Plymouth Hospital

BACKGROUND: We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. METHODS: In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. RESULTS: For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. CONCLUSIONS: Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].).

OBJECTIVE: The European Guidelines Meeting on Laparoscopic Liver Surgery was held in Southampton on February 10 and 11, 2017 with the aim of presenting and validating clinical practice guidelines for laparoscopic liver surgery. BACKGROUND: The exponential growth of laparoscopic liver surgery in recent years mandates the development of clinical practice guidelines to direct the speciality's continued safe progression and dissemination. METHODS: A unique approach to the development of clinical guidelines was adopted. Three well-validated methods were integrated: the Scottish Intercollegiate Guidelines Network methodology for the assessment of evidence and development of guideline statements; the Delphi method of establishing expert consensus, and the AGREE II-GRS Instrument for the assessment of the methodological quality and external validation of the final statements. RESULTS: Along with the committee chairman, 22 European experts; 7 junior experts and an independent validation committee of 11 international surgeons produced 67 guideline statements for the safe progression and dissemination of laparoscopic liver surgery. Each of the statements reached at least a 95% consensus among the experts and were endorsed by the independent validation committee. CONCLUSION: The European Guidelines Meeting for Laparoscopic Liver Surgery has produced a set of clinical practice guidelines that have been independently validated for the safe development and progression of laparoscopic liver surgery. The Southampton Guidelines have amalgamated the available evidence and a wealth of experts' knowledge taking in consideration the relevant stakeholders' opinions and complying with the international methodology standards.

Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH.

Importance: Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death. Objective: To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation. Design, Setting, and Participants: A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible. Interventions: There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min [interquartile range {IQR}, 0.5-2.0 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min [IQR, 0.5-1.5 L/min]). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute. Main Outcomes and Measures: Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI. Results: A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 21.6 [IQR, 18.2-26.1], mean [SD] forced expiratory volume in the first second of expiration of 0.6 L [0.2 L], and mean [SD] Paco2 while breathing room air of 59 [7] mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group. Conclusions and Relevance: Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months. Trial Registration: clinicaltrials.gov Identifier: NCT00990132.

AIMS: To determine the effect of exercise training on clinical events and health-related quality of life (HRQoL) of patients with systolic heart failure. METHODS AND RESULTS: We searched electronic databases including Medline, EMBASE, and Cochrane Library up to January 2008 to identify randomized controlled trials (RCTs) comparing exercise training and usual care with a minimum follow-up of 6 months. Nineteen RCTs were included with a total of 3647 patients, the majority of whom were male, low-to-medium risk, and New York Heart Association class II-III with a left ventricular ejection fraction of <40%. There was no significant difference between exercise and control in short-term (<or=12 months) or longer-term all-cause mortality or overall hospital admissions. Heart failure-related hospitalizations were lower [relative risk: 0.72, 95% confidence interval (CI): 0.52-0.99] and HRQoL improved (standardized mean difference: -0.63, 95% CI: -0.80 to -0.37) with exercise therapy. Any effect of cardiac exercise training on total mortality and HRQoL was independent of degree of left ventricular dysfunction, type of cardiac rehabilitation, dose of exercise intervention, length of follow-up, trial quality, and trial publication date. CONCLUSION: Compared with usual care, in selected heart failure patients, exercise training reduces heart failure-related hospitalizations and results in clinically important improvements in HRQoL. High-quality RCT and cost-effectiveness evidence is needed for the effect of exercise training in community-based settings and in more severe heart failure patients, elderly people, and women.

Bariatric surgery is recognized as the most clinically and cost-effective treatment for people with severe and complex obesity. Many people presenting for surgery have pre-existing low vitamin and mineral concentrations. The incidence of these may increase after bariatric surgery as all procedures potentially cause clinically significant micronutrient deficiencies. Therefore, preparation for surgery and long-term nutritional monitoring and follow-up are essential components of bariatric surgical care. These guidelines update the 2014 British Obesity and Metabolic Surgery Society nutritional guidelines. Since the 2014 guidelines, the working group has been expanded to include healthcare professionals working in specialist and non-specialist care as well as patient representatives. In addition, in these updated guidelines, the current evidence has been systematically reviewed for adults and adolescents undergoing the following procedures: adjustable gastric band, sleeve gastrectomy, Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch. Using methods based on Scottish Intercollegiate Guidelines Network methodology, the levels of evidence and recommendations have been graded. These guidelines are comprehensive, encompassing preoperative and postoperative biochemical monitoring, vitamin and mineral supplementation and correction of nutrition deficiencies before, and following bariatric surgery, and make recommendations for safe clinical practice in the U.K. setting.

