Impact of COVID-19 pandemic restrictions on pregnancy duration and outcome in Melbourne, Australia.

OBJECTIVE: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome. METHODS: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis. RESULTS: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116). CONCLUSIONS: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Foley catheter vs oral misoprostol for induction of labor: individual participant data meta-analysis.

OBJECTIVE: To compare the effectiveness and safety of Foley catheter and oral misoprostol for induction of labor (IOL). METHODS: The Cochrane Review on Mechanical Methods for Induction of Labour and Ovid MEDLINE, EMBASE via Ovid, Ovid Emcare, CINAHL Plus, ClinicalTrials.gov and Scopus, from inception to April 2019, were searched for randomized controlled trials (RCTs) comparing Foley catheter to oral misoprostol for IOL in viable singleton gestations. Eligible trials for which raw data were obtained were included and individual participant data meta-analysis was performed. Primary outcomes were vaginal birth, a composite of adverse perinatal outcome (including stillbirth, neonatal death, neonatal seizures, admission to the neonatal intensive care unit, severe respiratory compromise or meconium aspiration syndrome) and a composite of adverse maternal outcome (including admission to the intensive care unit, maternal infection, severe postpartum hemorrhage, maternal death or uterine rupture). The quality of the included RCTs was assessed using the Cochrane Risk of Bias 2 tool and the certainty of evidence was evaluated using the GRADE approach. A two-stage random-effects model was used for meta-analysis according to the intention-to-treat principle and interactions between treatment and baseline characteristics were assessed. RESULTS: Of seven eligible trials, four provided individual participant data for a total of 2815 participants undergoing IOL, of whom 1399 were assigned to Foley catheter and 1416 to oral misoprostol. All four trials provided data for each of the primary outcomes in all 2815 women. Compared with those receiving oral misoprostol, Foley catheter recipients had a slightly decreased chance of vaginal birth (risk ratio (RR), 0.95 (95% CI, 0.91-0.99); I2 , 2.0%; moderate-certainty evidence). A trend towards a lower rate of composite adverse perinatal outcome was found in women undergoing IOL using a Foley catheter compared with oral misoprostol (RR, 0.71 (95% CI, 0.48-1.05); I2 , 14.9%; low-certainty evidence). Composite adverse maternal outcome did not differ between the groups (RR, 1.00 (95% CI, 0.97-1.03); I2 , 0%; moderate-certainty evidence). Meta-analyses of effect modifications did not show significant interactions between intervention and parity or gestational age for any of the primary outcomes. CONCLUSIONS: For women undergoing IOL, Foley catheter is less effective than oral misoprostol, as it was associated with fewer vaginal births. However, while we found no significant difference in maternal safety, Foley catheter induction may reduce adverse perinatal outcomes. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis.

Pre-eclampsia is a common obstetric complication globally responsible for a significant burden of maternal and perinatal morbidity and mortality. Central to its pathophysiology is the anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1). sFLT-1 is released from a range of tissues into the circulation, where it antagonizes the activity of vascular endothelial growth factor and placental growth factor leading to endothelial dysfunction. It is this widespread endothelial dysfunction that produces the clinical features of pre-eclampsia including hypertension and proteinuria. There are multiple splice variants of sFLT-1. One, known as sFLT-1 e15a, evolved quite recently and is only present in humans and higher order primates. This sFLT-1 variant is also the main sFLT-1 secreted from the placenta. Recent work has shown that sFLT-1 e15a is significantly elevated in the placenta and circulation of women with pre-eclampsia. It is also biologically active, capable of causing endothelial dysfunction and the end-organ dysfunction seen in pre-eclampsia. Indeed, the over-expression of sFLT-1 e15a in mice recapitulates the pre-eclamptic phenotype in pregnancy. Therefore, here we propose that sFLT-1 e15a may be the sFLT-1 variant primarily responsible for pre-eclampsia, a uniquely human disease. Furthermore, this placental-specific sFLT-1 variant provides promise for use as an accurate biomarker in the prediction or diagnosis of pre-eclampsia.

Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity, and process of care.

