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2.  Longlasting insecticidal nets for prevention of Leishmania donovani infection in India and Nepal: paired cluster randomised trial 
Objective To test the effectiveness of large scale distribution of longlasting nets treated with insecticide in reducing the incidence of visceral leishmaniasis in India and Nepal.
Design Paired cluster randomised controlled trial designed to detect a 50% reduction in incidence of Leishmania donovani infection.
Setting Villages in Muzaffarpur district in India and Saptari, Sunsari, and Morang districts in Nepal.
Participants 13 intervention and 13 control clusters. 12 691 people were included in the analysis of the main outcome (infection), and 19 810 were enrolled for the secondary (disease) end point.
Intervention Longlasting insecticidal nets (treated with deltamethrin) were distributed in the intervention clusters in December 2006.
Main outcome measures Infection was determined by direct agglutination test at 12 and 24 months after the intervention in those who had negative results (titre <1:1600) at baseline. The effect estimate was computed as the geometric mean of the risk ratios for seroconversion for each cluster pair (net/no net), with its 95% confidence interval. Formal tests of effect of no intervention were obtained with a paired t test.
Results There was no significant difference in the risk of seroconversion over 24 months in intervention (5.4%; 347/6372) compared with control (5.5%; 345/6319 people) clusters (risk ratio 0.90, 95% confidence interval 0.49 to 1.65) nor in the risk of clinical visceral leishmaniasis (0.99, 0.46 to 1.40). Adjustment for covariates did not alter these conclusions.
Conclusions There is no evidence that large scale distribution of longlasting insecticidal nets provides additional protection against visceral leishmaniasis compared with existing control practice in the Indian subcontinent. The observed effect was small and not significant, though the confidence intervals did not exclude a 50% change in either direction.
Trial registration Clinical Trials NCT 2005-015374.
doi:10.1136/bmj.c6760
PMCID: PMC3011370  PMID: 21190965
3.  Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis 
Objective To examine whether treatment of periodontal disease with scaling and root planing during pregnancy is associated with a reduction in the preterm birth rate.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Cochrane Central Trials Registry, ISI Web of Science, Medline, and reference lists of relevant studies to July 2010; hand searches in key journals.
Study selection Randomised controlled trials including pregnant women with documented periodontal disease randomised to either treatment with scaling and root planing or no treatment.
Data extraction Data were extracted by two independent investigators, and a consensus was reached with the involvement a third. Methodological quality of the studies was assessed with the Cochrane’s risk of bias tool, and trials were considered either high or low quality. The primary outcome was preterm birth (<37 weeks). Secondary outcomes were low birthweight infants (<2500 g), spontaneous abortions/stillbirths, and overall adverse pregnancy outcome (preterm birth <37 weeks and spontaneous abortions/stillbirths).
Results 11 trials (with 6558 women) were included. Five trials were considered to be of high methodological quality (low risk of bias), whereas the rest were low quality (high or unclear risk of bias). Results among low and high quality trials were consistently diverse; low quality trials supported a beneficial effect of treatment, and high quality trials provided clear evidence that no such effect exists. Among high quality studies, treatment had no significant effect on the overall rate of preterm birth (odds ratio 1.15, 95% confidence interval 0.95 to 1.40; P=0.15). Furthermore, treatment did not reduce the rate of low birthweight infants (odds ratio 1.07, 0.85 to 1.36; P=0.55), spontaneous abortions/stillbirths (0.79, 0.51 to 1.22; P=0.28), or overall adverse pregnancy outcome (preterm births <37 weeks and spontaneous abortions/stillbirths) (1.09, 0.91 to 1.30; P=0.34).
Conclusion Treatment of periodontal disease with scaling and root planing cannot be considered to be an efficient way of reducing the incidence of preterm birth. Women may be advised to have periodical dental examinations during pregnancy to test their dental status and may have treatment for periodontal disease. However, they should be told that such treatment during pregnancy is unlikely to reduce the risk of preterm birth or low birthweight infants.
doi:10.1136/bmj.c7017
PMCID: PMC3011371  PMID: 21190966
4.  Mother to child transmission of HIV among Zimbabwean women who seroconverted postnatally: prospective cohort study 
Objectives To estimate the rates and timing of mother to infant transmission of HIV associated with breast feeding in mothers who seroconvert postnatally, and their breast milk and plasma HIV loads during and following seroconversion, compared with women who tested HIV positive at delivery.