These Joint British Diabetes Societies guidelines, commissioned by NHS Diabetes, for the perioperative management of the adult patient undergoing surgery are available in full in the Supporting Information. This document goes through the seven stages of the patient journey when having surgery. These are: primary care referral; surgical outpatients; preoperative assessment; hospital admission; surgery; post-operative care; discharge. Each stage is given its own considerations, outlining the roles and responsibilities of each group of healthcare professionals. The evidence base for the recommendations made at each stage, discussion of controversial areas and references are provided in the report. This document has two key recommendations. Firstly, that the management of the elective adult surgery patients should be with modification to their usual diabetes treatment if the fasting is minimized because the routine use of a variable rate intravenous insulin infusion is not recommended. Secondly, that poor preoperative glycaemic control leads to post-outcomes and thus, where appropriate, needs to be addressed prior to referral for surgery.

Safe vascular access is integral to anaesthetic and critical care practice, but procedures are a frequent source of patient adverse events. Ensuring safe and effective approaches to vascular catheter insertion should be a priority for all practitioners. New technology such as ultrasound and other imaging has increased the number of tools available. This guidance was created using review of current practice and literature, as well as expert opinion. The result is a consensus document which provides practical advice on the safe insertion and removal of vascular access devices.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

BACKGROUND: The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy. Existing trials of these augmentations are individually too small to be conclusive. We aimed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women. METHODS: We did two pragmatic, parallel-group, multicentre, randomised controlled trials for our study (PROSPECT [PROlapse Surgery: Pragmatic Evaluation and randomised Controlled Trials]) in 35 centres (a mix of secondary and tertiary referral hospitals) in the UK. We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres. We randomly assigned participants by a remote web-based randomisation system to one of the two trials: comparing standard (native tissue) repair alone with standard repair augmented with either synthetic mesh (the mesh trial) or biological graft (the graft trial). We assigned women (1:1:1 or 1:1) within three strata: assigned to one of the three treatment options, comparison of standard repair with mesh, and comparison of standard repair with graft. Participants, ward staff, and outcome assessors were masked to randomisation where possible; masking was obviously not possible for the surgeon. Follow-up was for 2 years after the surgery; the primary outcomes, measured at 1 year and 2 years, were participant-reported prolapse symptoms (i.e. the Pelvic Organ Prolapse Symptom Score [POP-SS]) and condition-specific (ie, prolapse-related) quality-of-life scores, analysed in the modified intention-to-treat population. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN60695184. FINDINGS: Between Jan 8, 2010, and Aug 30, 2013, we randomly allocated 1352 women to treatment, of whom 1348 were included in the analysis. 865 women were included in the mesh trial (430 to standard repair alone, 435 to mesh augmentation) and 735 were included in the graft trial (367 to standard repair alone, 368 to graft augmentation). Because the analyses were carried out separately for each trial (mesh trial and graft trial) some women in the standard repair arm assigned to all treatment options were included in the standard repair group of both trials. 23 of these women did not receive any surgery (15 in the mesh trial, 13 in the graft trial; five were included in both trials) and were included in the baseline analyses only. Mean POP-SS at 1 year did not differ substantially between comparisons (standard 5·4 [SD 5·5] vs mesh 5·5 [5·1], mean difference 0·00, 95% CI -0·70 to 0·71; p=0·99; standard 5·5 [SD 5·6] vs graft 5·6 [5·6]; mean difference -0·15, -0·93 to 0·63; p=0·71). Mean prolapse-related quality-of-life scores also did not differ between groups at 1 year (standard 2·0 [SD 2·7] vs mesh 2·2 [2·7], mean difference 0·13, 95% CI -0·25 to 0·51; p=0·50; standard 2·2 [SD 2·8] vs graft 2·4 [2·9]; mean difference 0·13, -0·30 to 0·56; p=0·54). Mean POP-SS at 2 years were: standard 4·9 (SD 5·1) versus mesh 5·3 (5·1), mean difference 0·32, 95% CI -0·39 to 1·03; p=0·37; standard 4·9 (SD 5·1) versus graft 5·5 (5·7); mean difference 0·32, -0·48 to 1·12; p=0·43. Prolapse-related quality-of-life scores at 2 years were: standard 1·9 (SD 2·5) versus mesh 2·2 (2·6), mean difference 0·15, 95% CI -0·23 to 0·54; p=0·44; standard 2·0 (2·5) versus graft 2·2 (2·8); mean difference 0·10, -0·33 to 0·52; p=0·66. Serious adverse events such as infection, urinary retention, or dyspareunia or other pain, excluding mesh complications, occurred with similar frequency in the groups over 1 year (mesh trial: 31/430 [7%] with standard repair vs 34/435 [8%] with mesh, risk ratio [RR] 1·08, 95% CI 0·68 to 1·72; p=0·73; graft trial: 23/367 [6%] with standard repair vs 36/368 [10%] with graft, RR 1·57, 0·95 to 2·59; p=0·08). The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 (12%) of 434. INTERPRETATION: Augmentation of a vaginal repair with mesh or graft material did not improve women's outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short term, but more than one in ten women had a mesh complication. Therefore, follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery. FUNDING: UK National Institute of Health Research.

