Lessons from the Gateway programme, aimed at improving health and life chances for young people committing low-level offences: a qualitative evaluation.

BACKGROUND: Young people who commit criminal offences are often affected by mental health issues, including drug and alcohol misuse, with many leading chaotic lifestyles. Gateway was a pioneering court-diversion programme aimed to reduce reoffending and improve the health and wellbeing of people aged 18-24 years who had been questioned for a low-level offence. The Gateway Study consisted of a pragmatic, parallel-group, superiority randomised controlled trial (RCT) of the programme's effectiveness, and its qualitative evaluation. We aimed to determine barriers and enablers for implementation of Gateway and recruitment into the RCT. METHODS: We evaluated the implementation of Gateway, a 16-week conditional caution designed by Hampshire Constabulary and delivered predominantly by third sector organisations. Following a needs assessment, young people received individual support from a Gateway navigator and attended self-development workshops. Recruitment into the RCT took place across four sites across Hampshire and Isle of Wight, UK. Semi-structured interviews were carried out with Gateway stakeholders over three time periods in 2018-22, with additional timepoints in the first time period. Purposive samples of Gateway clients and recruiters, as well as all of Gateway staff, were interviewed. Thematic analysis was applied, with an inductive and predominantly reflexive approach, for each group of participants in each time period. FINDINGS: Between Dec 19, 2018, and May 3, 2022, qualitative interviews were held with 28 Gateway clients, 17 Gateway project staff, and 13 police officers and civilian staff who acted as recruiters into the programme and RCT. Various themes related to engagement were identified, with multiple subthemes and unique insights. The core themes can be classified as follows (with examples of factors influencing engagement): (1) setup for Gateway delivery and RCT recruitment (eg, multi-agency partnerships, physical locations, training); (2) young people's lifestyles and needs (eg, personal circumstances, pre-existing expectations, attitude towards Gateway); (3) priorities and culture in the organisations (eg, workload priorities, job satisfaction, inter-stakeholder relationships). INTERPRETATION: The Gateway Study was a unique endeavour to gather evidence for a potentially life-changing intervention for an underserved population. Engaging vulnerable young people and the police in research comes with its own, specific challenges. The insights shared as a result of this evaluation can inform the design of interventions and studies that target similarly vulnerable people or are based in similar settings. Awareness of the potential barriers and facilitators can help public health researchers and practitioners plan accordingly and prevent or mitigate some of the low-engagement issues. FUNDING: National Institute for Health and Care Research (NIHR).

Liver Fibrosis Assessed Via Noninvasive Tests Is Associated With Incident Heart Failure in a General Population Cohort.

BACKGROUND & AIMS: The aim of this study was to determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association. METHODS: Using UK Biobank data, we prospectively examined the relationship between noninvasive fibrosis markers (nonalcoholic fatty liver disease [NAFLD] fibrosis score [NFS], Fibrosis-4 [FIB-4] and aspartate transaminase [AST] to platelet ratio index [APRI]) and incident hospitalization/death from heart failure (n = 413,860). Cox-regression estimated hazard ratios (HRs) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. RESULTS: A total of 12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high-risk NFS score HR, 1.59; 95% confidence interval [CI],1.47-1.76; P < .0001; FIB-4 HR, 1.69; 95% CI, 1.55-1.84; P < .0001; APRI HR, 1.85; 95% CI, 1.56-2.19; P < .0001; combined fibrosis scores HR, 1.90; 95% CI, 1.44-2.49; P < .0001). These associations persisted for people with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with alcohol consumption (Met-ALD), and harmful alcohol consumption. PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT did not attenuate the positive association between fibrosis markers and heart failure. For PNPLA3, a statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score, and heart failure. CONCLUSION: In the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk.

Exploring a role for community pharmacists in the identification of alcohol-related liver disease: a qualitative interview study with professionals, patients, and the public.