Design Prospective cohort study.
Setting Urban Zimbabwe.
Participants 14 110 women and infants enrolled in the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial (1997-2001).
Main outcome measures Mother to child transmission of HIV, and breast milk and maternal plasma HIV load during the postpartum period.
Results Among mothers who tested HIV positive at baseline and whose infant tested HIV negative with polymerase chain reaction (PCR) at six weeks (n=2870), breastfeeding associated transmission was responsible for an average of 8.96 infant infections per 100 child years of breast feeding (95% CI 7.92 to 10.14) and varied little over the breastfeeding period. Breastfeeding associated transmission for mothers who seroconverted postnatally (n=334) averaged 34.56 infant infections per 100 child years (95% CI 26.60 to 44.91) during the first nine months after maternal infection, declined to 9.50 (95% CI 3.07 to 29.47) during the next three months, and was zero thereafter. Among women who seroconverted postnatally and in whom the precise timing of infection was known (≤90 days between last negative and first positive test; n=51), 62% (8/13) of transmissions occurred in the first three months after maternal infection and breastfeeding associated transmission was 4.6 times higher than in mothers who tested HIV positive at baseline and whose infant tested HIV negative with PCR at six weeks. Median plasma HIV concentration in all mothers who seroconverted postnatally declined from 5.0 log10 copies/mL at the last negative enzyme linked immunosorbent assay (ELISA) to 4.1 log10 copies/mL at 9-12 months after infection. Breast milk HIV load in this group was 4.3 log10 copies/mL 0-30 days after infection, but rapidly declined to 2.0 log10 copies/mL and <1.5 log10 copies/mL by 31-90 days and more than 90 days, respectively. Among women whose plasma sample collected soon after delivery tested negative for HIV with ELISA but positive with PCR (n=17), 75% of their infants were infected or had died by 12 months. An estimated 18.6% to 20.4% of all breastfeeding associated transmission observed in the ZVITAMBO trial occurred among mothers who seroconverted postnatally.
Conclusions Breastfeeding associated transmission is high during primary maternal HIV infection and is mirrored by a high but transient peak in breast milk HIV load. Around two thirds of breastfeeding associated transmission by women who seroconvert postnatally may occur while the mother is still in the “window period” of an antibody based test, when she would test HIV negative using one of these tests.
Trial registration Clinical trials.gov NCT00198718.
doi:10.1136/bmj.c6580
PMCID: PMC3007097  PMID: 21177735
5.  Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT) 
Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term.
Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)).
Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008.
Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks’ gestation with suspected intrauterine growth restriction.
Interventions Induction of labour or expectant monitoring.
Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means.
Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference −9.9 days, 95% CI −11.3 to −8.6) and weighed 130 g less (mean difference −130 g, 95% CI −188 g to −71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference −0.8%, 95% CI −4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI −5.0% to 5.6%).
Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth.
Trial registration International Standard Randomised Controlled Trial number ISRCTN10363217.
doi:10.1136/bmj.c7087
PMCID: PMC3005565  PMID: 21177352
6.  Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials 
Objective To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers.
Design One stage meta-analysis of individual patient data.
Data sources A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer.
Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded.
Results Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18).
Conclusions Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.
doi:10.1136/bmj.c6945
PMCID: PMC3006495  PMID: 21177530
7.  The barrier method as a new tool to assist in career selection: covert observational study 
Objective To determine if senior doctors’ parking habits and skills are associated with clinical specialty and, if so, whether observation of junior doctors’ parking could provide guidance in choice of specialty.
Design Covert observational study.
Setting Pass-card controlled consultants’ car park (parking lot), December 2009.
Participants 103 consultants entering the car park on three consecutive mornings.
Main outcome measures The outcomes were specialty and sex of the consultants, manner of approaching the barrier (pass-card ready or not), and time taken to park, exit the vehicle, and walk to a designated point.
