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Emergency admissions in England for alcohol-related liver disease (ArLD) have increased steadily for decades. Statistics based on administrative data typically focus on the ArLD-specific code as the primary diagnosis and are therefore at risk of excluding ArLD admissions defined by other coding combinations.To deploy the Liverpool ArLD Algorithm (LAA), which accounts for alternative coding patterns (e.g., ArLD secondary diagnosis with alcohol/liver-related primary diagnosis), to national and local datasets in the context of studying trends in ArLD admissions before and during the COVID-19 pandemic.We applied the standard approach and LAA to Hospital Episode Statistics for England (2013-21). The algorithm was also deployed at 28 hospitals to discharge coding for emergency admissions during a common 7-day period in 2019 and 2020, in which eligible patient records were reviewed manually to verify the diagnosis and extract data.Nationally, LAA identified approximately 100% more monthly emergency admissions from 2013 to 2021 than the standard method. The annual number of ArLD-specific admissions increased by 30.4%. Of 39,667 admissions in 2020/21, only 19,949 were identified with standard approach, an estimated admission cost of £70 million in under-recorded cases. Within 28 local hospital datasets, 233 admissions were identified using the standard approach and a further 250 locally verified cases using the LAA (107% uplift). There was an 18% absolute increase in ArLD admissions in the seven-day evaluation period in 2020 versus 2019. There were no differences in disease severity or mortality, or in the proportion of admissions with decompensation of cirrhosis or alcoholic hepatitis.The LAA can be applied successfully to local and national datasets. It consistently identifies approximately 100% more cases than the standard coding approach. The algorithm has revealed the true extent of ArLD admissions. The pandemic has compounded a long-term rise in ArLD admissions and mortality.

Quantitative analysis of drug delivery with in biological systems is an integral challenge in drug development. Analytical techniques are important for assessing both drug target delivery, target action, and drug toxicology. Using mimetic tissue models, we have investigated the efficacy of Raman spectroscopy in quantitative detection of alkyne group and deuterated drugs in rat brain and rat liver tissue models. Lasers with 671 nm and 785 nm wavelengths were assessed for their feasibility in this application due to opposing relative benefits and disadvantages. Thin tissue sections have been tested as a practical means of reducing autofluorescent background by minimizing out-of-focus tissue and therefore maximizing photobleaching rates. Alkyne-tagged drugs were quantitatively measured at 18 ± 5 μg/g drug/tissue mass ratio in rat brain and at 34 ± 6 μg/g in rat liver. Quantification calibration curves were generated for a range of concentrations from 0–500 μg/g. These results show the potential of Raman spectroscopy as a diffraction-limited spatially resolved imaging technique for assessing drug delivery in tissue applications.

GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants. In this analysis, the plasma pharmacokinetics (PK) of GSK3389404 were characterized and compared in patients with CHB across the Asia-Pacific region (N = 64), including mainland China (

The current regulatory landscape for the development of oligonucleotide drugs may lead companies to perform a variety of small molecule-focussed absorption, distribution, metabolism and elimination (ADME) studies in support of filing packages. Asking the question, if the current activities are suitable for these modalities and should science-driven decisions on development of such molecules be implemented more in the industry.Challenges and opportunities within oligonucleotide ADME were presented and discussed at the online oligonucleotide ADME workshop (17th and 18th of November 2021). This article summarises the presentations and discussions from the workshop.The following topics were covered: Introduction to Delivery of Antisense RNA Therapeutics (DARTER), Nucleic Acid Therapy Accelerator (NATA) and OligoNova initiatives.Presentation of various oligonucleotide ADME strategies.Update on the Oligonucleotide Safety Working Group (OSWG) pharmacokinetics (PK)/ADME subcommittee's recommendations.Oligonucleotide quantitative whole-body autoradiography (QWBA) hot or not?Multimodal imaging of therapeutic oligonucleotides.

