Wirral University Teaching Hospital NHS Foundation Trust

OBJECTIVE: To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. DESIGN: Prospective observational study. SETTING: Two large general hospitals in Merseyside, England. PARTICIPANTS: 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. MAIN OUTCOME MEASURES: Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. RESULTS: There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is 466m pounds sterling (706m Euros, 847m dollars). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. CONCLUSION: The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.

BACKGROUND: The Surgical CAse REport (SCARE) guidelines were first published in 2016 as a tool for surgeons to document and report their surgical cases in a standardised and comprehensive manner. However, with advances in technology and changes in the healthcare landscape, it is important to revise and update these guidelines to ensure they remain relevant and valuable for surgeons. MATERIALS AND METHODS: The updated guidelines were produced through a Delphi consensus exercise. Members of the SCARE 2020 guidelines Delphi group, editorial board members, and peer reviewers were invited to participate. Potential contributors were contacted by e-mail. An online survey was completed to indicate their agreement with the proposed changes to the guideline items. RESULTS: A total of 54 participants were invited to participate and 44 (81.5%) completed the survey. There was a high degree of agreement among reviewers, with 36 items (83.7%) meeting the threshold for inclusion. CONCLUSION: Through a completed Delphi consensus exercise we present the SCARE 2023 guidelines. This will provide surgeons with a comprehensive and up-to-date tool for documenting and reporting their surgical cases while highlighting the importance of patient-centred care.

CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

CONTEXT: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. OBJECTIVE: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. INTERVENTIONS: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. RESULTS: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03). CONCLUSIONS: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

STUDY DESIGN: Three hundred patients, attending their general practitioners with attacks of acute low back pain, formed the subject population for a study of fear avoidance and other variables in the prediction of chronicity. Follow-up was at 2 and 12 months. OBJECTIVE: The hypothesis to be tested was that evidence of psychological morbidity, particularly fear-avoidance behavior, would be manifest from the outset of the presenting attack in susceptible subjects. SUMMARY OF BACKGROUND DATA: While back pain is an almost universal human experience, only about 5% of sufferers seek medical advice. Most of these respond to conservative treatment. However, approximately 10% of those who experience an acute attack of low back pain go on to become chronic sufferers. METHODS: Psychosocial and physiological data (including fear-avoidance measures) were collected from a sample of 300 acute low back pain patients within 1 week of presentation and at 2 months, to try to predict 12 month outcome. RESULTS: Data analysis showed that subjects who had not recovered by 2 months were those who went on to become chronic low back pain patients (7.3%). Using multiple regression analyses, fear-avoidance variables were the most successful in predicting outcome. Using multiple discriminant function analyses, the results suggest that the outcome in terms of the future course of low back pain can be correctly classified in 66% from fear-avoidance variables alone and in 88% of patients from all variables. CONCLUSIONS: The results suggest that, at the earliest stage of low back pain, fear of pain should be identified by clinicians and, where this is severe, pain confrontation should arguably form part of the approach to treatment.

BACKGROUND: This paper aims to move the debate forward regarding the potential for artificial intelligence (AI) and autonomous robotic surgery with a particular focus on ethics, regulation and legal aspects (such as civil law, international law, tort law, liability, medical malpractice, privacy and product/device legislation, among other aspects). METHODS: We conducted an intensive literature search on current or emerging AI and autonomous technologies (eg, vehicles), military and medical technologies (eg, surgical robots), relevant frameworks and standards, cyber security/safety- and legal-systems worldwide. We provide a discussion on unique challenges for robotic surgery faced by proposals made for AI more generally (eg, Explainable AI) and machine learning more specifically (eg, black box), as well as recommendations for developing and improving relevant frameworks or standards. CONCLUSION: We classify responsibility into the following: (1) Accountability; (2) Liability; and (3) Culpability. All three aspects were addressed when discussing responsibility for AI and autonomous surgical robots, be these civil or military patients (however, these aspects may require revision in cases where robots become citizens). The component which produces the least clarity is Culpability, since it is unthinkable in the current state of technology. We envision that in the near future a surgical robot can learn and perform routine operative tasks that can then be supervised by a human surgeon. This represents a surgical parallel to autonomously driven vehicles. Here a human remains in the 'driving seat' as a 'doctor-in-the-loop' thereby safeguarding patients undergoing operations that are supported by surgical machines with autonomous capabilities.

BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: Rotavirus is recognized as a significant cause of pediatric gastroenteritis worldwide. Comprehensive data on the burden of rotavirus disease in Europe were lacking. METHODS: A prospective, multicenter, observational study was conducted during the 2004-2005 season in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom, to estimate the incidence of acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) in children <5 years of age who require medical care in primary care, emergency department, and hospital settings. RESULTS: A total of 2846 children with AGE were included in the study, and, of the 2712 children for whom ELISA results were available, 1102 (40.6%) were found to be rotavirus positive. The estimated annual incidence of RVGE was 2.07-4.97 cases/100 children <5 years of age, and it was highest among children 6-23 months of age, with 56.7%-74.2% of all RVGE cases occurring in children in this age group. Overall, RVGE was estimated to account for 27.8%-52.0% of AGE cases, and it was responsible for up to two-thirds of hospitalizations and emergency department consultations, as well as one-third of primary care consultations for AGE. CONCLUSIONS: Rotavirus infections account for a significant proportion of AGE cases in children <5 years of age in Europe, many of whom require frequent primary care consultations or care in emergency department and/or hospital settings. The results of the present study suggest that routine rotavirus vaccination for infants <6 months of age could significantly reduce the substantial burden of this potentially serious childhood disease.

We have investigated those factors which influence the range of movement after total knee arthroplasty, including sex, age, preoperative diagnosis and preoperative flexion deformity and flexion range. We also compared cemented and cementless tibial fixation, the influence of collateral ligament and lateral parapatellar releases and of replacement of the patella, and of the period of postoperative immobilisation. We reviewed 516 Johnson-Elloy (Accord) knee arthroplasties performed between 1982 and 1989, with a minimum follow-up of 12 months. The most important factors in the range of flexion achieved after arthroplasty are the diagnosis and the preoperative range of flexion. In patients with osteoarthritis there was a mean loss of flexion; in rheumatoid arthritis there was a mean gain. In both groups, the stiffer knees gained motion and the more mobile knees lost it. Post-operative range of motion was not influenced significantly by cement fixation, collateral ligament or patellar retinacular releases, prolonged immobilisation or patellar replacement.

Abstract Chemistry and Human Health, Division VII of the International Union on Pure and Applied Chemistry (IUPAC), provides guidance on risk assessment methodology and, as appropriate, assessment of risks to human health from chemicals of exceptional toxicity. The aim of this document is to describe dose-response relationships for the health effects of low-level exposure to cadmium, in particular, with an emphasis on causation. The term “cadmium” in this document includes all chemical species of cadmium, as well as those in cadmium compounds. Diet is the main source of cadmium exposure in the general population. Smokers and workers in cadmium industries have additional exposure. Adverse effects have been shown in populations with high industrial or environmental exposures. Epidemiological studies in general populations have also reported statistically significant associations with a number of adverse health effects at low exposures. Cadmium is recognized as a human carcinogen, a classification mainly based on occupational studies of lung cancer. Other cancers have been reported, but dose-response relationships cannot be defined. Cardiovascular disease has been associated with cadmium exposure in recent epidemiological studies, but more evidence is needed in order to establish causality. Adequate evidence of dose-response relationships is available for kidney effects. There is a relationship between cadmium exposure and kidney effects in terms of low molecular mass (LMM) proteinuria. Long-term cadmium exposures with urine cadmium of 2 nmol mmol −1 creatinine cause such effects in a susceptible part of the population. Higher exposures result in increases in the size of these effects. This assessment is supported by toxicokinetic and toxicodynamic (TKTD) modelling. Associations between urine cadmium lower than 2 nmol mmol −1 creatinine and LMM proteinuria are influenced by confounding by co-excretion of cadmium with protein. A number of epidemiological studies, including some on low exposures, have reported statistically significant associations between cadmium exposure and bone demineralization and fracture risk. Exposures leading to urine cadmium of 5 nmol mmol −1 creatinine and more increase the risk of bone effects. Similar associations at much lower urine cadmium levels have been reported. However, complexities in the cause and effect relationship mean that a no-effect level cannot be defined. LMM proteinuria was selected as the critical effect for cadmium, thus identifying the kidney cortex as the critical organ, although bone effects may occur at exposure levels similar to those giving rise to kidney effects. To avoid these effects, population exposures should not exceed that resulting in cadmium values in urine of more than 2 nmol mmol −1 creatinine. As cadmium is carcinogenic, a ‘safe’ exposure level cannot be defined. We therefore recommend that cadmium exposures be kept as low as possible. Because the safety margin for toxic effects in kidney and bone is small, or non-existent, in many populations around the world, there is a need to reduce cadmium pollution globally.