Results Approaches to the barrier and parking were recorded for 103 consultants (79 men, 24 women): 28 anaesthetists (22 men, six women), 29 physicians (internists, 18 men, 11 women), 14 radiologists (nine men, five women), and 32 surgeons (30 men, two women). The manner of approaching the barrier (card ready) differed by specialty but not by sex. The total time taken to park (seconds) differed significantly between specialties: surgery (median 68, interquartile range 61-71 seconds), anaesthesia (82, 76-91), radiology (86, 70-103), and general medicine (112, 96-136). The time taken to park was overall longer among women, but this was explained by their specialty (men and women matched by specialty did not differ).
Conclusions The total time taken to park and manner of approaching the barrier to gain entry to the car park differed across specialties. Surgical consultants were fastest, followed by consultant anaesthetists and consultant radiologists, with physicians slowest. Sex was not an influencing factor. If reproducible in studies of a similar nature the “barrier method” could allow for a low cost means of guiding junior doctors in career selection.
doi:10.1136/bmj.c6968
PMCID: PMC3002171  PMID: 21159762
8.  Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group 
Objectives To prospectively assess the diagnostic performance of simple ultrasound rules to predict benignity/malignancy in an adnexal mass and to test the performance of the risk of malignancy index, two logistic regression models, and subjective assessment of ultrasonic findings by an experienced ultrasound examiner in adnexal masses for which the simple rules yield an inconclusive result.
Design Prospective temporal and external validation of simple ultrasound rules to distinguish benign from malignant adnexal masses. The rules comprised five ultrasonic features (including shape, size, solidity, and results of colour Doppler examination) to predict a malignant tumour (M features) and five to predict a benign tumour (B features). If one or more M features were present in the absence of a B feature, the mass was classified as malignant. If one or more B features were present in the absence of an M feature, it was classified as benign. If both M features and B features were present, or if none of the features was present, the simple rules were inconclusive.
Setting 19 ultrasound centres in eight countries.
Participants 1938 women with an adnexal mass examined with ultrasound by the principal investigator at each centre with a standardised research protocol.
Reference standard Histological classification of the excised adnexal mass as benign or malignant.
Main outcome measures Diagnostic sensitivity and specificity.
Results Of the 1938 patients with an adnexal mass, 1396 (72%) had benign tumours, 373 (19.2%) had primary invasive tumours, 111 (5.7%) had borderline malignant tumours, and 58 (3%) had metastatic tumours in the ovary. The simple rules yielded a conclusive result in 1501 (77%) masses, for which they resulted in a sensitivity of 92% (95% confidence interval 89% to 94%) and a specificity of 96% (94% to 97%). The corresponding sensitivity and specificity of subjective assessment were 91% (88% to 94%) and 96% (94% to 97%). In the 357 masses for which the simple rules yielded an inconclusive result and with available results of CA-125 measurements, the sensitivities were 89% (83% to 93%) for subjective assessment, 50% (42% to 58%) for the risk of malignancy index, 89% (83% to 93%) for logistic regression model 1, and 82% (75% to 87%) for logistic regression model 2; the corresponding specificities were 78% (72% to 83%), 84% (78% to 88%), 44% (38% to 51%), and 48% (42% to 55%). Use of the simple rules as a triage test and subjective assessment for those masses for which the simple rules yielded an inconclusive result gave a sensitivity of 91% (88% to 93%) and a specificity of 93% (91% to 94%), compared with a sensitivity of 90% (88% to 93%) and a specificity of 93% (91% to 94%) when subjective assessment was used in all masses.
Conclusions The use of the simple rules has the potential to improve the management of women with adnexal masses. In adnexal masses for which the rules yielded an inconclusive result, subjective assessment of ultrasonic findings by an experienced ultrasound examiner was the most accurate diagnostic test; the risk of malignancy index and the two regression models were not useful.
doi:10.1136/bmj.c6839
PMCID: PMC3001703  PMID: 21156740
9.  Urine output on an intensive care unit: case-control study 
Objective To compare urine output between junior doctors in an intensive care unit and the patients for whom they are responsible.
