Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial.

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.

Achieving high quality colonoscopy: using graphical representation to measure performance and reset standards.

AIM: Completeness and thoroughness of colonoscopy are measured by the caecal intubation rate (CIR) and the adenoma detection rate (ADR). National standards are ≥ 90% and ≥ 10% respectively. Variability in CIR and ADR have been demonstrated but comparison between individuals and units is difficult. We aimed to assess the performance of colonoscopy in endoscopy units in the northeast of England. METHOD: Data on colonoscopy performance and sedation use were collected over 3 months from 12 units. Colonoscopies performed by screening colonoscopists were included for the CIR only. Funnel plots with upper and lower 95% confidence limits for CIR and ADR were created. RESULTS: CIR was 92.5% (n = 5720) and ADR 15.9% (n = 4748). All units and 128 (99.2%) colonoscopists were above the lower limit for CIR. All units achieved the ADR standard with 10 above the upper limit. Ninety-nine (76.7%) colonoscopists were above 10%, 16 (12.4%) above the upper limit and 7 (5.4%) below the lower limit. Median medication doses were 2.2 mg midazolam, 29.4 mg pethidine and 83.3 µg fentanyl. In all, 15.1% of colonoscopies were unsedated. Complications were bleeding (0.10%) and perforation (0.02%). There was one death possibly related to bowel preparation. CONCLUSION: Results indicate that colonoscopies are performed safely and to a high standard. Funnel plots can highlight variability and areas for improvement. Analyses of ADR presented graphically around the global mean suggest that the national standard should be reset at 15%.

Endoscopic retrograde cholangio-pancreatography practice in district general hospitals in North East England: a Northern Regional Endoscopy Group (NREG) study.

AIM: Endoscopic retrograde cholangio-pancreatography (ERCP) is an important tool for the management of pancreato-biliary disease. The aim of this study was to compare the current practice of ERCP in North East England against the key 2004 National Confidential Enquiry Report into Patient Outcome and Death (NCEPOD) recommendations and the standards set by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG). METHODS: This was a prospective multicentre study involving all hospitals in North East England, coordinated through the Northern Regional Endoscopy Group (NREG). RESULTS: Fourteen endoscopy units submitted data for 481 ERCPs. Mean dose of midazolam was 3.24 mg (standard deviation 1.35; range 1-8 mg). Coagulation profile results were available on 469 patients (97%). Radiological investigations were documented in 96% of the procedures (463 of 481) prior to ERCP. The most common indication for ERCP was related to choledocholithiasis and its complications. All procedures were performed with a therapeutic intent. A total of 84% of all patients were either American Society of Anesthesiologists grade I or II. The selective biliary cannulation rate was 87.3%. The total completion rate of all procedures was 80.2% (381 of 475) and completion of therapy was 89.5% (425 of 475). The 30-day mortality rate was 2% (ten patients) and procedure-related complications occurred in 5% of patients. There were no deaths directly as a result of ERCP; all deaths were related to underlying medical conditions. CONCLUSIONS: The practice of ERCP in North East England adheres to the key recommendations of the NCEPOD and the standards set by JAG. The rates of complications compare favourably with those reported internationally.

Extracellular matrix proteins and tumor angiogenesis.

Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.

The role of dysregulated glucose metabolism in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

cAMP response element-binding protein is expressed at high levels in human ovarian adenocarcinoma and regulates ovarian tumor cell proliferation.

Approximately 90% of human ovarian tumors result from transformation of ovarian surface epithelial cells. It has been hypothesized that repeated destruction of the epithelial cells during ovulation, followed by proliferation and migration of epithelial cells to restore the ovarian surface, renders these cells susceptible to mutagenic events. One of the proteins found to promote ovarian surface epithelial cell survival and proliferation was the transcription factor, cAMP response element-binding protein (CREB). Thus, the objective of this study was to determine whether CREB was also highly expressed in tumor cells originating from the ovarian epithelium. Using an ovarian cancer tissue array, it was observed that approximately 54% of the epithelial-derived human ovarian tumors displayed moderate or high levels of CREB immunostaining, while none of the normal ovarian samples did. Comparison of CREB levels in a human ovarian tumor cell line to those of a normal ovarian epithelial cell line revealed elevated levels of CREB and phosphorylated CREB in the ovarian tumor cells. To determine whether CREB regulated proliferation and/or apoptosis in the ovarian tumor cell line, CREB expression was suppressed using RNA interference. Decreased CREB expression significantly reduced ovarian tumor cell proliferation, while there was no effect on apoptosis in these cells. Finally, we showed that CREB is highly expressed in an in vivo murine model of ovarian tumorigenesis. Therefore, CREB is frequently overexpressed in ovarian cancer where it appears to promote cell proliferation.