AIMS: To explore the views and attitudes of professionals, patients and the public to a role for community pharmacists in the identification of alcohol-related liver disease (ArLD). METHODS: Semi-structured interviews were conducted with a purposive sample of patients with ArLD, members of the public, pharmacy staff, and clinicians managing patients with ArLD across the Wessex region of south England. The interviews explored experiences of alcohol, ArLD and health advice in pharmacies and elicited views of what a pharmacist role in identifying ArLD could entail and factors influencing this. Transcripts were analysed using reflexive thematic analysis. RESULTS: Twenty-six participants were interviewed and three themes were generated: (i) acknowledging, seeking help and engaging with a hidden problem; (ii) professional roles, boundaries and attributes; (iii) communication, relationships, collaboration and support. Participants reported key challenges to identifying people at-risk of ArLD. Offering testing for ArLD was perceived to motivate engagement but there were concerns about pharmacists performing this. A role was mostly seen to be finding people at-risk and engaging them with further care such as referral to liver services. This was perceived to require developing interprofessional collaborations, remuneration and training for pharmacy staff, and community-based liver testing. CONCLUSIONS: Professionals, patient and public participants recognized a role for pharmacists in the identification of ArLD. This was envisaged to incorporate educating pharmacy users about ArLD risk, and identifying and directly engaging those at-risk with liver and support services through development of interprofessional collaborations. The findings of this study support and can inform future work to develop this role.

The impact of non-alcoholic fatty liver disease and liver fibrosis on adverse clinical outcomes and mortality in patients with chronic kidney disease: a prospective cohort study using the UK Biobank.

BACKGROUND: Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) frequently co-exist. We assess the impact of having NAFLD on adverse clinical outcomes and all-cause mortality for people with CKD. METHODS: A total of 18,073 UK Biobank participants identified to have CKD (eGFR < 60 ml/min/1.73 m2 or albuminuria > 3 mg/mmol) were prospectively followed up by electronic linkage to hospital and death records. Cox-regression estimated the hazard ratios (HR) associated with having NAFLD (elevated hepatic steatosis index or ICD-code) and NAFLD fibrosis (elevated fibrosis-4 (FIB-4) score or NAFLD fibrosis score (NFS)) on cardiovascular events (CVE), progression to end-stage renal disease (ESRD) and all-cause mortality. RESULTS: 56.2% of individuals with CKD had NAFLD at baseline, and 3.0% and 7.7% had NAFLD fibrosis according to a FIB-4 > 2.67 and NFS ≥ 0.676, respectively. The median follow-up was 13 years. In univariate analysis, NAFLD was associated with an increased risk of CVE (HR 1.49 [1.38-1.60]), all-cause mortality (HR 1.22 [1.14-1.31]) and ESRD (HR 1.26 [1.02-1.54]). Following multivariable adjustment, NAFLD remained an independent risk factor for CVE overall (HR 1.20 [1.11-1.30], p < 0.0001), but not ACM or ESRD. In univariate analysis, elevated NFS and FIB-4 scores were associated with increased risk of CVE (HR 2.42 [2.09-2.80] and 1.64 [1.30-2.08]) and all-cause mortality (HR 2.82 [2.48-3.21] and 1.82 [1.47-2.24]); the NFS score was also associated with ESRD (HR 5.15 [3.52-7.52]). Following full adjustment, the NFS remained associated with an increased incidence of CVE (HR 1.19 [1.01-1.40]) and all-cause mortality (HR 1.31 [1.13-1.52]). CONCLUSIONS: In people with CKD, NAFLD is associated with an increased risk of CVE, and the NAFLD fibrosis score is associated with an elevated risk of CVE and worse survival.

Testing to sustain hepatitis C elimination targets in people who inject drugs: A network-based model.