Design Case-control study.
Setting General intensive care unit in a tertiary referral hospital.
Participants 18 junior doctors responsible for clerking patients on weekday day shifts in the unit from 23 March to 23 April 2009 volunteered as “cases.” Controls were the patients in the unit clerked by those doctors. Exclusion criteria (for both groups) were pregnancy, baseline estimated glomerular filtration rate <15 ml/min/1.73 m2, and renal replacement therapy.
Main outcome measures Oliguria (defined as mean urine output <0.5 ml/kg/hour over six or more hours of measurement) and urine output (in ml/kg/hour) as a continuous variable.
Results Doctors were classed as oliguric and “at risk” of acute kidney injury on 19 (22%) of 87 shifts in which urine output was measured, and oliguric to the point of being “in injury” on one (1%) further shift. Data were available for 208 of 209 controls matched to cases in the data collection period; 13 of these were excluded because the control was receiving renal replacement therapy. Doctors were more likely to be oliguric than their patients (odds ratio 1.99, 95% confidence interval 1.08 to 3.68, P=0.03). For each additional 1 ml/kg/hour mean urine output, the odds ratio for being a case rather than a control was 0.27 (0.12 to 0.58, P=0.001). Mortality among doctors was astonishingly low, at 0% (0% to 18%).
Conclusions Managing our own fluid balance is more difficult than managing it in our patients. We should drink more water. Modifications to the criteria for acute kidney injury could be needed for the assessment of junior doctors in an intensive care unit.
doi:10.1136/bmj.c6761
PMCID: PMC3001704  PMID: 21156738
10.  Testing the validity of the Danish urban myth that alcohol can be absorbed through feet: open labelled self experimental study 
Objective To determine the validity of the Danish urban myth that it is possible to get drunk by submerging feet in alcohol.
Design Open labelled, self experimental study, with no control group.
Setting Office of a Danish hospital.
Participants Three adults, median age 32 (range 31-35), free of chronic skin and liver disease and non-dependent on alcohol and psychoactive drugs.
Main outcome measures The primary end point was the concentration of plasma ethanol (detection limit 2.2 mmol/L (10 mg/100 mL)), measured every 30 minutes for three hours while feet were submerged in a washing-up bowl containing the contents of three 700 mL bottles of vodka. The secondary outcome was self assessment of intoxication related symptoms (self confidence, urge to speak, and number of spontaneous hugs), scored on a scale of 0 to 10.
Results Plasma ethanol concentrations were below the detection limit of 2.2 mmol/L (10 mg/100 mL) throughout the experiment. No significant changes were observed in the intoxication related symptoms, although self confidence and urge to speak increased slightly at the start of the study, probably due to the setup.
Conclusion Our results suggest that feet are impenetrable to the alcohol component of vodka. We therefore conclude that the Danish urban myth of being able to get drunk by submerging feet in alcoholic beverages is just that; a myth. The implications of the study are many though.
doi:10.1136/bmj.c6812
PMCID: PMC3001960  PMID: 21156749
11.  Beauty sleep: experimental study on the perceived health and attractiveness of sleep deprived people 
Objective To investigate whether sleep deprived people are perceived as less healthy, less attractive, and more tired than after a normal night’s sleep.
Design Experimental study.
Setting Sleep laboratory in Stockholm, Sweden.
Participants 23 healthy, sleep deprived adults (age 18-31) who were photographed and 65 untrained observers (age 18-61) who rated the photographs.
Intervention Participants were photographed after a normal night’s sleep (eight hours) and after sleep deprivation (31 hours of wakefulness after a night of reduced sleep). The photographs were presented in a randomised order and rated by untrained observers.
Main outcome measure Difference in observer ratings of perceived health, attractiveness, and tiredness between sleep deprived and well rested participants using a visual analogue scale (100 mm).
Results Sleep deprived people were rated as less healthy (visual analogue scale scores, mean 63 (SE 2) v 68 (SE 2), P<0.001), more tired (53 (SE 3) v 44 (SE 3), P<0.001), and less attractive (38 (SE 2) v 40 (SE 2), P<0.001) than after a normal night’s sleep. The decrease in rated health was associated with ratings of increased tiredness and decreased attractiveness.
