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  • Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis.

    3 July 2018

    OBJECTIVES: To determine whether ingestion of milk thistle affects the pharmacokinetics of indinavir. METHODS: We conducted a three-period, randomized controlled trial with 16 healthy participants. We randomized participants to milk thistle or control. All participants received initial dosing of indinavir, and baseline indinavir levels were obtained (AUC(0-8)) (phase I). The active group were then given 450 mg milk-thistle extract capsules to be taken t.i.d. from day 2 to day 30. The control group received no plant extract. On day 29 and day 30, indinavir dosing and sampling was repeated in both groups as before (phase II). After a wash-out period of 7 days, indinavir dosing and sampling were repeated as before (phase III). RESULTS: All participants completed the trial, but two were excluded from analysis due to protocol violation. There were no significant between-group differences. Active group mean AUC(0-8) indinavir decreased by 4.4% (90% CI, -27.5% to -26%, P=0.78) from phase I to phase II in the active group, and by 17.3% (90% CI, -37.3% to +9%, P=0.25) in phase III. Control group mean AUC(0-8) decreased by 21.5% (90% CI, -43% to +8%, P=0.2) from phase I to phase II and by 38.5% (90% CI, -55.3% to -15.3%, P=0.01) of baseline at phase III. To place our findings in context, milk thistle-indinavir trials were identified through systematic searches of the literature. A meta-analysis of three milk thistle-indinavir trials revealed a non-significant pooled mean difference of 1% in AUC(0-8) (95% CI, -53% to 55%, P=0.97). CONCLUSIONS: Indinavir levels were not reduced significantly in the presence of milk thistle.

  • Systematic reviews of surgical interventions.

    3 July 2018

    All physicians are familiar with the type of general review articles found in many medical journals. Systematic reviews are different. They apply a strict, scientific methodology to the reviewing process to produce a review that is comprehensive, reliable, and as free from bias as possible. As a result, systematic reviews occupy the highest position in the "levels of evidence" tables associated with the practice of evidence-based health care. Systematic reviews relevant to surgery are no less relevant than systematic reviews in other areas of health care. They should be a prerequisite of any new research, a key component in decision making, and an opportunity for all surgical practitioners to get involved in the conduct and interpretation of research.

  • "No language restrictions" in database searches: what does this really mean?

    3 July 2018

    The aim of this study was to investigate the coverage of non-English journals by MEDLINE((R)) and EMBASE, the two major biomedical databases used for identifying studies for possible inclusion in systematic reviews and meta-analyses. A series of searches were conducted to compare the coverage of journals in languages other than English. The results were compared against listings in Ulrich's Periodicals Directory, an authoritative source of information on periodicals published in more than 200 countries. This study has highlighted the existence of a database coverage bias, in terms of the systematic exclusion of journals from certain countries and/or in certain languages. Searching that relies only on English language databases may result in failure to find many relevant studies published in languages other than English, irrespective of the research question and the avoidance of any language restrictions.

  • Methodology of neuropsychological research in multicentre randomized clinical trials: a model derived from the International Subarachnoid Aneurysm Trial.

    3 July 2018

    As advances in medicine and surgery lead to reductions in mortality rates for life-threatening conditions, it has become increasingly important to refine the methodology of auditing long-term morbidity. The inclusion of appropriate neuropsychological outcomes in a large multicentre randomized clinical trial poses considerable methodological and logistical difficulties. This paper presents a model developed to implement such a multicentre neuropsychological and quality of life audit for a subset of patients within the International Subarachnoid Aneurysm Trial (ISAT), the largest ever randomized trial in the treatment of subarachnoid haemorrhage. Based on our experience of collecting quality of life and neuropsychological outcomes from more than 550 patients, data are presented on the relative cost and efficacy of different organizational strategies, methods of canvassing patients and associated response rates. On the basis of this experience, we estimate a potential recruitment pool of 135 cases would be required to obtain some neuropsychological data on 100 cases. The design of any similar trial would therefore need to accommodate a loss to follow-up of approximately one third of the sample. In addition, our experience suggests that for a trial of this size and complexity, the deployment of centrally-based co-ordinators travelling to satellite centres is more cost-effective than employing co-ordinators based at those centres. Extrapolations from the observations and calculations reported here can be employed as an evidence base to inform the design of neuropsychological outcome studies in large multicentre trials.