Little is known about the level of testing required to sustain elimination of hepatitis C (HCV), once achieved. In this study, we model the testing coverage required to maintain HCV elimination in an injecting network of people who inject drugs (PWID). We test the hypothesis that network-based strategies are a superior approach to deliver testing. We created a dynamic injecting network structure connecting 689 PWID based on empirical data. The primary outcome was the testing coverage required per month to maintain prevalence at the elimination threshold over 5 years. We compared four testing strategies. Without any testing or treatment provision, the prevalence of HCV increased from the elimination threshold (11.68%) to a mean of 25.4% (SD 2.96%) over the 5-year period. To maintain elimination with random testing, on average, 4.96% (SD 0.83%) of the injecting network needs to be tested per month. However, with a 'bring your friends' strategy, this was reduced to 3.79% (SD 0.64%) of the network (p < .001). The addition of contact tracing improved the efficiency of both strategies. In conclusion, we report that network-based approaches to testing such as 'bring a friend' initiatives and contact tracing lower the level of testing coverage required to maintain elimination.

Supporting and enabling health research in a local authority (SERLA): an exploratory study.

BACKGROUND: The use of research evidence to underpin public health practice and policy decisions in local government is strongly promoted but its implementation has not been straightforward. This study aimed to explore the factors, relationships and processes that contribute towards accessing, using, and generating research evidence that is relevant to local authority public health and social care and shapes its practice. METHODS: Semi-structured individual interviews with elected councillors, officers directly involved with public health and social care and with community members from one urban unitary authority in South England were conducted. Interviews were audio recorded, transcribed verbatim and thematically analysed. RESULTS: Fourteen participants took part in the semi-structured interviews. Local knowledge and evidence are prioritised, and anecdotal evidence is valued. The Director of Public Health was the principal source of information and support. Academics were rarely mentioned as information sources, and their involvement was ad hoc. The use of research evidence varied between individuals and departments, with wider engagement among public health specialists. Key barriers to the use of research evidence included access (not reported among public health professionals), research timeliness, local applicability, competence in finding and interpreting evidence and the role of research evidence within a political context. Public health and adult social care teams are not currently research active or research ready. Major barriers exist due to financial constraints and the socio-political context of local authorities. COVID-19 disrupted siloed ways of working, strengthening and opening potential collaborations within the local authority. This changed perspectives about the value of research but is likely time-limited unless underpinned by sustainable funding. CONCLUSION: Creating strategic level roles within local government to work with the Director of Public Health to champion the research agenda and embedding researchers within and across teams would build capacity for local authorities to sustainably co-create, undertake, and use evidence to better inform future actions.

Injecting network structure determines the most efficient strategy to achieve Hepatitis C elimination in people who inject drugs.

Transmission of Hepatitis C (HCV) continues via sharing of injection equipment between people who inject drugs (PWID). Network-based modelling studies have produced conflicting results about whether random treatment is preferable to targeting treatment at PWID with multiple partners. We hypothesise that differences in the modelled injecting network structure produce this heterogeneity. The study aimed to test how changing network structure affects HCV transmission and treatment effects. We created three dynamic injecting network structures connecting 689 PWID (UK-net, AUS-net and USA-net) based on published empirical data. We modelled HCV in the networks and at 5 years compared prevalence of HCV 1) with no treatment, 2) with randomly targeted treatment and 3) with treatment targeted at PWID with the most injecting partnerships (degree-based treatment). HCV prevalence at 5 years without treatment differed significantly between the three networks (UK-net (42.8%) vs. AUS-net (38.2%), p < 0.0001 and vs. USA-net (54.0%), p < 0.0001). In the treatment scenarios UK-net and AUS-net showed a benefit of degree-based treatment with a 5-year prevalence of 1.0% vs. 9.6% p < 0.0001 and 0.15% vs. 0.44%, p < 0.0001. USA-net showed no significant difference (29.3% vs. 29.2%, p = 0.0681). Degree-based treatment was optimised with low prevalence, moderate treatment coverage conditions whereas random treatment was optimised in low treatment coverage, high prevalence conditions. In conclusion, injecting network structure determines the transmission rate of HCV and the most efficient treatment strategy. In real-world injecting network structures, the benefit of targeting HCV treatment at individuals with multiple injecting partnerships may have been underestimated.