Conclusion Our findings show that sleep deprived people appear less healthy, less attractive, and more tired compared with when they are well rested. This suggests that humans are sensitive to sleep related facial cues, with potential implications for social and clinical judgments and behaviour. Studies are warranted for understanding how these effects may affect clinical decision making and can add knowledge with direct implications in a medical context.
doi:10.1136/bmj.c6614
PMCID: PMC3001961  PMID: 21156746
12.  Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database 
Objective To develop, validate, and evaluate a new QRISK model to estimate lifetime risk of cardiovascular disease.
Design Prospective cohort study with routinely collected data from general practice. Cox proportional hazards models in the derivation cohort to derive risk equations accounting for competing risks. Measures of calibration and discrimination in the validation cohort.
Setting 563 general practices in England and Wales contributing to the QResearch database.
Subjects Patients aged 30–84 years who were free of cardiovascular disease and not taking statins between 1 January 1994 and 30 April 2010: 2 343 759 in the derivation dataset, and 1 267 159 in the validation dataset.
Main outcomes measures Individualised estimate of lifetime risk of cardiovascular disease accounting for smoking status, ethnic group, systolic blood pressure, ratio of total cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative aged <60 years, Townsend deprivation score, treated hypertension, rheumatoid arthritis, chronic renal disease, type 2 diabetes, and atrial fibrillation. Age-sex centile values for lifetime cardiovascular risk compared with 10 year risk estimated using QRISK2 (2010).
Results Across all the 1 267 159 patients in the validation dataset, the 50th, 75th, 90th, and 95th centile values for lifetime risk were 31%, 39%, 50%, and 57% respectively. Of the 10% of patients in the validation cohort classified at highest risk with either the lifetime risk model or the 10 year risk model, only 18 385(14.5%) were at high risk on both measures. Patients identified as high risk with the lifetime risk approach were more likely to be younger, male, from ethnic minority groups, and have a positive family history of premature coronary heart disease than those identified with the 10 year QRISK2 score. The lifetime risk calculator is available at www.qrisk.org/lifetime/.
Conclusions Compared with using a 10 year QRISK2 score, a lifetime risk score will tend to identify patients for intervention at a younger age. Although lifestyle interventions at an earlier age could be advantageous, there would be small gains under the age of 65, and medical interventions carry risks as soon as they are initiated. Research is needed to examine closely the cost effectiveness and acceptability of such an approach.
doi:10.1136/bmj.c6624
PMCID: PMC2999889  PMID: 21148212
13.  Bicycle weight and commuting time: randomised trial 
Objective To determine whether the author’s 20.9 lb (9.5 kg) carbon frame bicycle reduced commuting time compared with his 29.75 lb (13.5 kg) steel frame bicycle.
Design Randomised trial.
Setting Sheffield and Chesterfield, United Kingdom, between mid-January 2010 and mid-July 2010.
Participants One consultant in anaesthesia and intensive care.
Main outcome measure Total time to complete the 27 mile (43.5 kilometre) journey from Sheffield to Chesterfield Royal Hospital and back.
Results The total distance travelled on the steel frame bicycle during the study period was 809 miles (1302 km) and on the carbon frame bicycle was 711 miles (1144 km). The difference in the mean journey time between the steel and carbon bicycles was 00:00:32 (hr:min:sec; 95% CI –00:03:34 to 00:02:30; P=0.72).
Conclusions A lighter bicycle did not lead to a detectable difference in commuting time. Cyclists may find it more cost effective to reduce their own weight rather than to purchase a lighter bicycle.
doi:10.1136/bmj.c6801
PMCID: PMC2999990  PMID: 21148220
14.  Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures 
Objective To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence.
Design Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS).
Setting UK hospital outpatient clinics from 1 January 1993 to 31 December 2000.
Participants People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure.
Main outcome measure Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence.
Results At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results.
Conclusion After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken.