BACKGROUND: Consensus has been achieved about how depression should be treated in primary care, and guidelines have been issued by the Royal Colleges of General Practitioners and Psychiatrists, and by the British Association for Psychopharmacology. One of the principal recommendations is to prescribe antidepressant medicine at effective doses. This study was established to investigate how current prescribing practices in primary care compared with these guidelines. METHOD: Information on prescribing of antidepressant medicines was obtained using three independent data sources: Prescribing Analysis and Cost (PACT) data; medical notes; and a large, computerised patient record database. RESULTS: Data were obtained on populations in excess of 1.5 million people, and over 80,000 prescriptions were reviewed. All three data sources showed very similar patterns of prescribing, in particular that as many as 88% of prescriptions for older tricyclic antidepressants are prescribed by GPs at doses below those recommended by the consensus guidelines. Newer antidepressants-lofepramine and the SSRIs-are prescribed comparatively well. CONCLUSIONS: Prescribing of antidepressants by GPs is not in line with the consensus recommendations on dosage. This may have major educational implications for GPs. A pragmatic approach to improve prescribing in the short term may be to advocate the use of lofepramine or the SSRIs as first line treatment for depression. This study validates the use of PACT data as a useful audit tool in this area of clinical practice.

The annual incidence of rheumatoid arthritis (RA) in the UK is 24 per hundred thousand The current guideline provides practical evidence-based advice on recommended interventions in RA. The objective is to provide a framework of care for managing RA, including control of synovitis, symptom control, self-management, physical functioning, psychosocial functioning and screening/monitoring. The primary target of this guidance is health professionals and managers; however, it is also relevant to patients with RA. The guidance is limited to the first 2 yrs of RA. This is a short summary of the whole guideline. The full guideline is available on the journal website (see supplementary material for full guideline). The current guideline does not include psoriatic arthritis, disease-modifying anti-rheumatic drugs (DMARDs) or biological therapy in RA because these areas are described in separate British Society for Rheumatology (BSR) guidelines

1: ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment.Strong recommendation, low quality evidence. 2 : ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤ 8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation.Strong recommendation, moderate quality evidence. 3 : ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 7 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7-9 g/dL is desirable.Strong recommendation, low quality evidence. 4 : ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 8 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥ 10 g/dL is desirable.Strong recommendation, low quality evidence. 5: ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes.Strong recommendation, low quality of evidence. 6 : ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding.Strong recommendation, low quality evidence. 7 : ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available.Strong recommendation, low quality evidence. 8 : ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding.Strong recommendation, low quality evidence. 9: ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding.Strong recommendation, moderate quality evidence. 10: ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated.Strong recommendation, low quality evidence.

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: Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer. METHODS: Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network. RESULTS: We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54-4.98), P=0.001), N stage (HR 1.51 (1.01-2.26), P=0.04), curative intent surgery (HR 0.51 (0.34-0.76), P=0.001), tumour grade (HR 0.44 (0.30-0.65), P=0.001) and KRAS mutation (1.54 (1.23-2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27-2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15-4.25), P=0.01) and p.G12V (HR 1.69 (1.08-2.62), P=0.02) were predictive of overall survival. CONCLUSIONS: For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.