  • Number and size of randomized trials reported in general health care journals from 1948 to 1997.

    3 July 2018

    BACKGROUND: Randomized trials are important for controlling selection biases, and where sufficient numbers of participants are involved, have the potential to yield reliable estimates of treatment effects. METHODS: We investigated trends in the number and size of randomized trials reported in general health care journals from 1948 to 1997. From the handsearching of 18 general health care journals we collected data on the number of reports of randomized trials in each journal per year, and the number of participants in each trial. RESULTS: A total of 5503 reports of trials were identified in 18 general health care journals. More than a third appeared in the British Medical Journal. The peak period for trial reports was the mid 1980s, with more in 1986 than any other year (242). By the mid 1990s the number per year had declined by a third. Trials with fewer than 100 participants accounted for most of the reports (69%). In spite of the overall decline in the number of trial reports, those involving 100 participants or more continued to increase throughout the period studied. CONCLUSIONS: The continued increase in the number of larger trials reported is encouraging, especially if it represents an increase in the size of trials more generally. Further research is needed to determine whether the trends over time identified here are reflective more of trends in the actual conduct of, rather than simply the reporting, of randomized trials.

  • Railway suicide in England and Wales, 1850-1949.

    2 July 2018

    According to the official statistics of the Registrar General, the first railway suicide occurred in 1852 and more than 10,000 suicides recorded during the period 1852-1949. Throughout this time the number of male cases always exceeded the number of female cases and the railway accounted for a greater proportion of male than female suicides in all but two years. By the early decades of the twentieth century, the railway was used in 5-6% of male suicides and 3-4% of female suicides. The incidence of railway suicide was correlated with the growth of the railway system offering some evidence for the relationship between availability of a lethal means and suicide rates.

  • Carbapenems versus other beta-lactams in the treatment of hospitalised patients with infection: a mixed treatment comparison.

    3 July 2018

    OBJECTIVE: To compare the effectiveness of meropenem with cefepime and piperacillin/tazobactam in the absence of direct comparisons in randomised controlled trials. DATA SOURCES: Two previously conducted systematic reviews, one comparing the carbapenems (ertapenem and imipenem/cilastatin) versus 4th-generation cephalosporins (cefepime) or antipseudomonal penicillins (piperacillin/tazobactam), and the other comparing the carbapenems (imipenem/cilastatin versus meropenem), were updated to provide the basis for this mixed treatment comparison. Searching was completed in April 2007. No restriction was placed on language of publication. STUDY SELECTION AND DATA EXTRACTION: Randomised controlled trials of adult patients hospitalised with infection and treated with a carbapenem or cefepime or piperacillin/tazobactam. Two reviewers independently assessed the papers against the inclusion/exclusion criteria and for methodological quality with any differences in opinion adjudicated by a third party. Two reviewers independently extracted data on clinical response, bacteriological response, mortality, and adverse events. DATA SYNTHESIS: A mixed treatment comparison meta-analysis using Bayesian Markov Chain Monte Carlo simulation was used to perform the indirect comparison. The dataset comprised 34 trials: four comparing ertapenem versus piperacillin/tazobactam, one imipenem/cilastatin versus cefepime, 26 imipenem/cilastatin versus meropenem, three imipenem/cilastatin versus piperacillin/tazobactam. We calculated odds ratios (OR) using imipenem/cilastatin as the common comparator. Meropenem was associated with the highest probability of being the most effective treatment for clinical response (OR 1.52, 95% credible interval [CrI] 1.23-1.87) and bacteriological response (OR 1.45, 95% CrI 1.15-1.80) with a reduced risk of serious adverse events (overall: OR 0.88, 95% CrI 0.76-1.02; serious adverse events leading to withdrawal: OR 0.73, 95% CrI 0.42-1.20; and GI-related: OR 0.76, 95% CrI 0.55-1.02). There was little difference between the three carbapenems and cefepime on all-cause mortality. CONCLUSIONS: This mixed treatment comparison suggests meropenem has substantial advantages over cefepime, ertapenem, imipenem/cilastatin and piperacillin/tazobactam in the treatment of hospitalised patients with infection.