Personal and Public Involvement and its impact - Monitoring, measuring and evaluating the impact of Personal and Public Involvement (PPI) in Health and Social Care in Northern Ireland.

Introduction
This report details the findings from research conducted across Northern Ireland’s Health and Social Care Trusts during 2015 which examines the current state of Personal and Public Involvement (PPI). This is about how service users, carers and patients engage with staff, management and directors of statutory health and social care organisations. Most statutory health and social care organisations must, under legislation, meet the requirements of PPI. PPI has been part of health and social care policy in Northern Ireland since 2007 and became law two years later with the introduction of the Health and Social Care Reform Act (2009). It is, therefore, timely that PPI is now assessed in this systematic way in order to both examine the aspects which are working well and to highlight those areas where improvements need to be made. As far as possible, this Summary Report is written in an accessible way, avoiding jargon and explaining key research terms, so as to ensure it is widely understood. This is in keeping with established good practice in service user involvement research. This summary, therefore, gives a picture of PPI in Northern Ireland currently. There is also a fuller report which gives a lot more details about the research and findings. Information on this is available from the Public Health Agency and/or the Patient and Client Council.

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder.

BACKGROUND:Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder.METHOD: Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale.RESULTS:Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups.CONCLUSIONS: In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

Proton pump inhibitors and histamine-2-receptor antagonists and pancreatic cancer risk: a nested case-control study

Background: The relationship between use of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H₂RAs) and pancreatic cancer risk has yet to be examined. Data from a range of studies suggest biologically plausible mechanisms, whereby these drugs (or the conditions for which they are prescribed) may affect pancreatic cancer risk. The objective of this study was to investigate the relationship between use of PPIs/H₂RAs and pancreatic cancer risk.

Methods: A nested case – control study was conducted within the UK general practice research database (GPRD). Cases had a diagnosis of exocrine pancreatic cancer and controls were matched to cases on general practice site, sex and year of birth. Exposure to PPIs and to H₂RAs since entry into GPRD until 2 years before the diagnosis date (corresponding date in controls) and in the 5 years before the diagnosis date were separately assessed. Conditional logistic regression analyses were used to generate odds ratios (ORs) and 95% confidence intervals (CIs) associated with PPI or H₂RA use compared with nonuse.

Results: Ever use of PPIs since entry into the GPRD (excluding the 2 years prior to diagnosis) was not associated with risk of pancreatic cancer; OR (95% CI) 1.02 (0.85 – 1.22). Neither the dose nor the duration of PPI or H₂RA use was associated with pancreatic cancer risk. No consistent patterns of association were seen when cumulative exposure (dose and duration) to these drugs was examined separately or together.

Conclusion: PPI/H₂RA use, in a UK population, was not associated with pancreatic cancer risk.

The GalF protein of Escherichia coli is not a UDP-glucose pyrophosphorylase but interacts with the GalU protein possibly to regulate cellular levels of UDP-glucose

We report the functional characterization of the galF gene of strain VW187 (Escherichia coli O7:K1), which encodes a polypeptide displaying structural features common to bacterial UDP-glucose pyrophosphorylases, including the E. coli GalU protein. These enzymes catalyse a reversible reaction converting UTP and glucose-1-phosphate into UDP-glucose and PPi. We show that, although the GalF protein is expressed in vivo, GalF-expressing plasmids cannot complement the phenotype of a galU mutant and extracts from this mutant which only produces GalF are enzymatically inactive. In contrast, the presence of GalU and GalF proteins in the same cell-free extract caused a significant reduction in the rate of pyrophosphorolysis (conversion of UDP-glucose into glucose-1-phosphate) but no significant effect on the kinetics of synthesis of UDP-glucose. The presence of GalF also increased the thermal stability of the enzyme in vitro. The effect of GalF in the biochemical properties of the UDP-glucose pyrophosphorylase required the co-synthesis of GalF and GalU, suggesting that they could interact as components of the oligomeric enzyme. The physical interaction of GalU and GalF was demonstrated in vivo by the co-expression of both proteins as fusion products using a yeast two-hybrid system. Furthermore, using a pair of galF-/galU+ and galF/galU+ isogenic strains, we demonstrated that the presence of GalF is associated with an increased concentration of intracellular UDP-glucose as well as with an enhancement of the thermal stability of the UDP-glucose pyrophosphorylase in vivo. We propose that GalF is a non-catalytic subunit of the UDP-glucose pyrophosphorylase modulating the enzyme activity to increase the formation of UDP-glucose, and this function is important for bacterial adaptation to conditions of stress.

Distribution of atrophy in Helicobacter pylori-infected subjects taking proton pump inhibitors

Gastric atrophy is associated with Helicobacter pylori infection. Conflicting results have been obtained as to whether acid suppressant therapy hastens the development or changes the distribution of atrophy in the stomach. The aim of this study was to investigate whether concomitant proton pump inhibitor (PPI) therapy in H. pylori-infected individuals resulted in an increase or an alteration in atrophy distribution and whether this was reflected by the plasma gastrin.