Background: Type 2 diabetes is associated with an increase in age-related mortality. A systematic review and meta-analysis were performed to define the relative risks (RR) of all-cause or cause-specific mortality in type 2 diabetes and to determine gaps in current research. Methods: A comprehensive literature search was undertaken for studies (published 1990–2010) on mortality in type 2 diabetes. The study reports on the measure of mortality as defined by RR for all-cause and cause-specific mortality, heterogeneity, sensitivity analyses and biases. Results: In total 35 studies (220,689 patients; mean follow-up of 10.7 years) were eligible for inclusion: 33 studies reported increased mortality risks; 24 had full data on 95% confidence intervals (CIs), one study reported no excess mortality in men diagnosed after 65 years whereas three reported increased mortality in similar age groups in both sexes. Meta-analysis showed RR = 1.85 (95% CI 1.79–1.92) for all-cause mortality [men RR=1.57 (95% CI 1.46–1.68); women RR=2.0 (95% CI 1.89–2.12)], RR=1.76 (95% CI 1.66–1.88) for cardiovascular mortality and RR=2.26 (95% CI: 1.7-3.02) for stroke. There was no statistically significant evidence of publication bias. Conclusion: Type 2 diabetes increases mortality approximately two-fold increase and macrovascular disease is the principal cause of death.

The management of patients with stroke is often multidisciplinary, involving various specialties and healthcare professionals. Given the common shared risk factors for stroke and cardiovascular disease, input may also be required from the cardiovascular teams, as well as patient caregivers and next-of-kin. Ultimately, the patient is central to all this, requiring a coordinated and uniform approach to the priorities of post-stroke management, which can be consistently implemented by different multidisciplinary healthcare professionals, as part of the patient 'journey' or 'patient pathway,' supported by appropriate education and tele-medicine approaches. All these aspects would ultimately aid delivery of care and improve patient (and caregiver) engagement and empowerment. Given the need to address the multidisciplinary approach to holistic or integrated care of patients with heart disease and stroke, the European Society of Cardiology Council on Stroke convened a Task Force, with the remit to propose a consensus on Integrated care management for optimizing the management of stroke and associated heart disease. The present position paper summarizes the available evidence and proposes consensus statements that may help to define evidence gaps and simple practical approaches to assist in everyday clinical practice. A post-stroke ABC pathway is proposed, as a more holistic approach to integrated stroke care, would include three pillars of management: A: Appropriate Antithrombotic therapy.B: Better functional and psychological status.C: Cardiovascular risk factors and Comorbidity optimization (including lifestyle changes).

The agent that causes tick-borne fever (TBF) in sheep was first described in 1940, 8 years after the disease was first recognized in Scotland. The same agent was soon shown to cause TBF in sheep and pasture fever in cattle in other parts of the UK, Scandinavia, and other parts of Europe. After the initial use of the name Rickettsia phagocytophila, the organism was given the name Cytoecetes phagocytophila to reflect its association with granulocytes and its morphological similarity with Cytoecetes microti. This name continued to be used by workers in the UK until the recent reclassification of the granulocytic ehrlichiae affecting ruminants, horses, and humans as variants of the same species, Anaplasma phagocytophilum. TBF and pasture fever are characterized by high fever, recurrent bacteremia, neutropenia, lymphocytopenia, thrombocytopenia, and general immunosuppression, resulting in more severe secondary infections such as tick pyemia, pneumonic pasteurellosis, listeriosis, and enterotoxemia. During the peak period of bacteremia as many as 90% of granulocytes may be infected. The agent is transmitted transtadially by the hard tick Ixodes ricinus, and possibly other ticks. After patent bacteremia, sheep, goats, and cattle become persistently infected "carriers," perhaps playing an important role in the maintenance of infection, in the flock/herd. Little is known about how efficiently ticks acquire and maintain infection in ruminant populations or whether "carrier" domestic ruminants play an important role as reservoirs of infection, but deer, other free-living ruminants, and wild rodents are also potential sources of infection. During the late 1990s serological evidence of infection of humans was demonstrated in several European countries, creating a renewed interest and increased awareness of the zoonotic potential of TBF variants. More recently, a few cases of human granulocytic anaplasmosis (HGA) have been reported in some European countries, but it remains to be established whether the variants causing HGA in Europe are genetically and biologically different from those causing TBF in ruminants. TBF is readily diagnosed by demonstrating intracytoplasmic inclusions in peripheral blood granulocytes or monocytes of febrile animals or by detecting specific DNA by polymerase chain reaction (PCR), and TBF variants of A. phagocytophilum can be cultivated in tick cell lines, but the differentiation of TBF variants from HGA variants awaits further investigations.