Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

Next Stop a Longer Life.

Aim A request was made to the Department of Public Health in early 2019 for some interesting statistics (funtistics) for a planned health promotion campaign encouraging public transport users to increase their physical activity levels by alighting one stop earlier and walking to their destination. For a novel presentation of the benefits of increasing physical activity it was decided to calculate the potential increase in life-expectancy that a given amount of physical activity would correspond to (at a population level). Method Estimated increase in weekly walking time was calculated for the Dublin Bus commuter walking the last stop of their journey. The reduced risk of mortality was estimated for this increase in physical activity and applied to Irish life tables to calculate change in life expectancy. Results Alighting from a bus one stop earlier in Dublin would lead to an average of 4.42 minutes additional walking (44.21 minutes additional walking per week for a commuter). In the Dublin Bus commuter population, this leads to an estimated 50 day increase in life expectancy (male population). Conclusion At the lower end of the dose response curve for physical activity, health benefits include: reduced risk of cardiovascular disease, reduced risk of diabetes, psychosocial benefit, reduced risk of musculoskeletal problems. For the prevention of weight gain and some cancers, activity at the upper end of the range (1000 MET.min/week, approximately 300 minutes of walking/week) is thought to be required.

Cannabis use and Associated Health Problems ­ What's the Harm?

Aim Cannabis is the most widely used illegal drug in Ireland. We sought to describe the changing pattern of cannabis use and cannabis related health harms. Methods Data was collated from two national population surveys and three national treatment databases, focusing on people under 34 years. Results Past month cannabis use among adolescents and young adults increased after 2011, coinciding with a decline in perceived risk of regular use. The prevalence estimate for cannabis dependence increased from 1.1% to 3.6% from 2011 to 2015. From 2008 to 2016, there were increases in the rates of cannabis related addiction treatment episodes among adolescents and among young adults of 40% and 168% respectively. Cannabis related admissions to general and psychiatric hospitals increased by 90% and 185% respectively. Conclusion A concerted public health response is required to address escalating cannabis related health harms which have coincided with the arrival of more potent cannabis.

Author Correction: Anti-angiogenic drug scheduling optimisation with application to colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Anti-angiogenic drug scheduling optimisation with application to colorectal cancer.

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by "normalizing" abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic treatment and chemotherapeutic treatment on tumour volume. Model predictions were validated using CRC xenografts which underwent treatment with a clinically relevant combinatorial anti-angiogenic regimen. Bayesian model selection revealed the most appropriate term for capturing the effect of treatments on the tumour size, and provided insights into a switch-like dependence of FOLFOX delivery on the tumour vasculature. Our experimental data and mathematical model suggest that delivering chemotherapy prior to bvz may be optimal in the colorectal cancer setting.

Is Increasing Life Expectancy Leading To More Complexity?

Life expectancy is increasing in Ireland, but whether this has resulted in healthier life years among the elderly and its impact (if any) on hospital services is unknown. The purpose of the study was to use routinely available data to explore the relationship of age and indicators of clinical complexity in acute hospitals over ten years. The study included all in-patients aged 65+ years from the Hospital In-Patient Enquiry (HIPE) discharged between 2005 and 2014. Indicators of complexity included the Charlson index, overall length of stay (LOS), intensive care unit LOS and deaths in hospital, analysed by the major clinical classification software (CCS). Over the period, the number and rate of admissions increased, especially among those aged 85+. Indicators of patient complexity increased and LOS decreased. In-hospital mortality decreased from 5.9% to 4.7%. Hospitals appear to be managing the emergency care of the older and more complex patient more efficiently and with better outcomes.

The Epidemiology of Emergency In-Patient Hospitalisations Among Those with 'No Fixed Abode' (Homeless) 2005-2014: What Lessons Can Be Learnt.

Estimates show that homelessness is increasing in Ireland. This study analysed the epidemiology of emergency hospitalisations among those experiencing homelessness between 2005-2014. All in-patient admissions to acute hospitals classified with 'no fixed abode' were extracted from the Hospital In-patient Enquiry System. Data were analysed using JMP. There were 2,051 in-patient emergency admissions of people classified with 'no fixed abode' during the study period, an increase of 406% since 2005 (78 in 2005 vs. 395 in 2014). The mean age was 40.6 (S.D. 13.2). The majority of patients (1,176 /2,051; 57%) had a mental/ behavioural diagnosis. Over one in ten (280; 13.7%) were admitted for ambulatory care sensitive conditions (ACSCs) including convulsions/epilepsy (N=92/280; 32.9%), cellulitis (62/280; 22.1%) and COPD (29/280; 10.4%). The health of homeless people is a fundamental issue that needs addressing. Access to, and use of, community and preventative services is needed to reduce utilisation of emergency hospital services.