Dose-dependent reductions in hepatitis B virus (HBV) RNA, DNA, and viral proteins following bepirovirsen administration were observed in HepG2.2.15 cells. In HBV-transgenic mice treated at 50 mg/kg/wk, hepatic HBV RNA and DNA were reduced by 90% and 99%, respectively. Subsequently, a phase 1 first-in-human study assessed pharmacokinetics and tolerability of single (75-450 mg) and multiple (150-450 mg on days 1, 4, 8, 11, 15, and 22) subcutaneous bepirovirsen doses in 96 healthy volunteers. Bepirovirsen at all dose levels was rapidly absorbed (maximum plasma concentration 3-8 hours after dosing), rapidly distributed to peripheral tissues, and slowly eliminated (median plasma terminal half-life: 22.5-24.6 days across cohorts). Plasma exposure (dose-proportional at 150-450 mg) and concentration-time profiles were similar following the first and sixth doses, suggesting little to no plasma accumulation (steady state achieved by day 22). Renal elimination of full-length bepirovirsen accounted for2% of the total dose. Across the single and multiple dose cohorts, 197 treatment-emergent adverse events were reported, with 99% and 65% classified as mild in severity and local injection site reactions, respectively. In conclusion, bepirovirsen showed an acceptable safety profile in humans with observed pharmacokinetics consistent with the chemical class, warranting further evaluation of bepirovirsen in chronic HBV infection.

Introduction Alcohol-related liver disease (ARLD) can present with neuropsychiatric complications. Epidemiological studies have not investigated the impact of confusional states on patient journeys. As part of the Connected Health Cities programme, we retrospectively investigated coding data from a regional administrative dataset to identify the burden of recognised cognitive impairment (CI) in a pre-identified cohort of patients during their index admission of ARLD (fiscal years 2014–18). Methodology Inpatient spells for a cohort of 3,887 index ARLD admissions were screened for ICD-10 codes indicative of acute and chronic CI. Descriptive analytics and stepwise multivariate logistic regression models were generated using Stata 15 (StataCorp, 2017) for predefined outcomes: inpatient mortality, length of stay, all-cause outpatient attendance and all-cause A&E attendance. These were casemix-adjusted for age, sex, co-morbidity, deprivation and variables associated with severity of liver decompensation. Results 20 codes corresponded to acute or chronic CI, most frequently encoding encephalopathy and alcohol-related amnesiac syndrome respectively. Codes for intoxication and withdrawal were excluded and adjusted for. 277 spells (7.1%) were coded with > 1 ICD code for acute CI, and 78 (2.0%) for chronic CI, with minimal overlap (0.6%). Comparisons were made with patients without relevant codes. Overall, these patients were older (mean age 57.5 and 64.1 respectively) with higher levels of co-morbidity (mean Charlson index 16.4 and 12.6 respectively) with median bed-days of 13 and 14. Multivariate logistic regression models demonstrated patients with acute CI had higher odds of inpatient mortality (OR 2.13) and long admission >21 days (OR 2.30). Patients coded with chronic CI had higher odds of long admission (OR 3.09) and A&E attendance within 90 days (OR 2.01), and were less likely to attend an outpatient clinic at 14-day (OR 0.28) and 30-day (OR 0.4) intervals post-discharge. CI did not predict risk of readmission. Conclusion In terms of mortality, acute CI is likely to reflect higher disease severity, particularly as encephalopathy is a poor prognosticator in this group of patients. The evidence suggests that chronic CI in patients with ARLD is under-detected in clinical practice. Our analysis demonstrates patients with recognised chronic CI experience extended admissions, are more likely to experience unplanned care and less likely to engage with outpatient care up to 90 days post-discharge. This suggests that current care models may not be appropriate for this subgroup, and alternative pathways integrating prompt identification and supported discharge mechanisms should be developed.

