ERT) and substrate replacement therapy (SRT) for patients with Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann-Pick type C (NPC) disease. DESIGN Cohort study including prospective and retrospective clinical- and patient-reported data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. SETTING National Specialised Commissioning Group-designated lysosomal storage disorder (LSD) treatment centres in England. PARTICIPANTS Consenting adults and children with a diagnosis of Gaucher disease (n = 272), Fabry disease (n = 499), MPS I (n = 126), MPS II (n = 58), NPC (n = 58) or Pompe disease (n = 93) who had attended a treatment centre in England. INTERVENTIONS ERT and SRT. MAIN OUTCOME MEASURES Clinical outcomes chosen by clinicians to reflect disease progression for each disorder; patient-reported quality-of-life (QoL) data; cost of treatment and patient-reported service-use data; numbers of hospitalisations, outpatient and general practitioner appointments; medication use; data pertaining to associated family/carer costs and QoL impacts. RESULTS Seven hundred and eleven adults and children were recruited. In those with Gaucher disease (n = 175) ERT was associated with improved platelet count, haemoglobin, liver function and reduced risk of enlarged liver or spleen. No association was found between ERT and QoL. In patients with Fabry disease (n = 311) increased time on ERT was associated with small decreases in left ventricular mass and improved glomerular filtration rate, but not with changes in risk of stroke/transient ischaemic attacks or the need for a hearing aid. There was a statistically significant association between duration of ERT use and worsening QoL and fatigue scores. We found no statistical difference in estimates of treatment effectiveness between the two preparations, agalsidase beta (Fabrazyme(®), Genzyme) (n = 127) and agalsidase alpha (Replagal(®), Shire HGT) (n = 91), licensed for this condition. In Pompe disease (n = 77) our data provide some evidence of a beneficial effect on muscle strength and mobility as measured by a 6-minute walk test in adult-onset patients; there were insufficient data from infantile-onset Pompe patients to estimate associations between ERT and outcome. Among subjects with MPS I (n = 68), 42 of the 43 patients with MPS I subtype Hurlers disease had undergone a bone marrow transplant. No significant associations were found between ERT and any outcome measure for the MPS I subtype Scheie disease and heparan sulphate patients. An association between duration of ERT and growth in children was the only statistically significant finding among patients with MPS II (n = 39). There were insufficient data for patients with NPC disease to draw any conclusions regarding the effectiveness of SRT. The current annual cost to the NHS of the different ERTs means that between 3.6 and 17.9 discounted quality-adjusted life-years (QALYs) for adult patients and between 2.6 and 10.5 discounted QALYs for child patients would need to be generated for each year of being on treatment for ERTs to be considered cost-effective by conventional criteria. CONCLUSIONS These data provide further evidence on the effectiveness of ERT in people with LSDs. However, the results need to be interpreted in light of the fact that the data are observational and the relative lack of power due to the small numbers of patients with MPS I, MPS II, Pompe disease and NPC disease. Future work should aim to effectively address the unanswered questions and this will require agreement on a common set of outcome measures and their consistent collection across all treatment centres. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 39. See the HTA programme website for further project information.

Surveillance of cirrhosis for hepatocellular carcinoma: a cost–utility analysis

Using a decision-analytic model, we evaluated the effectiveness and cost-effectiveness of surveillance for hepatocellular carcinoma (HCC) in individuals with cirrhosis. Separate cohorts with cirrhosis due to alcoholic liver disease, hepatitis B and hepatitis C were simulated. Results were also combined to approximate a mixed aetiology population. Comparisons were made between a variety of surveillance algorithms using α-foetoprotein (AFP) assay and/or ultrasound at 6- and 12-monthly intervals. Parameter estimates were obtained from comprehensive literature reviews. Uncertainty was explored using one-way and probabilistic sensitivity analyses. In the mixed aetiology cohort, 6-monthly AFP+ultrasound was predicted to be the most effective strategy. The model estimates that, compared with no surveillance, this strategy may triple the number of people with operable tumours at diagnosis and almost halve the number of people who die from HCC. The cheapest strategy employed triage with annual AFP (incremental cost-effectiveness ratio (ICER): £20 700 per quality-adjusted life-year (QALY) gained). At a willingness-to-pay threshold of £30 000 per QALY the most cost-effective strategy used triage with 6-monthly AFP (ICER: £27 600 per QALY gained). The addition of ultrasound to this strategy increased the ICER to £60 100 per QALY gained. Surveillance appears most cost-effective in individuals with hepatitis B-related cirrhosis, potentially due to younger age at diagnosis of cirrhosis. Our results suggest that, in a UK NHS context, surveillance of individuals with cirrhosis for HCC should be considered effective and cost-effective. The economic efficiency of different surveillance strategies is predicted to vary markedly according to cirrhosis aetiology.