The combined effect of alcohol and body mass index on risk of chronic liver disease: A systematic review and meta-analysis of cohort studies.

BACKGROUND & AIMS: Increasingly populations are both overweight/obese and consume alcohol. The risk of liver disease from the combination of these factors is unclear. We performed a systematic review and meta-analysis to address this important gap in evidence. Protocol registered with PROSPERO(CRD42016046508). METHODS: We performed electronic searches of Ovid Medline, Embase Classic + Embase, until 17th June 2020 for cohort studies of adults without pre-existing liver disease. Primary outcome was morbidity/mortality from chronic liver disease. Exposures were alcohol consumption categorised as within or above UK recommended limits (14 units/112 g per week) and BMI categorised as normal, overweight or obese. Non-drinkers were excluded. A Poisson regression log-linear model was used to test for statistical interaction between alcohol and BMI and to conduct a one-stage meta-analysis. RESULTS: Searches identified 3129 studies-16 were eligible. Of these, nine cohorts (1,121,514 participants) had data available and were included in the analysis. The Poisson model showed no significant statistical interaction between alcohol consumption and BMI on the risk of chronic liver disease. Compared to normal weight participants drinking alcohol within UK recommended limits, relative risk of chronic liver disease in overweight participants drinking above limits was 3.32 (95% CI 2.88 to 3.83) and relative risk in obese participants drinking above limits was 5.39 (95% CI 4.62 to 6.29). CONCLUSIONS: This meta-analysis demonstrated a significantly increased risk of chronic liver disease in participants who were both overweight/obese and consumed alcohol above UK recommended limits. This evidence should inform advice given to patients and risk stratification by healthcare professionals.

The Enhanced Liver Fibrosis test maintains its diagnostic and prognostic performance in alcohol-related liver disease: a cohort study.

BACKGROUND: Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease. METHODS: Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with chronic liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality. RESULTS: ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI 0.823-0.968) and 0.923 (95% CI 0.866-0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI 0.908-0.960); non-alcohol = 0.907 (95% CI 0.895-0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI 1.55-4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI 1.39-2.99, p < 0.001). CONCLUSIONS: ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease.

Systematic review: Accuracy of the enhanced liver fibrosis test for diagnosing advanced liver fibrosis and cirrhosis.

BACKGROUND AND AIMS: The rising incidence of chronic liver disease (CLD) has increased the need for early recognition. This systematic review assesses the diagnostic accuracy of the enhanced liver fibrosis (ELF) test in cases of advanced fibrosis and cirrhosis due to multiple etiologies in at-risk populations. METHODS: Studies evaluating the ELF accuracy in identifying advanced fibrosis or cirrhosis, defined as METAVIR stage F ≥ 3 and F = 4 or equivalent, in patients with non-alcoholic fatty liver disease (NAFLD), alcohol liver disease (ALD), or viral hepatitis were included. Liver biopsy was used as the reference standard. Medline and Embase databases were searched. The QUADAS-2 tool was used as a framework to assess risk of bias and applicability. The area under the receiver operator curve (AUROC) was extracted as a summary measure of diagnostic accuracy. RESULTS: Thirty-six studies were included: 11 hepatitis C, 4 hepatitis B, 9 NAFLD, 2 ALD, and 10 mixed. The ELF test showed good diagnostic performance in detecting advanced fibrosis in patients with viral hepatitis (AUROC 0.69 to 0.98) and excellent performance in NAFLD (AUROC 0.78 to 0.97) and ALD (AUROC from 0.92 to 0.94). There is also evidence of good diagnostic performance for detecting cirrhosis in patients with viral hepatitis (AUROC 0.63 to 0.99), good performance in NAFLD (AUROC 0.85 to 0.92), and excellent performance in patients with ALD (AUROC 0.93 to 0.94). CONCLUSION: This systematic review supports the use of the ELF test across a range of CLD as a possible alternative to liver biopsy in selected cases.

