SummaryBackgroundHigh-volume prescribing of antibiotics in primary care is a major driver of antibiotic resistance. Education of physicians and patients can lower prescribing levels, but it frequently relies on highly trained staff. We assessed whether internet-based training methods could alter prescribing practices in multiple health-care systems.MethodsAfter a baseline audit in October to December, 2010, primary-care practices in six European countries were cluster randomised to usual care, training in the use of a C-reactive protein (CRP) test at point of care, in enhanced communication skills, or in both CRP and enhanced communication. Patients were recruited from February to May, 2011. This trial is registered, number ISRCTN99871214.ResultsThe baseline audit, done in 259 practices, provided data for 6771 patients with lower-respiratory-tract infections (3742 [55·3%]) and upper-respiratory-tract infections (1416 [20·9%]), of whom 5355 (79·1%) were prescribed antibiotics. After randomisation, 246 practices were included and 4264 patients were recruited. The antibiotic prescribing rate was lower with CRP training than without (33% vs 48%, adjusted risk ratio 0·54, 95% CI 0·42–0·69) and with enhanced-communication training than without (36% vs 45%, 0·69, 0·54–0·87). The combined intervention was associated with the greatest reduction in prescribing rate (CRP risk ratio 0·53, 95% CI 0·36–0·74, p<0·0001; enhanced communication 0·68, 0·50–0·89, p=0·003; combined 0·38, 0·25–0·55, p<0·0001).InterpretationInternet training achieved important reductions in antibiotic prescribing for respiratory-tract infections across language and cultural boundaries.FundingEuropean Commission Framework Programme 6, National Institute for Health Research, Research Foundation Flanders.

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ObjectivesTo explore the influence of overdiagnosis information on women's decisions about mammography.DesignA qualitative focus group study with purposive sampling and thematic analysis, in which overdiagnosis information was presented.SettingCommunity and university settings in London.Participants40 women within the breast screening age range (50–71 years) including attenders and non-attenders were recruited using a recruitment agency as well as convenience sampling methods.ResultsWomen expressed surprise at the possible extent of overdiagnosis and recognised the information as important, although many struggled to interpret the numerical data. Overdiagnosis was viewed as less-personally relevant than the possibility of ‘under diagnosis’ (false negatives), and often considered to be an issue for follow-up care decisions rather than screening participation. Women also expressed concern that information on overdiagnosis could deter others from attending screening, although they rarely saw it as a deterrent. After discussing overdiagnosis, few women felt that they would make different decisions about breast screening in the future.ConclusionsWomen regard it as important to be informed about overdiagnosis to get a complete picture of the risks and benefits of mammography, but the results of this study indicate that understanding overdiagnosis may not always influence women's attitudes towards participation in breast screening. The results also highlight the challenge of communicating the individual significance of information derived from population-level modelling.

1. An intravenous dose of 14C-propofol (0.47 mg/kg) administered to six male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and less than 2% in faeces. 2. The dose was cleared by metabolism with less than 0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulphate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. 3. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 microgram/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 h post dose. 4. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 1/min.

The pharmacokinetics of propofol (2,6 diisopropylphenol) were compared in 12 patients aged 65-80 yr and 12 patients aged 18-35 yr. After premedication with papaveretum i.m., anaesthesia was induced with propofol 2.0 mg kg-1 in the elderly and 2.5 mg kg-1 in the younger patients. Alcuronium 12-20 mg was then given and the patient's lungs ventilated with halothane and nitrous oxide in oxygen. Blood was taken after various time intervals up to 24 h for the measurement of propofol concentrations by HPLC and for the estimation of propofol protein binding. The mean blood propofol concentration was generally higher in the elderly group, but this difference was only significant at 2 min after induction. The clearance of propofol was significantly lower in the elderly (1.44 +/- 0.10 (SE) litre min-1) than in the younger patients (1.79 +/- 0.12 litre min-1). The volume of the central compartment in the elderly patients was significantly smaller (19.6 +/- 5.2 litre) than that in the young (26.3 +/- 2.9 litre). There was no difference in the volume of distribution at equilibrium (1608 +/- 246 litre in the elderly and 1757 +/- 360 litre in the young), in the volume of distribution at steady state (691 +/- 139 litre in the elderly and 771 +/- 236 litre in the young) or in the half-lives of distribution and elimination. The plasma protein binding of propofol was similar in both groups and showed no trend with time after dose.

1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.

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The disposition kinetics of propofol have been determined in 12 patients (six female) receiving propofol 2.5 mg kg-1 for induction of anaesthesia, which was maintained with 67% nitrous oxide in oxygen and 1-1.5% halothane. Peripheral blood samples were collected at selected times up to 8 h after the injection of the drug, and whole blood propofol concentrations determined by HPLC with fluorescence detection. Drug concentration-time data were analysed by the non-linear regression program ELSFIT. This showed the data to be describable by a tri-exponential equation, corresponding to a three-compartment model. There were no differences in the derived kinetic indices for the male and female patients, with the exception of a greater Vdss:V gamma ratio in the males. The terminal half-life in the male patients was 262 min (SEM 44), and in the female patients 309 min (60). Vdss was 329 litre (67) and 313 litre (69) in male and female patients, respectively. The clearance in both groups was 1.8 litre min-1. Seven out of 12 patients showed significant secondary peaks in blood propofol concentration associated with recovery from anaesthesia.