The epidemiology of assault-related hospital in-patient admissions and ED attendances.

The aim of this study was to describe the epidemiology and impact of serious assault warranting in-patient care over six years and its impact on ED attendances in a large teaching hospital in Dublin over 2 years. There were 16,079 emergency assault-related inpatient hospital discharges reducing from 60.1 per 100,000 population in 2005 to 50.6 per 100,000 population in 2010. The median length of stay was 1 day (1-466) representing 49,870 bed days. The majority were young males (13,921, 86.6%; median age 26 years). Overall crime figures showed a similar reduction. However, knife crimes did not reduce over this period. Data on ED attendances confirmed the age and gender profile and also showed an increase at weekends. Alcohol misuse was recorded in 2,292/16079 (14%) of in-patient cases and 242/2484 (10%) in ED attendances. An inter-sectoral preventative approach specifically targeting knife crime is required to reduce this burden on health services.

Non-invasive molecular imaging for preclinical cancer therapeutic development.

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development.

A qualitative study of the perceived impact of a community mobilisation intervention to reduce alcohol consumption among amateur sportsmen.

Aim The aim of this study was to examine the perceived impact of a community mobilisation intervention programme to reduce alcohol consumption among amateur sportsmen aged 16-34 years. METHOD: A qualitative focus group format was used to identify potentially important themes or concepts relating to players' and coaches' experiences of the intervention. Six focus groups were conducted (five with four to seven players per focus group and one with six coaches) to elicit participants' experiences of the intervention. RESULTS: Three major themes emerged from the analyses: patterns of alcohol consumption and associated factors; perceived impact of the intervention; and suggested changes to the community mobilisation intervention. Excessive binge drinking (i.e. the consumption of six or more standard drinks on any one occasion) was common among players. The perceived impact of the intervention programme among players was low; players and coaches believed that if future programmes were to succeed, a 'bottom-up' rather than a 'top-down' approach should be adopted. CONCLUSIONS: The findings suggest that players perceived the community mobilisation programme to have had only limited success in changing attitudes or behaviour towards alcohol consumption in this amateur sports setting.

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design.

BACKGROUND: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design. METHODS: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily). RESULTS: Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA decline was 0.6 log(10) IU/ml in the first 24 h in the single-dose protocol and 1.5 log(10) IU/ml after 6 days of PHX1766 dosing. CONCLUSIONS: An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction.

Trends in COPD mortality and in-patient admissions in men & women: evidence of convergence.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality. Although more prevalent in men, it is anticipated that, due to the convergence in smoking rates, the prevalence rate in women will surpass that of men. There were 14,519 deaths attributable to COPD in the period 2000-2009. Although deaths decreased for both sexes, reduction in deaths was significantly higher among men (test for trend, p<0.01 for men vs. p=0.06 for women). Smoking rates decreased for both sexes from 1980-2009 with the percentage reduction in smoking significantly greater in men (11.5% vs. 7.0%, p<0.001). There has been a convergence in COPD deaths and COPD hospital in-patient discharges for men and women that mirrors the trend in the convergence of male and female smoking rates. This study provides evidence of the need for effective smoking cessation programmes that are targeted at women as well as men.

Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients.