OBJECTIVES: Previous studies have found higher mortality rates among inpatients (IPs) compared with new admissions (outpatients, OPs) with acute upper gastrointestinal bleeding (AUGIB), but no studies have investigated the cause for this. The objective of this study was to determine whether the difference in outcomes between IPs and OPs with AUGIB can be explained by differences in baseline characteristics, bleeding severity, or processes of care. METHODS: Data were collected from 6,657 presentations with all-cause AUGIB from 212 UK hospitals as part of a nationwide audit. RESULTS: IPs were older (77 vs. 65 years, P<0.001), had greater comorbidity, and presented with more severe bleeding. There was no difference in median time to endoscopy (24 vs. 24 h, P=0.67) or receipt of endotherapy (19% vs. 17%, P=0.29). IPs had an odds of mortality 4.8 times that of OPs (26% vs. 7%; odds ratio (OR) 4.8, 95% confidence interval (CI) 3.9-5.8); after adjusting for baseline characteristics, this fell by 24% to 3.3 (95% CI 3.2-4.9) and after adjusting for bleeding severity alone to 4.0 (95% CI 3.2-4.9); adjusting for care processes had minimal effect. IPs had more than a twofold increased odds of rebleeding (20% vs. 12%; OR 2.1, 95% CI 1.7-2.5); adjusting for both baseline characteristics and severity of bleeding reduced this by 50% (OR 1.4, 95% CI 1.3-2.4), but process of care had no additional impact. CONCLUSIONS: IPs present with both higher baseline risks and more severe bleeding. These differences in baseline characteristics explain some but not all of the greater mortality of IPs with AUGIB.

National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding.

BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.

Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study.

BACKGROUND AND STUDY AIMS: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. PATIENTS AND METHODS: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. RESULTS: In 4478 patients, earlier endoscopy ( < 12 hours) was not associated with a lower mortality or need for surgery compared with later ( > 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy ( > 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). CONCLUSIONS: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision.

Comparison of circulating total sFLT-1 to placental-specific sFLT-1 e15a in women with suspected preeclampsia.

INTRODUCTION: Soluble fms-like tyrosine kinase 1 (sFLT-1), a circulating anti-angiogenic factor that binds and antagonizes placental growth factor (PlGF), appears key to preeclamptic pathophysiology. Two main sFLT-1 splice variants exist: sFLT-1 e15a and sFLT-1 i13. Total sFLT-1/PlGF ratios are increasingly used clinically; we explore whether using placental-specific sFLT-1 e15a improves test performance compared with total sFLT-1 in preeclampsia diagnosis. METHODS: Consent was obtained for serum sampling from 96 women with suspected preeclampsia. Total sFLT-1 and PlGF were quantified using the B.R.A.H.M.S Kryptor Compact Plus automated immunoassay platform, and sFLT-1 e15a by custom enzyme-linked immunosorbent assay. Test performance was then assessed by subsequent diagnosis. RESULTS: Of 96 participants, 32 did not develop preeclampsia, 32 had early-onset (<34 weeks') disease and 32 had late-onset (≥34 weeks') disease. In those with preeclampsia, median sFLT-1 and sFLT-1 e15a were significantly increased (7361.0 vs 2463.0 pg/mL, and 946.6 vs 305.4 ng/mL respectively; p < 0.001 for both), and PlGF significantly reduced (43.5 vs 154.4 pg/mL; p < 0.001) compared to those without preeclampsia. Those with early-onset, compared to late-onset, preeclampsia chiefly had lower median PlGF levels (16.0 vs 57.3; p < 0.001), which contributed to higher sFLT-1/PlGF and sFLT-1 e15a/PlGF ratios (830.1 vs 86.7, and 109258.9 vs 12608.7 respectively; p < 0.001 for both). DISCUSSION: sFLT-1 e15a performs comparably to total sFLT-1 in women with suspected preeclampsia, however with higher translational burden. Our results support the expanding clinical use of the sFLT-1/PlGF ratio in suspected preeclampsia, particularly early-onset, to assist with disease diagnosis.

Mortality from acute upper gastrointestinal bleeding in the United kingdom: does it display a "weekend effect"?