All coffee types decrease the risk of adverse clinical outcomes in chronic liver disease: a UK Biobank study.

BACKGROUND: Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide, particularly in low to middle-income countries with high disease burden and limited treatment availability. Coffee consumption has been linked with lower rates of CLD, but little is known about the effects of different coffee types, which vary in chemical composition. This study aimed to investigate associations of coffee consumption, including decaffeinated, instant and ground coffee, with chronic liver disease outcomes. METHODS: A total of 494,585 UK Biobank participants with known coffee consumption and electronic linkage to hospital, death and cancer records were included in this study. Cox regression was used to estimate hazard ratios (HR) of incident CLD, incident CLD or steatosis, incident hepatocellular carcinoma (HCC) and death from CLD according to coffee consumption of any type as well as for decaffeinated, instant and ground coffee individually. RESULTS: Among 384,818 coffee drinkers and 109,767 non-coffee drinkers, there were 3600 cases of CLD, 5439 cases of CLD or steatosis, 184 cases of HCC and 301 deaths from CLD during a median follow-up of 10.7 years. Compared to non-coffee drinkers, coffee drinkers had lower adjusted HRs of CLD (HR 0.79, 95% CI 0.72-0.86), CLD or steatosis (HR 0.80, 95% CI 0.75-0.86), death from CLD (HR 0.51, 95% CI 0.39-0.67) and HCC (HR 0.80, 95% CI 0.54-1.19). The associations for decaffeinated, instant and ground coffee individually were similar to all types combined. CONCLUSION: The finding that all types of coffee are protective against CLD is significant given the increasing incidence of CLD worldwide and the potential of coffee as an intervention to prevent CLD onset or progression.

Coffee Consumption and Kidney Function: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, with limited strategies for prevention and treatment. Coffee is a complex mixture of chemicals, and consumption has been associated with mostly beneficial health outcomes. This work aimed to determine the impact of coffee consumption on kidney function. STUDY DESIGN: Genome-wide association study (GWAS) and Mendelian randomization. SETTING & PARTICIPANTS: UK Biobank baseline data were used for a coffee consumption GWAS and included 227,666 participants. CKDGen Consortium data were used for kidney outcomes and included 133,814 participants (12,385 cases of CKD) of mostly European ancestry across various countries. EXPOSURE: Coffee consumption. OUTCOMES: Estimated glomerular filtration rate (eGFR), CKD GFR categories 3 to 5 (G3-G5; eGFR<60mL/min/1.73m2), and albuminuria. ANALYTICAL APPROACH: GWAS to identify single-nucleotide polymorphisms (SNPs) associated with coffee consumption in UK Biobank and use of those SNPs in Mendelian randomization analyses of coffee consumption and kidney outcomes in CKDGen. RESULTS: 2,126 SNPs were associated with coffee consumption (P<5×10-8), 25 of which were independent and available in CKDGen. Drinking an extra cup of coffee per day conferred a protective effect against CKD G3-G5 (OR, 0.84; 95% CI, 0.72-0.98; P=0.03) and albuminuria (OR, 0.81; 95% CI, 0.67-0.97; P=0.02). An extra cup was also associated with higher eGFR (ß=0.022; P=1.6×10-6) after removal of 3 SNPs responsible for significant heterogeneity (Cochran Q P = 3.5×10-15). LIMITATIONS: Assays used to measure creatinine and albumin varied between studies that contributed data and a sex-specific definition was used for albuminuria rather than KDIGO guideline recommendations. CONCLUSIONS: This study provides evidence of a beneficial effect of coffee on kidney function. Given widespread coffee consumption and limited interventions to prevent CKD incidence and progression, this could have significant implications for global public health in view of the increasing burden of CKD worldwide.