Introduction In-hospital mortality from alcohol-related liver disease (ARLD) remains high, with concern that some patients are dying during their first (index) emergency hospitalisation. However, the mortality rate during index ARLD admission in England is not well characterised. Nor do we know the relative proportion of fatalities that are genuinely ‘hidden’ to the system as opposed to having had prior contacts with primary or secondary care. Methods The CPRD dataset contains a nationally representative sample of the English population (approx. 13 million, 23.2%) with linked data from both primary and secondary care. We obtained data for all people with an alcohol or liver-related READ code in their primary care record or an alcohol-specific ICD-10 diagnosis in secondary care (n=496,762). We then selected all patients admitted as an emergency for index ARLD in fiscal year 2017/18 (applying our recently reported diagnostic algorithm for ARLD and screening the preceding 10 years), characterised their prior contacts with services across the decade before admission, their clinical characteristics and in-hospital mortality. Results Within the CPRD sample population for 2017/18, there were 2,423 patients with an index admission for ARLD (their first in last decade). In-hospital mortality for index admissions in England was 15.1% (n=366), with a mean age of 59 years, 60.7% male and mean Charlson index 18. Of the deaths, 28% had no record of an emergency admission for any cause in last 10 years – individuals who appear hidden to hospital services. However, 47% of those dying had at least one previous admission for an alcohol-specific diagnosis (other than liver disease) with a mean interval of 760 days between their first admission and fatal ARLD index. Of the deaths, 9% had no record of any primary care contact (seemingly unknown to GP services). However, 63.7% of those dying had a previous READ code for an alcohol-related problem in their GP record. Conclusion In England in 2017/18, fifteen percent of patients admitted for the first time with ARLD died during admission. Of patients who died, almost one in ten had had no contact with primary care, and over one in four had no record of a secondary care admission in the preceding 10 years. Patients lacking contact with both primary and secondary care represent a ‘hidden group’, with apparent lack of opportunity for healthcare intervention. However, a high proportion of patients who died are known to both primary and secondary care. There may be missed opportunities or ineffective healthcare intervention at both primary and secondary care levels. New, more effective strategies are needed to detect and help people at high risk of presenting acutely for the first time with fatal ARLD. Characteristics of survivors vs. those who died Number of deaths = 477 (13.91%); 141 (29.56%) had no previous GP contact; 16 (3.35%) had a GP liver flag only; 189 (39.62%) have an alcohol flag only and 131 (27.46%) both alcohol and liver codes. Number of survivors = 2,952 (86.09%); 868 (29.40%) had no previous GP contact; 43 (1.46) with a liver flag only; 1,309 (44.34%) with an alcohol flag only and 732 (24.80%) with both alcohol and liver codes. Mann-Whitney- comparison of the total number of days between the 2017/2018 index, and the date of first GP: alcohol, liver and combined alcohol + liver code. Showed no statistical significance between the length in time from GP code and index, within the died vs survived cohorts. Mortality cohort (n=477) Mean age = 59 (SD– 12.6) ARLD code in primary = 61.6% Short stay ( AKI= 64.8% Ascites = 51.2% Varices = 22.9 Survived cohort (n=2,952) Mean age = 53 (SD–11.9) ARLD code in primary = 46.3% Short stay ( AKI= 14.8% Ascites = 29.1% Varices = 16.9%

Background Variations in emergency care quality for alcohol‐related liver disease (ARLD) have been highlighted. Aim To determine whether introduction of a regional quality improvement (QI) programme was associated with a reduction in potentially avoidable inpatient mortality. Method Retrospective observational cohort study using hospital administrative data spanning a 1‐year period before (2014/2015) and 3 years after a QI initiative at seven acute hospitals in North West England. The intervention included serial audit of a bundle of process metrics. An algorithm was developed to identify index (“first”) emergency admissions for ARLD (n = 3887). We created a standardised mortality ratio (SMR) to compare relative mortality and regression models to examine risk‐adjusted odds of death. Results In 2014/2015, three of seven hospitals had an SMR above the upper control limit (“outliers”). Adjusted odds of death for patients admitted to outlier hospitals was higher than non‐outliers (OR 2.13, 95% CI 1.32‐3.44, P = 0.002). Following the QI programme there was a step‐wise reduction in outliers (none in 2017/2018). Odds of death was 67% lower in 2017/2018 compared to 2014/2015 at original outlier hospitals, but unchanged at other hospitals. Process audit performance of outliers was worse than non‐outliers at baseline, but improved after intervention. Conclusions There was a reduction in unexplained variation in hospital mortality following the QI intervention. This challenges the pessimism that is prevalent for achieving better outcomes for patients with ARLD. Notwithstanding the limitations of an uncontrolled observational study, these data provide hope that co‐ordinated efforts to drive adoption of evidence‐based practice can save lives.