OBJECTIVES: An increased mortality in patients presenting to hospital at weekends has been observed for several medical conditions. The aim of this study is to examine the relationship between weekend presentation to hospital following acute upper gastrointestinal bleeding and mortality. METHODS: Data were collected on 6,749 patients presenting to 212 UK hospitals. A logistic regression model was used to examine the relationship between weekend presentation to hospital and mortality. RESULTS: Patients presenting at the weekend were more likely to present with shock (39% vs. 36%), hematemesis (41% vs. 38%), and receive red cell transfusion (42% vs. 39%). Only 38% of those presenting at weekends underwent endoscopy within 24 h compared with 55% admitted on weekdays (adjusted odds ratio (OR)=0.47, 95% confidence interval (CI)=0.41-0.54), although the proportion of all patients receiving endoscopic therapy was identical at weekends compared with weekdays (24%). After adjustment for confounders, there was no evidence of a difference between weekend and weekday mortality (OR=0.93; 95% CI=0.75-1.16). Similar results were seen when restricting the analysis to those patients who underwent endoscopy (n=5,004) (OR=0.87, 95% CI=0.65-1.16). There was no difference in the OR for mortality for weekend compared with weekday presentation between patients presenting to hospitals with an out-of-hours (OOH) endoscopy rota compared with those presenting to hospitals without such a facility. CONCLUSIONS: In this large prospective study of acute upper gastrointestinal bleeding in the United Kingdom, there was no increase in mortality for weekend vs. weekday presentation despite patients being more critically ill and having greater delays to endoscopy at weekends. Provision of an OOH endoscopy service at weekends in the remaining UK hospitals may not lead to further reductions in case fatality, although a reduction in OOH endoscopy provision from current levels could lead to an increase in mortality at weekends.

Placental expression of a novel primate-specific splice variant of sFlt-1 is upregulated in pregnancies complicated by severe early onset pre-eclampsia.

sFlt-1 is increased in the placenta and serum of women with pre-eclampsia. A novel primate-specific splice variant has recently been discovered, but its expression in severe pre-eclampsia has yet to be reported. We investigated placental expression of the previously described variant, sFlt-1/sFlt-i13, and the novel variant, sFlt-e15a, in pregnancies complicated by severe early onset pre-eclampsia (n = 14) and HELLP (haemolysis, elevated liver enzymes and a low platelet count) syndrome (n = 8). There was significant upregulation of both variants in pre-eclampsia and HELLP syndrome compared with normotensive term (n = 35) and preterm controls (n = 8). We conclude that the novel primate-specific splice variant of sFlt-1 is highly expressed in both severe pre-eclampsia and HELLP.

Sulforaphane Bioavailability and Effects on Blood Pressure in Women with Pregnancy Hypertension.

Sulforaphane, an isothiocyanate found in cruciferous vegetables such as broccoli, shows promise as an adjuvant therapy for preeclampsia. To inform future clinical trials, we set out to determine the bioavailability of sulforaphane in non-pregnant and preeclamptic women. In six healthy female volunteers, we performed a crossover trial to compare the bioavailability of sulforaphane and metabolites afforded by an activated and non-activated broccoli extract preparation. We then undertook a dose escalation study of the activated broccoli extract in 12 women with pregnancy hypertension. In non-pregnant women, an equivalent dose of activated broccoli extract gave higher levels of sulforaphane and metabolites than a non-activated extract (p < 0.0001) and greater area under the curve (AUC) (3559 nM vs. 2172 nM, p = 0.03). Compared to non-pregnant women, in women with preeclampsia, the same dose of activated extract gave lower levels of total metabolites (p < 0.000) and AUC (3559 nM vs. 1653 nM, p = 0.007). Doubling the dose of the activated extract in women with preeclampsia doubled levels of sulforaphane and metabolites (p = 0.02) and AUC (1653 nM vs. 3333 nM, p = 0.02). In women with preeclampsia, activated broccoli extract was associated with modest decreases in diastolic blood pressure (p = 0.05) and circulating levels of sFlt-1 (p = 0.0002). A myrosinase-activated sulforaphane formulation affords better sulforaphane bioavailability than a non-activated formulation. Higher doses of sulforaphane are required to achieve likely effective doses in pregnant women than in non-pregnant women. Sulforaphane may improve endothelial function and blood pressure in women with pregnancy hypertension.

Sulforaphane improves syncytiotrophoblast mitochondrial function after in vitro hypoxic and superoxide injury.