The impact of implementing national hypertension guidelines on prevalence and workload in primary care: a population-based survey of older people.

Recently revised UK and US hypertension guidelines have reduced thresholds for both diagnosis and treatment and differ in their recommendations. We have used data from a random, stratified community-based sample of 4784 people aged 65 years and over to compare the prevalence of treatable hypertension and the potential impact on patients and primary care from using current guidelines. BHS, NICE and JNC7 guidelines were applied to blood pressures obtained from primary care medical records (94%) or measured at a screening clinic (6%). Risk factors were obtained by questionnaire and from medical records, supplemented by epidemiological data. Workload was estimated for a representative practice population of 10 000 patients. Blood pressures were obtained on 4514 patients (94%). Prevalence of treatable hypertension was over 67%. Compared to BHS4, prevalence estimates using NICE guidelines were comparable for men but significantly lower for women (P<0.05). They were significantly higher using JNC7 compared with BHS4 and NICE guidance (P<0.05). A general practice of 10 000 patients could expect 1287 older hypertensive patients using BHS4 guidelines and 1231 patients using NICE guidelines. Under BHS4, an extra 94 patients will require annual, rather than 5-yearly review compared with that using the previous guideline. In conclusion, implementation of BHS4 guidelines, with their revised thresholds for diagnosis, will not add materially to the prevalence of treatable hypertension compared to previous BHS3 guidelines but will have a major impact on practice workload. Use of NICE guidelines in preference to BHS4 will result in GPs treating fewer patients and reviewing untreated patients less often.

Anatomy of the lumbosacral spinal cord in rabbits.

This study provides an accurate, anatomical description of the rabbit's lumbosacral spinal cord. Following humane euthanasia, 64 rabbits were radiographed and dissected. The number of thoracic (T) and lumbar (L) vertebrae was 12T/7L in 43.8%, 13T/6L in 32.8%, and 13T/7L in 23.4% in the 64 rabbits studied. The 13th ribs were rudimentary, asymmetric, or both in 15 animals. The spinal cord terminated within the second sacral vertebra (S2) in 79.3%, within the first sacral vertebra (S1) in 19.0%, and within the third sacral vertebra (S3) in 1.7% of the sample. Spinal nerve contributions to the femoral, obturator, sciatic, and pudendal nerves were determined. Formulas to predict the termination of the cord relative to the vertebral column were established. Age, weight, sex, and method of preparation did not show a significant correlation with the length of the spinal cord.

The "improved" public house, 1870-1950: the key to civilized drinking or the primrose path to drunkenness?

The Victorian temperance movement aimed to eliminate, not reform, public houses, but from 1870 interest began to be taken in promoting an "improved" public house which could promote counter-attractions to drink. Disinterested management, based upon public ownership or a trust company, was advocated as the best means of achieving this. There was, however, an ambiguity about the nature of the "improved" public house. Was the goal an austere establishment where the drinking could be controlled in the public interest, or was it a comfortable leisure centre which would promote civilized drinking? This ambiguity lay unresolved during the period of the Carlisle experiment in state control in the period after 1915. Increasingly during the inter-war years the policies of the state-run Carlisle scheme and the more go-ahead brewers converged. The issue was originally conceptualized as a moral one, then as one of national efficiency and finally as a commercial one.

Open access gastroscopy findings are unrelated to the use of aspirin and non-steroidal anti-inflammatory drugs.