Obesity associated severe asthma represents a distinct clinical phenotype - Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index

BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airways inflammation. However, the role of obesity in severe asthma remains unclear. OBJECTIVE: To explore the association between obesity (defined by BMI) and severe asthma. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between three body mass index (BMI) categories (normal weight: 18.5 -24.99, overweight: 25 -29.99, obese: =30) in a well characterised group of severe asthmatic adults. RESULTS: The study population consisted of 666 severe asthmatics with a median BMI of 29.8 (interquartile range 22.5 -34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% versus 40.4% and 34.5% in the overweight and normal weight groups, respectively), steroid burst therapy and short-acting ß2-agonist (SABA) use per day. Significant differences were seen with gastro-oesophageal reflux disease (GORD) (53.9% versus 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor (PPI) use. Bone density scores were higher in the obese group, whilst pulmonary function testing revealed a reduced FVC and raised Kco. Serum IgE levels decreased with increasing BMI and the obese group were more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Severe asthmatics display particular characteristics according to BMI that support the view that obesity associated severe asthma may represent a distinct clinical phenotype.1Royal Brompton Hospital, London, UK;2Department of Computing, Imperial College, UK3Airways Disease, National Heart & Lung Institute, Imperial College, UK;4Centre for infection and immunity, Queen's University of Belfast, UK;5University of Leicester, UK;6The University of Manchester and University Hospital of South Manchester, UK;7Birmingham Heartlands Hospital, University of Birmingham, UK;8Gartnavel General Hospital, University of Glasgow, UK;9Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Dr Andrew N. Menzies-Gow, Royal Brompton Hospital, Fulham Road, London SW3 6HP.

Novel opportunities for thymidylate metabolism as a therapeutic target

For over 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) has remained the central agent in therapeutic regimens employed in the treatment of colorectal cancer and is frequently combined with the DNA-damaging agents oxaliplatin and irinotecan, increasing response rates and improving overall survival. However, many patients will derive little or no benefit from treatment, highlighting the need to identify novel therapeutic targets to improve the efficacy of current 5-FU-based chemotherapeutic strategies. dUTP nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi, providing substrate for thymidylate synthase (TS) and DNA synthesis and repair. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA as uracil is lethal. Importantly, uracil misincorporation represents an important mechanism of cytotoxicity induced by the TS-targeted class of chemotherapeutic agents including 5-FU. A growing body of evidence suggests that dUTPase is an important mediator of response to TS-targeted agents. In this article, we present further evidence showing that elevated expression of dUTPase can protect breast cancer cells from the expansion of the intracellular uracil pool, translating to reduced growth inhibition following treatment with 5-FU. We therefore report the implementation of in silico drug development techniques to identify and develop small-molecule inhibitors of dUTPase. As 5-FU and the oral 5-FU prodrug capecitabine remain central agents in the treatment of a variety of malignancies, the clinical utility of a small-molecule inhibitor to dUTPase represents a viable strategy to improve the clinical efficacy of these mainstay chemotherapeutic agents.

Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage

Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA is lethal. Importantly, uracil misincorporation is a mechanism of cytotoxicity induced by fluoropyrimidine chemotherapeutic agents including 5-fluorouracil (5-FU) and elevated expression of dUTPase is negatively correlated with clinical response to 5-FU-therapy. In this study we performed the first functional characterization of the dUTPase promoter and demonstrate a role for E2F-1 and Sp1 in driving dUTPase expression. We establish a direct role for both mutant and wild-type forms of p53 in modulating dUTPase promoter activity. Treatment of HCT116 p53(+/+) cells with the DNA-damaging agent oxaliplatin induced a p53-dependent transcriptional downregulation of dUTPase not observed in the isogenic null cell line. Oxaliplatin treatment induced enrichment of p53 at the dUTPase promoter with a concomitant reduction in Sp1. The suppression of dUTPase by oxaliplatin promoted increased levels of dUTP that was enhanced by subsequent addition of fluoropyrimidines. The novel observation that oxaliplatin downregulates dUTPase expression may provide a mechanistic basis contributing to the synergy observed between 5-FU and oxaliplatin in the clinic. Furthermore, these studies provide the first evidence of a direct transcriptional link between the essential enzyme dUTPase and the tumor suppressor p53.

Network signatures based on gene pair expression ratios improve classification and the analysis of muscle-invasive urothelial cancer

Urothelial cancer (UC) is highly recurrent and can progress from non-invasive (NMIUC) to a more aggressive muscle-invasive (MIUC) subtype that invades the muscle tissue layer of the bladder. We present a proof of principle study that network-based features of gene pairs can be used to improve classifier performance and the functional analysis of urothelial cancer gene expression data. In the first step of our procedure each individual sample of a UC gene expression dataset is inflated by gene pair expression ratios that are defined based on a given network structure. In the second step an elastic net feature selection procedure for network-based signatures is applied to discriminate between NMIUC and MIUC samples. We performed a repeated random subsampling cross validation in three independent datasets. The network signatures were characterized by a functional enrichment analysis and studied for the enrichment of known cancer genes. We observed that the network-based gene signatures from meta collections of proteinprotein interaction (PPI) databases such as CPDB and the PPI databases HPRD and BioGrid improved the classification performance compared to single gene based signatures. The network based signatures that were derived from PPI databases showed a prominent enrichment of cancer genes (e.g., TP53, TRIM27 and HNRNPA2Bl). We provide a novel integrative approach for large-scale gene expression analysis for the identification and development of novel diagnostical targets in bladder cancer. Further, our method allowed to link cancer gene associations to network-based expression signatures that are not observed in gene-based expression signatures.