INTRODUCTION: Placental mitochondrial dysfunction contributes to the oxidative stress that underlies preeclampsia. Here, we assessed whether sulforaphane (SFN) could improve syncytiotrophoblast mitochondrial function after in vitro hypoxic and superoxide injury. METHODS: Placental cytotrophoblasts were isolated from healthy term placentae (n = 12) and incubated for 48 h in 8% O2 ± 1 µM SFN before acute (4hrs) or chronic (24hrs) hypoxic (1% O2), or superoxide (xanthine/xanthine oxidase) injury. Cytotrophoblasts were also isolated from preeclamptic placentae (n = 5) and cultured in 8% O2 ± 1 µM SFN. Mitochondrial respiration was measured using the Seahorse MitoStress XF assay. Cells were stained with mitotracker red to assess mitochondrial membrane health and mitochondrial gene expression assessed using RT-qPCR. RESULTS: SFN prevented significant reductions in syncytiotrophoblast mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production following acute hypoxia. Chronic hypoxia only reduced maximal and spare respiratory capacity. SFN prevented these negative changes and increased respiration overall. Alternatively, acute superoxide injury significantly increased mitochondrial maximal respiration and spare respiratory capacity. SFN treatment further increased basal respiration following superoxide injury and prevented significant decreases in ATP production and coupling efficiency. In preeclamptic placentae, SFN significantly increased mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production, and decreased proton leak. SFN up-regulated mRNA expression of mitochondrial complexes and corrected an up-regulation in fission gene expression observed after hypoxic-superoxide injury. Finally, preliminary results suggest SFN prevented hypoxia-induced impairment of mitochondrial membrane structure. DISCUSSION: SFN mitigated hypoxia and superoxide induced changes to syncytiotrophoblast mitochondrial function in vitro, and improved mitochondrial respiration in trophoblast cells from preeclamptic placentae.

Genetic deletion of murine SPRY domain-containing SOCS box protein 2 (SSB-2) results in very mild thrombocytopenia.

The SSB family is comprised of four highly homologous proteins containing a C-terminal SOCS box motif and a central SPRY domain. No function has yet been ascribed to any member of this family in mammalian species despite a clear role for other SOCS proteins in negative regulation of cytokine signaling. To investigate its physiological role, the murine Ssb-2 gene was deleted by homologous recombination. SSB-2-deficient mice were shown to have a reduced rate of platelet production, resulting in very mild thrombocytopenia (25% decrease in circulating platelets). Tissue histology and other hematological parameters were normal, as was the majority of serum biochemistry, with the exception that blood urea nitrogen (BUN) levels were decreased in mice lacking SSB-2. Quantitative analysis of SSB mRNA levels indicated that SSB-1, -2, and -3 were ubiquitously expressed; however, SSB-4 was only expressed at very low levels. SSB-2 expression was observed in the kidney and in megakaryocytes, a finding consistent with the phenotype of mice lacking this gene. Deletion of SSB-2 thus perturbs the steady-state level of two tightly controlled homeostatic parameters and identifies a critical role for SSB-2 in regulating platelet production and BUN levels.

Pharmacokinetics of valsartan in patients with liver disease.

OBJECTIVES: Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is impaired, a pharmacokinetic study (open, single dose) was performed in patients with mild and moderate impairment of liver function. PATIENTS: Biliary excretion of valsartan (after intravenous administration of 20 mg valsartan) was assessed in a patient who underwent a hepaticojejunostomy with subsequent bile drainage. Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan. RESULTS: After intravenous administration, valsartan was eliminated mainly as unchanged drug in the bile. Mean exposure (measured as area under the plasma valsartan concentration-time curve) to valsartan was increased about twofold in both the mild and the moderate groups compared with matched (age, sex, and weight) healthy volunteers. CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination.

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis.

BACKGROUND: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. METHODS: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. RESULTS: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). CONCLUSION: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.

The outcome of peptic ulcer haemorrhage in relation to consumption of nonsteroidal anti-inflammatory drugs or aspirin.