Introduction Indeterminate biliary strictures (BS) may be identified in symptomatic patients or incidentally on imaging. Patients need investigation to exclude cholangiocarcinoma or other significant pathology. The first line investigation is with Magnetic Resonance Cholangio-Pancreatography (MRCP) however this is not always diagnostic. Such cases are all reviewed through our tertiary Multi-disciplinary team (MDT) meeting for further evaluation. Diagnostic Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is often used to further investigate these abnormalities1 but carries a risk of complications. Methods A retrospective analysis was performed of patients reviewed through our regional HPB MDT from October 2014 to December 2016. Patients with indeterminate BS with no mass lesion were identified from our MDT database. Following MDT discussion, all patients were investigated with ERCP ±cholangioscopy (POC). Liver Function Tests (LFTs) and details of suspected BS were obtained from the medical records. Diagnoses were obtained from the endoscopy database and histopathology reports, where applicable. Results 66 patients were identified with a mean age of 63.7 (SD 14.5). 47% were male. 82% of patients had abnormal LFTs, 35% had jaundice and 61% had upstream dilatation on radiological imaging. 31 (47%) required POC in addition to ERCP. 85% of patients (n=56) had an abnormal diagnosis. 8 (12.1%) had malignancy, 13 (19.7%) PSC or other cholangiopathy and 10 (15.2%) stone disease. In our centre, complications associated with these ERCPs were low: pancreatitis: 1 (1.6%); cholangitis: 1 (1.6%); bleeding:1 (1.6%). There were 2 delayed bleeds (peptic ulcer and variceal). Upstream dilatation was shown to be a predictor of abnormal diagnosis on both univariate (p=0.004) and multivariate analysis (p=0.01) with a sensitivity of 72.5%, specificity of 72.7%, positive predictive value of 92.5% and negative predictive value of 36.4%. Conclusions Of those with suspected BS on imaging, 85% had pathology demonstrated on direct cholangiography ±POC. 15.2% of those reviewed through a tertiary HPB MDT had stone disease evident at ERCP that was not diagnosed on review of MRCP and other imaging modalities. Diagnostic ERCP in appropriate centres still has a role to play in the evaluation of indeterminate biliary strictures following specialist MDT review when non-invasive imaging is inconclusive. Reference . British Society of Gastroenterology. ERCP – the way forward, A Standards Framework 2014. https://www.bsg.org.uk/resource/ercp---the-way-forward--a-standards-framework-pdf.html

Introduction The rising burden and high mortality for alcohol-related liver disease (ARLD) is well-recognised in the UK. Efforts to plan adequate liver and alcohol services and to identify unwarranted variation are limited by lack of robust, actionable information about true workload and real-world risk-adjusted outcomes. We report an informatics programme (Connected Health Cities, Northwest Coast) that is generating new analytical resources to support services. Methods A healthcare data lab. team of data scientists is linked to a secure ‘data ark’ hosting regional commissioning datasets (Admitted Patient Care, A and E, Outpatients, fiscal years 14/15 to 16/17) and is working with clinical teams to construct novel ways to interrogate data (‘algorithmic approach’), model outcomes and unexplained variation and visualise data (small area mapping). Entire patient journeys were linked, to identify ARLD cases and their all-cause emergency admissions (categorised by diagnosis), capture phenotyping flags (e.g. first occurrence of codes for varices), pre-admission events and outcomes (e.g. in-hospital mortality; all-cause 30 day readmission). Maps were used to communicate catchment areas and identify admission ‘hot spots’. Site-level benchmarking reports were shared with teams at 7 hospitals. Results Compared to the standard approach for capturing cases (i.e. primary diagnosis at discharge; 6 specific ICD-10 codes; ‘ARLD-Primary’ Method), the algorithmic approach (ARLD-Alg) identified 9 other patterns of primary and secondary diagnoses with >60 primary ICD-10 codes consistent with emergency care for ARLD. Activity: Across 7 NHS Trusts, estimates of total 3 year activity for ARLD increased from 3185 (ARLD-Primary) to 5912 (ARLD-Alg) for admissions, 35 840 to 56 010 for bed days (equivalent to 50 extra in-patient beds), and 485 to 665 for in-hospital deaths. Case-mix for the 2 approaches was similar (mean age: 51.6 v 51.4; males 63.2 v 63.6%; Charlson Index: 1.6 v 1.7) but ARLD-Alg captured more shorter stays (median LoS: 7 v 6 days;% short stay [0–2 days]: 12.1 v 16.5). Varices cases account for 15%–20%. Outcomes Crude mortality across hospitals varied significantly by method ARLD-Primary: 13.0%–21.7%; ARLD-Alg: 10.2%–14.5%. All binary logistic models identified male patients were at lower risk of in-hospital death than females (Adj OR: 0.70). Treatment provider was a predictor of outcome. Conclusions Standard approaches to analysis of administrative data under-estimate the burden of unplanned care for ARLD (by up to 60%) and have dubious value for service planning or benchmarking. More sophisticated clinically-driven Methods can leverage greater value from routine data. These novel tools are scalable for nationwide deployment and have potential to inform policy and support data-driven service improvement. Funding Department of Health