The testing of people with any risk factor for hepatitis C in community pharmacies is cost-effective.

New antiviral drugs with high efficacy mean the hepatitis C virus (HCV) can now be eliminated. To achieve this, it is necessary to identify undiagnosed cases of HCV. However, the costs of testing should be considered when judging the overall cost-effectiveness of treatment. This study describes the cost-effectiveness of a community pharmacy testing service in a population of people at risk of HCV living on the Isle of Wight (United Kingdom). Dry blood spot testing was conducted in anyone with a known risk factor for HCV in 20 community pharmacies. The outcomes and costs were entered into a Markov model. Cost and health utilities from the model were used to calculate an incremental cost-effectiveness ratio (ICER). In 24 months, 186 tests were conducted, 13 were positive for HCV RNA and six of these (46%) received treatment during the follow-up period. All achieved a sustained virological response at 3 months. The overall cost of the testing and treatment intervention was £242 183, and the ICER for the service was £3689 per quality-adjusted life year (QALY) gained. If screening had been restricted to just people with a history of injecting drug use (PWID) the ICER would have been £4865 per QALY gained. The service was effective at identifying people with HCV infection, and despite the additional cost of targeted testing, its cost-effectiveness was below the commonly accepted thresholds. In this setting, restricting targeted testing to PWID would not improve the cost-effectiveness.

The Enhanced Liver Fibrosis test is associated with liver-related outcomes in postmenopausal women with risk factors for liver disease.

BACKGROUND: Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). METHODS: In a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ≥25 kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5 years. RESULTS: Using Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37-10.03) (unadjusted model) and 4.62 (95% CI 2.12-10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22-3.97) (unadjusted model) and 2.18 (95% CI 1.19-4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10-3.39) (unadjusted) and 2.05 (95% CI 1.16-3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09-3.15) (unadjusted) and 1.80 (95% CI 1.04-3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49-0.68), and for second subsequent ELF 0.61 (95% CI 0.52-0.71). CONCLUSION: This study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care. TRIAL REGISTRATION: This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.

Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The development of non-invasive liver fibrosis tests may enable earlier identification of patients with non-alcoholic fatty liver disease (NAFLD) requiring referral to secondary care. We developed and evaluated a pathway for the management of patients with NAFLD, aimed at improving the detection of cases of advanced fibrosis and cirrhosis, and avoiding unnecessary referrals. METHODS: This was a prospective longitudinal cohort study, with analyses performed before and after introduction of the pathway, and comparisons made to unexposed controls. We used a 2-step algorithm combining the use of Fibrosis-4 score followed by the ELF™ test if required. RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (odds ratio [OR]5.18;95%CI2.97-9.04; p <0.0001), while reducing unnecessary referrals from primary care to secondary care by 81% (OR0.193; 95%CI 0.111-0.337; p <0.0001). Although it was used for only 48% of referrals, significant benefits were observed in practices exposed to the pathway compared to those which were not, with unnecessary referrals falling by 77% (OR0.23; 95% CI0.658-0.082; p = 0.006) and a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR4.32; 95% CI1.52-12.25; p = 0.006). Compared to referrals made before the introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%), representing an 88% reduction in unnecessary referrals when the pathway was followed (OR0.12; 95%CI0.042-0.349; p <0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis improves the detection of advanced fibrosis and cirrhosis, while reducing unnecessary referrals in patients with NAFLD. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease, leading to a reduction in unnecessary referrals by 80% and greatly improving the detection of cases of advanced fibrosis and cirrhosis.

Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease.