AIM: To compare the outcome of 76 patients who presented with severe peptic ulcer haemorrhage whilst taking nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin with that of 112 patients who were not taking these drugs and who developed peptic ulcer haemorrhage over the same time period. METHODS: The two groups of patients were managed identically and endoscopic therapy was attempted in all cases. RESULTS: The group taking NSAIDs or aspirin tended to be older and had a higher prevalence of cardio-respiratory disease. The severity of bleeding (as assessed by the presence of shock, anaemia and endoscopic stigmata) was similar in the two groups. Outcome in terms of uncontrolled haemorrhage, rebleeding and blood transfusion requirements did not differ significantly in the two groups. The NSAID group had a significantly longer duration of admission, almost certainly attributable to a higher prevalence of co-morbid diseases. CONCLUSIONS: Despite the deleterious effects of NSAIDs and aspirin upon renal and platelet function, the prognosis of peptic ulcer bleeding is not adversely affected by NSAID or aspirin therapy.

The effects of renzapride, a novel prokinetic agent, in diabetic gastroparesis.

Gastric emptying was measured in 9 diabetic patients with autonomic neuropathy (Group 1) and 8 normal controls (Group 2) on 4 occasions after swallowing placebo, 0.5, 1.0 or 2.0 mg of the newly developed prokinetic drug renzapride given double-blind and in random order. The liquid component of the test meal was labelled with In113m and the solid with Tc99m. Liquid emptying was uni-exponential. Solid emptying comprised an initial lag phase, followed by a linear component. Following placebo, the mean lag phase of solid emptying was 40 +/- 7 (S.E.M.) min in Group 1 and 16 +/- 2 min in Group 2 (P less than 0.01). In Group 1 subjects renzapride reduced the mean lag phase by 20-26 min at all doses (P less than 0.01). No effect was seen in Group 2. The linear rate of solid emptying was similar in both groups (0.9 +/- 0.1 and 1.0 +/- 0.2%/min) and was not altered by renzapride. Mean liquid t1/2 was similar in Groups 1 and 2 after placebo (30 +/- 6 and 29 +/- 4 min, respectively) and was decreased with increasing doses of renzapride in both groups. No adverse effects were encountered in any subjects. Renzapride may be useful in the treatment of diabetic gastroparesis.

Successful Helicobacter pylori eradication incorporating a one-week antibiotic regimen.

BACKGROUND: The optimum regimen for the eradication of Helicobacter pylori remains unclear. The aim of this study was to determine the efficacy and tolerability of omeprazole 40 mg daily given for 2 weeks, plus amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. given for the first 7 days, in the treatment of H. pylori associated peptic ulcer disease. RESULTS: One hundred and thirty-two consecutive patients with peptic ulcer disease were entered into the study (89 male, 41 female; median age 47 years; inter-quartile range: 36-58 years). H. pylori was eradicated successfully in 109 of 130 patients (intention-to-treat: 83%; 95% confidence limits: 76-89%); per protocol: 85% (95% CI: 78-91%)). Ninety per cent of patients completed the full course of therapy. Only four patients (3%) stopped treatment as a result of side effects although these occurred in 41% of patients. One patient developed pseudomembranous colitis requiring hospital admission. CONCLUSION: Omeprazole combined with one week of treatment of amoxycillin and metronidazole is an effective and well tolerated Helicobacter eradication regimen. Occasional severe side effects remain a risk, even when the duration of antibiotic exposure is reduced.

Alverine citrate fails to relieve the symptoms of irritable bowel syndrome: results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Alverine citrate has been used in the treatment of irritable bowel syndrome for many years. AIMS: To compare the efficacy and safety of a new formulation of alverine citrate, a 120-mg capsule, with placebo given three times daily for 12 weeks. METHODS: One hundred and seven patients with irritable bowel syndrome were entered into this three-centre, double-blind, randomized, placebo-controlled, parallel group trial. The primary end-point was relief of abdominal pain indicated by improvement in the scores for severity and frequency. Secondary efficacy variables included scores for other clinical symptoms and for overall well-being. RESULTS: The severity and frequency of abdominal pain improved in 66% and 68% of patients treated with alverine citrate vs. 58% and 69% of the placebo group, but these differences were not significant. The mean percentage reduction in the scores for abdominal pain from baseline to the final assessment, although greater in the alverine citrate group (43.7%) compared with the placebo group (33.3%), was not statistically significant. CONCLUSIONS: Alverine citrate is no better than placebo at relieving the symptoms of irritable bowel syndrome. Future trials should be designed to take into account the high and persistent placebo response seen in this condition.