OBJECTIVE: Dutogliptin is a novel, orally available, potent, and selective DPP4 inhibitor that improves glycemic control in type 2 diabetic patients. The objective of this study was to evaluate the potential pharmacokinetic and pharmacodynamic interactions, as well as the tolerability, of dutogliptin and metformin alone and in combination in type 2 diabetic patients. METHODS: This was a single-center, randomized, open-label, 3-way, crossover study in type 2 diabetic patients. All patients received three treatment regimens, each of 5 days duration in order to reach steady state: 400 mg once daily of dutogliptin (the anticipated clinical dose); 1000 mg metformin twice daily (maximum effective clinical dose); and concomitant administration of 400 mg dutogliptin once daily and 1000 mg metformin twice daily. RESULTS: Co-administration of dutogliptin and metformin did not alter the pharmacokinetics of either agent. The geometric mean ratio, GMR (dutogliptin + metformin/dutogliptin) of the area under the plasma concentration-time curve (AUC(0-24h)) at steady state was 0.91 (90% CI: 0.79-1.06; p = 0.29); the GMR of the maximum plasma concentrations (C(max)) was 0.95 (90% CI: 0.76-1.19; p = 0.70); the time to maximum plasma concentrations (T(max)) was essentially the same for dutogliptin with or without metformin. The GMR (dutogliptin + metformin/metformin) of AUC(0-12h) at steady state was 0.99 (90% CI: 0.84-1.17; p = 0.93); the GMR of C(max) was 0.91 (90% CI: 0.79-1.04; p = 0.18); T(max) was comparable for metformin with or without dutogliptin. Metformin added to dutogliptin had no effect on plasma DPP4 inhibition. All three treatment regimens were well tolerated. CONCLUSIONS: In this small, multiple dose study, the steady state pharmacokinetics of either dutogliptin or metformin were not altered by co-administration of the two agents. Dutogliptin and metformin were well tolerated either alone or in combination and co-administered metformin did not alter the ex vivo DPP4 inhibition by dutogliptin. There is no need to consider pharmacokinetic and pharmacodynamic interactions when determining the dosage of either agent for co-administration. A phase 3 clinical trial is underway to provide more definitive data on the safety and efficacy of dutogliptin administered on a background of metformin treatment.

Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial.

AIM: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. METHODS: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2-week single-blind placebo run-in, patients aged 18-75 years with a body mass index of 25-48 kg/m(2) and baseline HbA1c of 7.3-11.0% were randomized 2:2:1 to receive once-daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. RESULTS: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by -0.52% (p < 0.001) and -0.35% (p = 0.006), respectively (placebo-corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of -0.82, -0.64 and -0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo-corrected difference was -1.00 mmol/l (p < 0.001) for the 400 mg group and -0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC (0-2h) in both the 400 and 200 mg groups (placebo corrected values -2.58 mmol/l/h, p < 0.001 and -1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin-treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12-week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. CONCLUSIONS: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.

Alcohol levels in killed drivers and pedestrians on Irish roads 2003-2005: a national study.

No official data are provided in Ireland to indicate what proportion of the deaths on Irish roads have alcohol as a contributory factor. The aim of this study was to identify the blood alcohol concentration (BAC) in fatally injured drivers and pedestrians in Ireland. An Garda Síochána (The Irish police) gather data on all fatal road crashes and individual paper files are kept on each crash. The authors examined all such files for deaths in 2003-2005. Of the 611 drivers fatally injured, 184 (30.1%) were over the BAC legal limit (80 mg/100 ml). BACs were available for only 397 (64.9%) of drivers. Of the 397 drivers who had their BACs recorded, 184 (46.3%) had a BAC over the legal limit of 80 mg/100 ml and 220 (55.4%) had BACs 20 mg/100 ml or higher. Fatally injured drivers with BACs 20 mg/100 ml or greater were more likely to be male (88.6%/o, p<0.01). Alcohol-related crashes were more likely to occur on week end nights. Pedestrian alcohol consumption was considered to be a contributory factor in 50 (24.4%) of the pedestrian deaths with 22 (10.7%) of the pedestrians having alcohol levels exceeding 240 mgl/100 ml. This study confirms that alcohol is a significant factor in road deaths. Further targeted action including a reduction in the legal limit is required.

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase-4 (DPP4) inhibitor, in patients with type 2 diabetes. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled, 4-week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A(1c) (HbA(1c)) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once-daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. RESULTS: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC(0-2 h) by approximately 20% (+0.11 +/- 0.50, -2.08 +/- 0.51, -1.73 +/- 0.49 and -1.88 +/- 0.48 mmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC(0-2 h) of intact glucagon-like peptide-1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 +/- 2.83, 11.63 +/- 2.86, 16.42 +/- 2.72 and 15.75 +/- 2.71 pmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA(1c) was lower in all dose groups; the placebo-corrected change in the groups receiving 400 mg PHX1149 was -0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149-treated and placebo subjects. CONCLUSIONS: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.

Under-reporting of notifiable infectious disease hospitalizations in a health board region in Ireland: room for improvement?