This study aims to determine whether priority should be given to patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin when selecting which dyspeptic patients to refer for open access gastroscopy. A total of 8156 patients underwent gastroscopy, all of whom had upper gastrointestinal symptoms. Patients taking NSAIDs or aspirin showed no significant differences in the frequency of ulcer disease when age-matched groups were compared. Although NSAIDs and aspirin are frequently implicated in gastrointestinal bleeding in the elderly, patients referred for investigation of dyspepsia show no increase in major endoscopic pathology.

Digoxin toxicity presenting as encephalopathy.

We describe two cases of digoxin toxicity presenting with clinical and electroencephalographic evidence of encephalopathy without other features of digoxin toxicity.

Embryotoxicity induced by diethylstilbestrol in vitro.

The embryotoxic potential of diethylstilbestrol (DES) was examined in a whole embryo culture system containing a P-450-dependent bioactivating system. Sprague-Dawley rat embryos were explanted on day 10 and cultured for 24 hours. Concentration-dependent effects of DES on embryonic growth parameters, viability, and embryotoxicity were observed. Concentrations of DES greater than 0.26 mM (final concentration) produced 100% embryolethality, while those below 0.15 mM were without significant effects. At a final concentration of 0.19 mM, DES produced only a slight increase in embryolethality. The same concentration elicited a marked increase in observed embryotoxicity, including prosencephalic hypoplasia, incomplete axial rotation, and open neural tubes. In addition, reductions in embryonic length, somite number, and protein and DNA content were observed. An exogenous P-450-dependent hepatic biotransforming (catechol-generating) system failed to alter either the incidence of observed toxic effects or measured growth parameters. Likewise, exposure of cultured embryos to 20% carbon monoxide (CO) failed to reduce DES-induced embryotoxicity, indicating a lack of participation of an endogenous P-450-dependent embryonic bioactivating system. Arachidonic acid (0.20 mM) and/or indomethacin (0.50 mM) also had no observable effect on DES-induced embryotoxicity, suggesting that prostaglandin synthase was not involved in the embryotoxic activity of DES, as has been proposed to explain its carcinogenic effect. The antioxidants N-acetylcysteine (1.14 mM) and alpha-tocopherol (0.08 mM) failed to protect against DES-induced embryotoxicity, while the anti-estrogen tamoxifen (up to 0.85 mM) actually enhanced this effect of DES in culture. The DES analogs Z,Z-dienestrol (DIES, 0.10 mM) and hexestrol (HES, 0.48 mM) were both embryotoxic in vitro. The presence of an exogenous P-450-dependent hepatic biotransforming system appeared to protect against HES-induced embryolethality but had little effect upon DIES-induced embryotoxicity. The results were consistent with a direct effect of DES independent of either estrogenicity or exogenously generated metabolites.

The toxicity of niridazole in rat embryos in vitro.

The antischistosomal drug niridazole (NDZ) was found to be teratogenic in a concentration-dependent manner from 10 to 50 micrograms/ml (47-233 microM) in rat embryos cultured from day 10 to day 11. A striking malformation consisting of axial asymmetry in which the right side of the embryo showed severe necrosis was the predominant malformation. The drug showed significantly greater dysmorphogenic activity at low (5%) compared to high (20%) oxygen tensions in cultures. Coincubation of embryos and NDZ with an exogenous source of metabolic enzymes and cofactors (NADPH) failed to modify teratogenicity. Inclusion of CO in the culture atmosphere significantly reduced the malformation incidence as did preincubation of the drug with S-9 and cofactors in medium with low O2 tension. Treatment of gravida with NDZ up to and including the maternal-lethal dose failed to result in observable malformations despite the use of several routes of exposure. These data lead us to hypothesize that rat embryos are capable of performing the reductive activation of NDZ in a fashion analogous to the schistosome but that reductive extraembryonic metabolism may result in teratogenic bioinactivation.

Methacrylic acid as a teratogen in rat embryo culture.