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Introduction Alcohol-related emergency admissions (ARA) are a major and rising hospital burden, resulting from conditions that range from short-term toxicity to end-stage organ damage, notably liver disease. We report a project to develop analyses of routine coding data, with a particular focus on metrics related to ‘frequent flyers’ (FFs) as targets for new service interventions. Methods Sources of data: Hospital Episode Statistics for all English hospitals (2006–2008); Inpatient coding data and AED attendances for our Trust (2006–2013). Analysis: Screening of all non-emergency episodes for alcohol-related codes at any position to flag ARAs; linkage of individual cases to extract all admissions and order chronologically; allocation of each admission to a category based on primary and lower order diagnoses (flagging LIVER and NON-LIVER admissions); identification of frequent flyers (FFs) based on various definitions of admission count; linkage of ARAs to all-cause AED attendances in local data; funnel-plot analyses of patterns across English Trusts; longitudinal trends in local data. Results Nationally: 219,158 ARAs in 139,077 patients (2006–2008), mean age (sd): 49.5 yrs (16); males : 99,271 (71%); Deprivation : Quintile 1 (most deprived) 36.4%, Quintile 5 (least): 9.4%; Co-morbidity (Charlson), 0.44 (0.68); LoS : 7 (14) days; Inpatient death : 6,656 (4.8%). No. admissions ranged from 1–60 per individual. Frequent Flyers : In two years, a cut-off of 5+ admissions identified 5,404 FFs (4% of patients; accounting for 18% of ARAs nationally) whereas 10+ identified 909 FFs (1% of patients; 6% of ARAs). Mean ARAs per Trust was 927 (range: 235–3930) with 6-fold variation in% of FFs (1.3% to 7.7%) and 4-fold variation in% with liver disease across English hospitals (range: 7.6–30.2%). As expected, FFs coded with liver disease had significantly higher LoS and mortality risk consistent with end-stage organ damage and “unavoidable” admissions. Locally: 21,308 ARAs in 16,305 patients (2006–2012), with annual number of cases rising from 1,615 to 4,603. Defining FFs as 5+ ARAs per year, there were 320 FFs (2% of patients; 10% of ARAs). There was a year-on-year rise in ARAs (2,454–5,510) and AED attendances without admission (2,499–5,979). However, FFs (5+ admissions) declined from 64 to 47 between 2006 and 2012 and non-liver FFs from 25 to 12, suggesting a positive impact of new local services on multiple attenders, especially those lacking established liver disease. Conclusion We have developed a set of candidate metrics focussed on FFs, short stays and selected baskets of conditions to provide data to support front-line acute alcohol services. Disclosure of Interest None Declared.

Introduction Harmful alcohol use is associated with substantial health and economic burden. 1 Patients with alcohol-related conditions (ARCs) present acutely to hospital with a wide spectrum of disorders, impacting a range of medical & surgical specialties - a major challenge to the organisation and delivery of effective care within a hospital. Public health metrics derived from hospital (coding) data provide useful top-level indicators but do not provide clinically-relevant information for hospital teams. Gastroenterologists are seen increasingly as potential leaders in alcohol services. The aim of this project is to develop clinically-meaningful analyses and metrics that allow clinicians to better-understand alcohol-related emergency admission data to help in service planning. Methods We analysed a 2-year download of HES data (~24M. care episodes) for acute NHS Trusts in England in IBM-SPSS stats package. Emergency admissions containing any alcohol code were extracted, all recorded diagnoses were tabulated and reviewed by clinical steering group. Logical baskets of conditions were generated, reflecting common clinical presentations and allocated to specialties. The resulting coding rules and hierarchies were applied to the national data to label each admission and summary data generated. Results Of 7,440,546 emergency admissions to 150 trusts, ARCs accounted for 228,994 (3%). 12 diagnostic-specialty categories of admission were defined, of which Hepatology (alcoholic liver disease) and Gastroenterology (other GI conditions) ranked 1st and 3rd for admissions (17.4% and 13.8%) with alcohol withdrawal/intoxication ranked 2nd (17.3%). Remaining categories fall within medical specialties (e.g. general neurology, cardiology, respiratory) with only 3.9% of admissions attributable to surgical conditions or trauma. Shortest mean LOS were Poisoning/Psychiatry admissions (1.97 days). Greatest single contributor to total bed days was Hepatology at 240,576 per year and (excluding cancer) this had highest inpatient mortality (18.2%). Conclusion 3% of emergency admissions to English hospitals were for ARCs and the majority (95.7%) of admissions fall within the remit of physicians rather than surgeons. Half the recorded diagnoses for admitted patients are within the sub-specialties of hepatology or gastroenterology and these contribute the highest share of both bed days and mortality. This system of classifying hospital data provides a basis for re-design of services, manpower planning and potential metrics for performance. Disclosure of Interest None Declared. Reference Moriarty KJ, Platt H, Crompton S et al. Collabarative care for alcohol-related liver disease. Clin Med. 2007 Apr; 7(2):125–8.