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ObjectivesWe conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.MethodsWe searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.ResultsOf 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).DiscussionGiven the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

Objectives To determine and compare the diagnostic accuracy of serum natriuretic peptide levels (B type natriuretic peptide, N terminal probrain natriuretic peptide (NTproBNP), and mid-regional proatrial natriuretic peptide (MRproANP)) in people presenting with acute heart failure to acute care settings using thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure.Design Systematic review and diagnostic meta-analysis.Data sources Medline, Embase, Cochrane central register of controlled trials, Cochrane database of systematic reviews, database of abstracts of reviews of effects, NHS economic evaluation database, and Health Technology Assessment up to 28 January 2014, using combinations of subject headings and terms relating to heart failure and natriuretic peptides.Eligibility criteria for selecting studies Eligible studies evaluated one or more natriuretic peptides (B type natriuretic peptide, NTproBNP, or MRproANP) in the diagnosis of acute heart failure against an acceptable reference standard in consecutive or randomly selected adults in an acute care setting. Studies were excluded if they did not present sufficient data to extract or calculate true positives, false positives, false negatives, and true negatives, or report age independent natriuretic peptide thresholds. Studies not available in English were also excluded.Results 37 unique study cohorts described in 42 study reports were included, with a total of 48 test evaluations reporting 15 263 test results.At the lower recommended thresholds of 100 ng/L for B type natriuretic peptide and 300 ng/L for NTproBNP, the natriuretic peptides have sensitivities of 0.95 (95% confidence interval 0.93 to 0.96) and 0.99 (0.97 to 1.00) and negative predictive values of 0.94 (0.90 to 0.96) and 0.98 (0.89 to 1.0), respectively, for a diagnosis of acute heart failure. At the lower recommended threshold of 120 pmol/L, MRproANP has a sensitivity ranging from 0.95 (range 0.90-0.98) to 0.97 (0.95-0.98) and a negative predictive value ranging from 0. 90 (0.80-0.96) to 0.97 (0.96-0.98). At higher thresholds the sensitivity declined progressively and specificity remained variable across the range of values. There was no statistically significant difference in diagnostic accuracy between plasma B type natriuretic peptide and NTproBNP.Conclusions At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure. Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required. There is no statistical difference between the diagnostic accuracy of plasma B type natriuretic peptide and NTproBNP. Introduction of natriuretic peptide measurement in the investigation of patients with suspected acute heart failure has the potential to allow rapid and accurate exclusion of the diagnosis.Correspondence to: A J Ludman a.ludman@nhs. IntroductionMaking the correc...

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Background and aims To assess the efficacy and tolerability of adjunctive pharmacotherapy for smoking cessation in adults with serious mental illness (SMI) by means of a systematic review and network meta-analysis. Method We searched Embase, Medline, PsychINFO and the Cochrane Central Register of Controlled Trials, from database inception to 1 December 2014 for randomised controlled trials (RCTs) published in English. We included all studies of smokers with SMI (including schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder and depressive psychoses) who were motivated to quit smoking. Pharmacotherapies included nicotine replacement therapy (NRT), bupropion and varenicline delivered as monotherapy or in combination compared with each other or placebo. The efficacy outcome was self-reported sustained smoking cessation, biochemically verified at the longest reported time point. The tolerability outcome was number of patients discontinuing the trial due to any adverse event Results Seventeen study reports were included which represented fourteen individual RCTs. No trials were found in patients with depressive psychoses, delusional disorder or which compared NRT monotherapy with placebo. A total of 356 and 423 participants were included in the efficacy and tolerability analyses respectively. From the network meta-analysis both bupropion and varenicline were more effective than placebo (OR 4.51 95% Credible Interval (CrI) 1.45 to 14.04 and OR 5.17 95% CrI 1.78 to 15.06 respectively). Data were insensitive to an assessment of varenicline versus bupropion (OR 1.15 95% CrI 0.24 to 5.45). There were no significant differences in tolerability. All outcomes were rated by GRADE criteria as very low quality. Conclusions The limited evidence available to date suggests that bupropion and varenicline are effective and tolerable for smoking cessation in adults with serious mental illnesses.