BACKGROUND: The identification of patients with advanced liver fibrosis secondary to non-alcoholic fatty liver disease (NAFLD) remains challenging. Using non-invasive liver fibrosis tests (NILT) in primary care may permit earlier detection of patients with clinically significant disease for specialist review, and reduce unnecessary referral of patients with mild disease. We constructed an analytical model to assess the clinical and cost differentials of such strategies. METHODS: A probabilistic decisional model simulated a cohort of 1000 NAFLD patients over 1 year from a healthcare payer perspective. Simulations compared standard care (SC) (scenario 1) to: Scenario 2: FIB-4 for all patients followed by Enhanced Liver Fibrosis (ELF) test for patients with indeterminate FIB-4 results; Scenario 3: FIB-4 followed by fibroscan for indeterminate FIB-4; Scenario 4: ELF alone; and Scenario 5: fibroscan alone. Model estimates were derived from the published literature. The primary outcome was cost per case of advanced fibrosis detected. RESULTS: Introduction of NILT increased detection of advanced fibrosis over 1 year by 114, 118, 129 and 137% compared to SC in scenarios 2, 3, 4 and 5 respectively with reduction in unnecessary referrals by 85, 78, 71 and 42% respectively. The cost per case of advanced fibrosis (METAVIR ≥F3) detected was £25,543, £8932, £9083, £9487 and £10,351 in scenarios 1, 2, 3, 4 and 5 respectively. Total budget spend was reduced by 25.2, 22.7, 15.1 and 4.0% in Scenarios 2, 3, 4 and 5 compared to £670 K at baseline. CONCLUSION: Our analyses suggest that the use of NILT in primary care can increases early detection of advanced liver fibrosis and reduce unnecessary referral of patients with mild disease and is cost efficient. Adopting a two-tier approach improves resource utilization.

Biomarkers of Hepatic Fibrosis in Chronic Hepatitis C: A Comparison of 10 Biomarkers Using 2 Different Assays for Hyaluronic Acid.

BACKGROUND: Advancing fibrosis is regarded as the most important factor when stratifying patients with chronic hepatitis C for retreatment. GOALS: (1) To compare the performance of 10 biomarkers of fibrosis, including patented tests, among patients with chronic hepatitis C and treatment failure; and (2) to assess the impact on biomarker performance of using 2 different assays of hyaluronic acid (HA). STUDY: For 80 patients, liver histology (Metavir) was compared with biomarker scores using sera obtained within 6 months of liver biopsy (indirect biomarkers: AST:ALT ratio, APRI, Forns index, FIB-4, Fibrometer V3G; direct biomarkers: ELF, Fibrospect II, Hyaluronic acid-HA, Fibrometer V2G, Hepascore). Direct biomarker scores were calculated using 2 validated assays for HA (ELISA and radiometric). RESULTS: Using the ELISA assay for HA to calculate the direct panels, all 10 of the biomarkers exhibited comparable overall discriminatory performance (unweighted Obuchowski measure, ordROC 0.92-0.94, P-value>0.05) except AST:ALT ratio and APRI (ordROC 0.86-0.88, P-value<0.05). For the detection of moderate (F2-4) and advanced (F3-4) fibrosis, the AUROC of Fibrometer 2G were significantly higher than AST:ALT ratio and APRI but none of the other biomarkers. Good correlation was observed between the 2 HA assays (intraclass correlation coefficient=0.873) with the ELISA assay exhibiting superior diagnostic performance (ordROC 0.92 vs. 0.88, P-value=0.003). Importantly, the performance of many of the direct biomarkers at their diagnostic thresholds was heavily influenced by the choice of HA assay. CONCLUSIONS: Although many biomarkers exhibited good diagnostic performance for the detection of advancing fibrosis, our results indicate that diagnostic performance may be significantly affected by the selection of individual component assays.

Risk of chronic liver disease in post-menopausal women due to body mass index, alcohol and their interaction: a prospective nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: We investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: 95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1-15, 16-20 and ≥21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE). RESULTS: First LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10-1.87) in the overweight group and HR = 2.25 (95% CI; 1.70-2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55-0.88) for <1-15 units/week, 0.93 (95% CI; 0.50-1.73) for 16-20 units/week and 1.82 (95% CI; 0.97-3.39) for ≥21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming ≥21 units/week was 2.86 (95% CI; 0.67-12.42), 1.58 (95% CI; 0.96-2.61) for obese women drinking <1-15 units/week and 1.93 (95% CI; 0.66-5.62) in those with normal BMI consuming ≥21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol. CONCLUSION: High BMI and alcohol consumption and abstinence are risk factors for CLD in post-menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.