Rapid notification of infectious diseases is essential for prompt public health action and for monitoring of these diseases in the Irish population at both a local and national level. Anecdotal evidence suggests, however, that the occurrence of notifiable infectious diseases is seriously underestimated. This study aims to assess the level of hospitalization for notifiable infectious diseases for a 6-year period in one health board region in Ireland and to assess whether or not there was any under-reporting during this period. All hospital in-patient admissions from 1997 to 2002 inclusive with a principal diagnosis relating to 'infectious and parasitic diseases' (ICD codes 001-139) of residents from a health board region in Ireland were extracted from the Hospital In-Patient Enquiry System (HIPE). All notifiable infectious diseases were identified based on the 1981 Irish Infectious Disease Regulations and the data were analysed in the statistical package, JMP. These data were compared with the corresponding notification data. Analysis of the hospital in-patient admission data revealed a substantial burden associated with notifiable infectious diseases in this health board region: there were 2758 hospitalizations by 2454 residents, 17,034 bed days and 33 deaths. The statutory notification data comprises both general practitioner and hospital clinician reports of infectious disease. Therefore, only in cases where there are more hospitalizations than notifications can under-reporting be demonstrated. This occurred in nine out of 22 notifiable diseases and amounted to an additional 18% of notifications (or 572 cases) which were 'missed' due to hospital clinician under-reporting. The majority of these under-reported cases were for viral meningitis (45%), infectious mononucleosis (27%), viral hepatitis C unspecified (15%) and acute encephalitis (5.8%). This study has highlighted the extent of under-reporting of hospitalized notifiable infectious diseases, in a health board region in Ireland, which is a cause for concern from a surveillance point of view. If this under-reporting is similar in other health boards, then it would appear that the epidemiology of some notifiable diseases is incomplete both regionally and nationally. This under-reporting negatively impacts on the effectiveness of the notification process as a 'real-time' surveillance tool and an early warning system for outbreaks.

Hospital admission for acute pancreatitis in the Irish population, 1997 2004: could the increase be due to an increase in alcohol-related pancreatitis?

OBJECTIVE: To investigate trends in the incidence of acute pancreatitis by examining emergency admissions to acute public hospitals over an 8-year period; to compare trends for alcohol-related pancreatitis admissions with biliary tract-related admissions and to profile the patients admitted with an acute pancreatitis diagnosis. METHODS: All in-patient emergency admissions for which an acute pancreatitis diagnosis (ICD-9-CM Code 577.0) was recorded as principal diagnosis were identified for years 1997-2004 inclusive. Alcohol-related acute pancreatitis admissions (i.e. had alcohol misuse recorded as co-morbidity) were identified using ICD-9-CM-codes 303 and 305. Biliary tract disease-related admissions (i.e. had biliary tract disease recorded as co-morbidity) were identified using ICD-9-CM codes 574.0-576.0 inclusive. Pearson's chi2-test was used to compare proportions in groups of categorical data and chi2-tests for trend were used to identify linear trends. RESULTS: There were 6291 emergency admissions with a principal diagnosis of acute pancreatitis during the 8 year study period, with 622 admissions in 1997 compared to 959 admissions in 2004, an increase of 54.1%. Age standardized rates rose significantly from 17.5 per 100,000 population in 1997 to 23.6 per 100,000 in 2004, (P<0.01 for linear trend). There were 1205 admissions with alcohol misuse recorded as a co-morbidity increasing from 13.9% (87/622) of acute pancreatitis admissions in 1997 to 23.2% (223/959) in 2004. This increase was significantly greater than the increase observed for biliary tract disease-related admissions, 19.6% (122/622) in 1997 to 23.5% (225/959) in 2004. Rates for total acute pancreatitis admissions were highest in those aged 70 years and over; the majority (3563, 56.6%) of the admissions were male with a mean age of 51.1 years (SD 19.9); the mean age for male admissions was significantly younger than for female admissions (49.1 versus 53.6 years, P<0.001). However, for alcohol-related admissions, rates were highest in those aged 30-49 years and patients admitted with alcohol misuse recorded were significantly younger than those who did not have alcohol misuse recorded (42.0 versus 53.2 years, P<0.001). Median length of stay was 7 days. CONCLUSIONS: Hospital admissions for acute pancreatitis rose from 17.5 per 100,000 population in 1997 to 23.6 per 100,000 in 2004. The proportion of admissions that had alcohol misuse recorded as a co-morbidity rose more markedly than those with biliary tract disease and the rise was more pronounced in younger age groups. The increasing trend in alcohol-related acute pancreatitis parallels the rise in per capita alcohol consumption. Given the continuing rise in binge drinking, particularly among young people, this is a cause for concern.