Trial registration Current Controlled Trials ISRCTN98767960.
doi:10.1136/bmj.c6477
PMCID: PMC2998675  PMID: 21147743
15.  Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial  
Objective To assess the efficacy and safety of varenicline (a licensed cigarette smoking cessation aid) in helping users of smokeless tobacco to quit.
Design Double blind, placebo controlled, parallel group, multicentre, randomised controlled trial.
Setting Medical clinics (mostly primary care) in Norway and Sweden.
Participants Men and women aged ≥18 who used smokeless tobacco at least eight times a day, with no abstinence period over three months within one year before screening, who wanted to quit all tobacco use. Participants were excluded if they used any other form of tobacco (except smokeless tobacco) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition.
Interventions Varenicline 1 mg twice daily (titrated during the first week) or placebo for 12 weeks, with 14 weeks’ follow-up after treatment.
Main outcome measures The primary end point was the four week continuous abstinence rate at the end of treatment (weeks 9-12) confirmed with cotinine concentration. A secondary end point was continuous abstinence rate for weeks 9-26. Safety and tolerability were also evaluated.
Results 431 participants (213 varenicline; 218 placebo) were randomised and received at least one dose of study drug. Participants’ demographics and baseline use of smokeless tobacco were similar (89% (189) and 90% (196), respectively, were men; mean age in both groups was 43.9; participants used smokeless tobacco products about 15 times a day, and about 80% first used smokeless tobacco within 30 minutes after awakening). Continuous abstinence rate at week 9-12 was higher in the varenicline group than the placebo group (59% (125) v 39% (85); relative risk 1.60, 95% confidence interval 1.32 to 1.87, P<0.001; risk difference 20%; number needed to treat 5). The advantage of varenicline over placebo persisted through 14 weeks of follow-up (continuous abstinence rate at week 9-26 was 45% (95) v 34% (73); relative risk 1.42, 1.08 to 1.79, P=0.012; risk difference 11%; number needed to treat 9). The most common adverse events in the varenicline group compared with the placebo group were nausea (35% (74) v 6% (14)), fatigue (10% (22) v 7% (15)), headache (10% (22) v 9% (20)), and sleep disorder (10% (22) v 7% (15)). Few adverse events led to discontinuation of treatment (9% (19) and 4% (9), respectively), and serious adverse events occurred in two (1%) and three (1%) participants, respectively.
Conclusion Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile. The response rate in the placebo group in this study was high, suggesting a population less resistant to treatment than smokers.
Trial Registration NCT00717093.
doi:10.1136/bmj.c6549
PMCID: PMC2997603  PMID: 21134997
16.  Nature of socioeconomic inequalities in neonatal mortality: population based study 
Objective To investigate time trends in socioeconomic inequalities in cause specific neonatal mortality in order to assess changing patterns in mortality due to different causes, particularly prematurity, and identify key areas of focus for future intervention strategies.
Design Retrospective cohort study.
Setting England.
Participants All neonatal deaths in singleton infants born between 1 January 1997 and 31 December 2007.
Main outcome measure Cause specific neonatal mortality per 10 000 births by deprivation tenth (deprivation measured with UK index of multiple deprivation 2004 at super output area level).
Results 18 524 neonatal deaths occurred in singleton infants born in the 11 year study period. Neonatal mortality fell between 1997-9 and 2006-7 (from 31.4 to 25.1 per 10 000 live births). The relative deprivation gap (ratio of mortality in the most deprived tenth compared with the least deprived tenth) increased from 2.08 in 1997-9 to 2.68 in 2003-5, before a fall to 2.35 in 2006-7. The most common causes of death were immaturity and congenital anomalies. Mortality due to immaturity before 24 weeks’ gestation did not decrease over time and showed the widest relative deprivation gap (2.98 in 1997-9; 4.14 in 2003-5; 3.16 in 2006-7). Mortality rates for all other causes fell over time. For congenital anomalies, immaturity, and accidents and other specific causes, the relative deprivation gap widened between 1997-9 and 2003-5, before a slight fall in 2006-7. For intrapartum events and sudden infant deaths (only 13.5% of deaths) the relative deprivation gap narrowed slightly.