Hepatitis C bio-behavioural surveys in people who inject drugs-a systematic review of sensitivity to the theoretical assumptions of respondent driven sampling.

BACKGROUND: New, more effective and better-tolerated therapies for hepatitis C (HCV) have made the elimination of HCV a feasible objective. However, for this to be achieved, it is necessary to have a detailed understanding of HCV epidemiology in people who inject drugs (PWID). Respondent-driven sampling (RDS) can provide prevalence estimates in hidden populations such as PWID. The aims of this systematic review are to identify published studies that use RDS in PWID to measure the prevalence of HCV, and compare each study against the STROBE-RDS checklist to assess their sensitivity to the theoretical assumptions underlying RDS. METHOD: Searches were undertaken in accordance with PRISMA systematic review guidelines. Included studies were English language publications in peer-reviewed journals, which reported the use of RDS to recruit PWID to an HCV bio-behavioural survey. Data was extracted under three headings: (1) survey overview, (2) survey outcomes, and (3) reporting against selected STROBE-RDS criteria. RESULTS: Thirty-one studies met the inclusion criteria. They varied in scale (range 1-15 survey sites) and the sample sizes achieved (range 81-1000 per survey site) but were consistent in describing the use of standard RDS methods including: seeds, coupons and recruitment incentives. Twenty-seven studies (87%) either calculated or reported the intention to calculate population prevalence estimates for HCV and two used RDS data to calculate the total population size of PWID. Detailed operational and analytical procedures and reporting against selected criteria from the STROBE-RDS checklist varied between studies. There were widespread indications that sampling did not meet the assumptions underlying RDS, which led to two studies being unable to report an estimated HCV population prevalence in at least one survey location. CONCLUSION: RDS can be used to estimate a population prevalence of HCV in PWID and estimate the PWID population size. Accordingly, as a single instrument, it is a useful tool for guiding HCV elimination. However, future studies should report the operational conduct of each survey in accordance with the STROBE-RDS checklist to indicate sensitivity to the theoretical assumptions underlying the method. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019245.

Type 2 diabetes and risk of hospital admission or death for chronic liver diseases.

BACKGROUND & AIMS: The impact of type 2 diabetes (T2DM) on hospital admissions and deaths due to common chronic liver diseases (CLDs) is uncertain. Our aim was to investigate associations between T2DM and CLDs in a national retrospective cohort study and to investigate the role of sex and socio-economic status (SES). METHODS: We used International Classification of Disease codes to identify incident alcoholic liver disease (ALD), autoimmune liver disease, haemochromatosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and viral liver disease from linked diabetes, hospital, cancer and death records for people of 40-89years of age in Scotland 2004-2013. We used quasi Poisson regression to estimate rate ratios (RR). RESULTS: There were 6667 and 33624 first mentions of CLD in hospital, cancer and death records over ∼1.8 and 24million person-years in people with and without T2DM, respectively. The most common liver disease was ALD among people without diabetes and was NAFLD among people with T2DM. Age-adjusted RR for T2DM compared to the non-diabetic population (95% confidence intervals) varied between 1.27 (1.04-1.55) for autoimmune liver disease and 5.36 (4.41-6.51) for NAFLD. RRs were lower for men than women and for more compared to less deprived populations for both ALD and NAFLD. CONCLUSIONS: T2DM is associated with increased risk of hospital admission or death for all common CLDs and the strength of the association varies by type of CLD, sex and SES. Increasing prevalence of T2DM is likely to result in increasing burden of all CLDs.