Using day 10 rat embryos cultured in vitro, we have shown that methacrylic acid is teratogenic at concentrations ranging from 1.2 to 2.1 mM. At these concentrations, methacrylic acid produced concentration-dependent decreases in growth parameters, i.e., crown-rump length, number of somites, and embryo protein content. In addition, methacrylic acid exposure produced malformed embryos characterized primarily by abnormal neurulation. Less frequent abnormalities included hypoplasia of the prosencephalon, edema, malpositioned heart, abnormal flexion, and dilated otic vesicles. Accompanying these abnormalities was an underlying increase in methacrylic acid-induced cell death.

On the capacity of nitroheterocyclic compounds to elicit an unusual axial asymmetry in cultured rat embryos.

A series of nitroheterocyclic compounds with antimicrobial and radiosensitizing properties was tested for embryotoxicity in cultured Sprague-Dawley rat embryos, and their effects were compared with various other five-membered heterocycles. Nifuroxime, furazolidone, nitrofurazone, niridazole, 2-nitroimidazole, and ronidazole each elicited a striking malformation characterized by asymmetrical, right-sided hypoplasia when coincubated with embryos for 26 hr. Minimum concentrations required to elicit this unusual defect ranged from 0.01 mM with nifuroxime and furazolidone to 0.5 mM with ronidazole and were roughly correlated with single electron redox potentials; i.e., agents with relatively high redox potentials were generally more effective than those with low potentials. Nitrofurantoin failed to elicit this unusual malformation but exhibited an extremely steep dose-response curve for embryolethality. Metronidazole and 4-nitroimidazole, nitroheterocyclic agents with relatively low redox potentials, did not produce the asymmetric abnormality nor were they highly embryotoxic, even at concentrations up to 2 mM. 2-Amino-5-nitrothiazole and 4'-methylniridazole also failed to evoke the asymmetric malformation but produced significant embryotoxicity as manifested by decreased growth parameters and elicitation of other kinds of malformations. Heterocyclic compounds not bearing a nitro group (furosemide, 2-aminothiazole, and 2-aminoimidazole) failed to elicit axial asymmetry at concentrations up to 1.0 mM but produced other signs of embryotoxicity at the highest concentrations tested. The results suggest that the presence of a reducible nitro group is critical for generation of the unusual malformation and that the single-electron redox potential of the nitro group plays a dominant but not exclusive role in the capacity of these chemicals to evoke axial asymmetry in cultured rat embryos.

Generation of reactive dysmorphogenic intermediates by rat embryos in culture: effects of cytochrome P-450 inducers.

We have investigated the capacity of cultured whole rat embryos to convert 2-acetylaminofluorene (AAF) to reactive metabolites capable of eliciting dysmorphogenic effects in the same embryos. Cultured embryos (Sprague-Dawley) were exposed to AAF for periods of 2 or 24 hr, after which metabolites were isolated from the culture medium and identified with HPLC. Embryotoxic effects were evaluated in the same embryos. Day 10 embryos preexposed in utero to pregnenolone-16 alpha-carbonitrile (PCN) exhibited marked increases in capacity to convert AAF to a variety of hydroxylated metabolites. 3-Methylcholanthrene (3MC) was also a very effective inducer in utero but Aroclor 1254 (PCB), and isosafrole (ISF) evoked only minimal induction while phenobarbital (PB) was not demonstrably effective. Exogenously added hepatic postmitochondrial supernatant (S9) fractions from adult male rats pretreated with PCB, 3MC, or ISF exhibited induced monooxygenase activities as well as increased capacity to convert AAF to dysmorphogenic intermediates in the culture system. PB and PCN displayed much lesser effects. PCN was a very effective inducer of hepatic monooxygenases of pregnant rats but, when this tissue was utilized as an enzyme source, no significant increase in malformations was observed. Embryos with relatively high monooxygenase activities also displayed a high incidence of embryonic abnormalities when cocultured with AAF. Malformation incidence was strongly correlated with hydroxy metabolite generation, suggesting that induction in utero of P-450-dependent, embryonic monooxygenases resulted in the production of embryotoxic metabolites by the embryos own enzymes. The data also indicated that endogenous bioactivation (within the conceptus) was considerably more effective than bioactivation effected by an exogenous (hepatic) enzyme source.