Conclusions Almost 80% of the relative deprivation gap in all cause mortality was explained by premature birth and congenital anomalies. To reduce socioeconomic inequalities in mortality, a change in focus is needed to concentrate on these two influential causes of death. Understanding the link between deprivation and preterm birth should be a major research priority to identify interventions to reduce preterm birth.
doi:10.1136/bmj.c6654
PMCID: PMC2996545  PMID: 21127118
17.  Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study 
Objective To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy.
Design A review of all published cohort studies to identify key indications and a population based case-control study to test these indications.
Setting Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005.
Participants The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births.
Main outcome measures Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes.
Results The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect.
Conclusion Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.
doi:10.1136/bmj.c6581
PMCID: PMC2996546  PMID: 21127116
18.  Community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (COPD) in Guangdong, China: cluster randomised controlled trial 
Objective To evaluate the effects of a community based integrated intervention for early prevention and management of chronic obstructive pulmonary disease (COPD) in China.
Design Cluster randomised controlled trial.
Setting Eight healthcare units in two communities.
Participants Of 1062 people aged 40-89, 872 (101 with COPD and 771 without COPD) who fulfilled the inclusion and exclusion criteria were allocated to the intervention or the usual care programmes.
Intervention Participants randomly assigned to integrated intervention (systematic health education, intensive and individualised intervention, treatment, and rehabilitation) or usual care.
Main outcome measures Annual rate of decline in forced expiratory rate in one second (FEV1) before use of bronchodilator.
Results Annual rate of decline in FEV1 was significantly lower in the intervention community than the control community, with an adjusted difference of 19 ml/year (95% confidence interval 3 to 36) and 0.9% (0.1% to 1.8%) of predicted values (all P<0.05), as well as a lower annual rate of decline in FEV1/FVC (forced vital capacity) ratio (adjusted difference 0.6% (0.1% to 1.2%) P=0.029). There were also higher rates of smoking cessation (21% v 8%, P<0.004) and lower cumulative death rates from all causes (1% v 3%, P<0.009) in the intervention community than in the control community during the four year follow-up. Improvements in knowledge of COPD and smoking hazards, outdoor air quality, environmental tobacco smoke, and working conditions were also achieved (all P<0.05). The difference in cumulative incidence rate of COPD (both around 4%) and cumulative death rate from COPD (2% v 11%) did not reach significance between the two communities.
Conclusions A community based integrated intervention can have a significant impact on the prevention and management of COPD, mainly reflected in the annual rate of decline in FEV1.
Trial registration Chinese Clinical Trials Registration (ChiCTR-TRC-00000532).
doi:10.1136/bmj.c6387
PMCID: PMC2995286  PMID: 21123342
19.  Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial 
Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).
Design Randomised controlled trial.
Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.
Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation.
Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C).
Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups.
Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99).
Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations.
Trial registration Clinical trials NCT00168558.
doi:10.1136/bmj.c6495
PMCID: PMC2994348  PMID: 21118875
20.  Explaining variation in referral from primary to secondary care: cohort study 
Objectives To determine the extent to which referral for defined symptoms from primary care varies by age, sex, and social deprivation and whether any sociodemographic variations in referral differ according to the presence of national referral guidance and the potential of the symptoms to be life threatening.
Design Cohort study using individual patient data from the health improvement network database in primary care.
Setting United Kingdom.
Participants 5492 patients with postmenopausal bleeding, 23 121 with hip pain, and 101 212 with dyspepsia from 326 general practices, 2001-7.
Main outcome measures Multivariable associations between odds of immediate referral for postmenopausal bleeding and age and social deprivation; hazard rates of referral for hip pain or dyspepsia and age, sex, and social deprivation. Analyses for dyspepsia were stratified for people aged less than and more than 55 years because referral guidance differs by age.