OBJECTIVE: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS: We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide-positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes. RESULTS: A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6-3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients). CONCLUSIONS: This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

Serum ferritin level is one of the most commonly requested investigations in both primary and secondary care. Whilst low serum ferritin levels invariably indicate reduced iron stores, raised serum ferritin levels can be due to multiple different aetiologies, including iron overload, inflammation, liver or renal disease, malignancy, and the recently described metabolic syndrome. A key test in the further investigation of an unexpected raised serum ferritin is the serum transferrin saturation. This guideline reviews the investigation and management of a raised serum ferritin level. The investigation and management of genetic haemochromatosis is not dealt with however and is the subject of a separate guideline.

Neuraxial anaesthesia is increasingly performed in thrombocytopenic patients at the time of delivery of pregnancy. There is a lack of data regarding the optimum platelet count at which spinal procedures can be safely performed. Reports are often confounded by the presence of other risk factors for spinal haematomata, such as anticoagulants, antiplatelet agents and other acquired or congenital coagulopathies/platelet function defects or rapidly falling platelet counts. In the absence of these additional risk factors, a platelet count of 80 x 10(9)/l is a 'safe' count for placing an epidural or spinal anaesthetic and 40 x 10(9)/l is a 'safe' count for lumbar puncture. It is likely that lower platelet counts may also be safe but there is insufficient published evidence to make recommendations for lower levels at this stage. For patients with platelet counts of 50-80 x 10(9)/l requiring epidural or spinal anaesthesia and patients with a platelet count 20-40 x 10(9)/l requiring a lumbar puncture, an individual decision based on assessment of risks and benefits should be made.

Delirium is a common condition in the elderly, affecting up to 30% of all older patients admitted to hospital. There is a particularly high risk of delirium in surgical inpatients, especially following operations for hip fracture or vascular surgery, but also for patients in the intensive care unit. Patients with delirium have higher morbidity and mortality rates, higher re-admission rates, and a greater risk of long term institutionalisation care, thereby having a significant impact on both health and social care expenditure. Delirium frequently goes unrecognised by clinicians and is often inadequately managed. Recent evidence suggests that a better understanding and knowledge of delirium among health care professionals can lead to early detection, the reduction of modifiable risk factors, and better management of the condition in the acute phase. Many cases of delirium are potentially preventable, and primary and secondary care services should be taking active steps in order to do prevent this condition.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

BACKGROUND: Most patients with coronary artery disease receive aspirin for primary or secondary prevention of myocardial infarction, stroke, and death. Aspirin poses a risk of bleeding in patients undergoing surgery, but it is unclear whether aspirin should be stopped before coronary artery surgery. METHODS: We used a 2-by-2 factorial trial design to randomly assign patients who were scheduled to undergo coronary artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin trial are reported here. Patients were randomly assigned to receive 100 mg of aspirin or matched placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Among 5784 eligible patients, 2100 were enrolled; 1047 were randomly assigned to receive aspirin and 1053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P=0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P=0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P=0.08). CONCLUSIONS: Among patients undergoing coronary artery surgery, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. (Funded by the Australian National Health and Medical Research Council and others; Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.).

Between November 1983 and February 1986, 358 patients with previously untreated metastatic prostatic carcinoma entered a multicentre, randomised trial in the United Kingdom and the Republic of Ireland, in which the LHRH analogue Zoladex (ICI Pharmaceuticals PLC), administered subcutaneously every 28 days, was compared with orchiectomy. Both treatments were equally effective in lowering serum testosterone concentrations to within the surgically castrate range and this was accompanied by equivalent subjective and objective response rates and times to treatment failure. At a median follow-up of 2 years there was no difference in overall survival, confirming that Zoladex is an effective medical alternative to orchiectomy in patients with metastatic disease.

This paper summarises the consequences of emergency department crowding. It provides a comparison of the scales used to measure emergency department crowding. We discuss the multiple causes of crowding and present an up-to-date literature review of the interventions that reduce the adverse consequences of crowding. We consider interventions at the level of an individual hospital and a policy level.