Results 61.4% (3374/5492) of patients with postmenopausal bleeding, 17.4% (4019/23 121) with hip pain, and 13.8% (13 944/101 212) with dyspepsia were referred. The likelihood of referral for postmenopausal bleeding declined with increasing age: the adjusted odds ratio for patients aged 85 or more compared with those aged 55-64 was 0.39 (95% confidence interval 0.31 to 0.49). Patients aged 85 or more with hip pain were also less likely to be referred than those aged 55-64 (0.68, 0.57 to 0.81). Women were less likely than men to be referred for hip pain (hazard ratio 0.90, 95% confidence interval 0.84 to 0.96). More deprived patients with hip pain or dyspepsia (if aged <55) were less likely to be referred. Adjusted hazard ratios for those in the most deprived Townsend fifth compared with the least deprived were 0.72 (95% confidence interval 0.62 to 0.82) and 0.76 (0.68 to 0.85), respectively. No socioeconomic gradient was evident in referral for postmenopausal bleeding.
Conclusions Inequalities in referral associated with socioeconomic circumstances were more likely to occur in the absence of both explicit guidance and potentially life threatening conditions, whereas inequalities with age were evident for all conditions.
doi:10.1136/bmj.c6267
PMCID: PMC2995017  PMID: 21118873
21.  Effect of integrated care for sick listed patients with chronic low back pain: economic evaluation alongside a randomised controlled trial 
Objective To evaluate the cost effectiveness, cost utility, and cost-benefit of an integrated care programme compared with usual care for sick listed patients with chronic low back pain.
Design Economic evaluation alongside a randomised controlled trial with 12 months’ follow-up.
Setting Primary care (10 physiotherapy practices, one occupational health service, one occupational therapy practice) and secondary care (five hospitals) in the Netherlands, 2005-9.
Participants 134 adults aged 18-65 sick listed because of chronic low back pain: 66 were randomised to integrated care and 68 to usual care.
Interventions Integrated care consisted of a workplace intervention based on participatory ergonomics, with involvement of a supervisor, and a graded activity programme based on cognitive behavioural principles. Usual care was provided by general practitioners and occupational physicians according to Dutch guidelines.
Main outcome measures The primary outcome was duration until sustainable return to work. The secondary outcome was quality adjusted life years (QALYs), measured using EuroQol.
Results Total costs in the integrated care group (£13 165, SD £13 600) were significantly lower than in the usual care group (£18 475, SD £13 616). Cost effectiveness planes and acceptability curves showed that integrated care was cost effective compared with usual care for return to work and QALYs gained. The cost-benefit analyses showed that every £1 invested in integrated care would return an estimated £26. The net societal benefit of integrated care compared with usual care was £5744.
Conclusions Implementation of an integrated care programme for patients sick listed with chronic low back pain has a large potential to significantly reduce societal costs, increase effectiveness of care, improve quality of life, and improve function on a broad scale. Integrated care therefore has large gains for patients and society as well as for employers.
doi:10.1136/bmj.c6414
PMCID: PMC2995018  PMID: 21118874
22.  Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial 
Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids, or both, could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke.
Design Double blind, randomised, placebo controlled trial; factorial design.
Setting Recruitment throughout France via a network of 417 cardiologists, neurologists, and other physicians.
Participants 2501 patients with a history of myocardial infarction, unstable angina, or ischaemic stroke.
Intervention Daily dietary supplement containing 5-methyltetrahydrofolate (560 μg), vitamin B-6 (3 mg), and vitamin B-12 (20 μg) or placebo; and containing omega 3 fatty acids (600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1) or placebo. Median duration of supplementation was 4.7 years.
Main outcome measures Major cardiovascular events, defined as a composite of non-fatal myocardial infarction, stroke, or death from cardiovascular disease.
Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19% compared with placebo, but had no significant effects on major vascular events (75 v 82 patients, hazard ratio, 0.90 (95% confidence interval 0.66 to 1.23, P=0.50)). Allocation to omega 3 fatty acids increased plasma concentrations of omega 3 fatty acids by 37% compared with placebo, but also had no significant effect on major vascular events (81 v 76 patients, hazard ratio 1.08 (0.79 to 1.47, P=0.64)).
Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke, at least when supplementation is introduced after the acute phase of the initial event.
Trial registration Current Controlled Trials ISRCTN41926726.
doi:10.1136/bmj.c6273
PMCID: PMC2993045  PMID: 21115589
23.  Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study 
Objectives To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16.
Design Prospective cohort study.
Setting Avon Longitudinal Study of Parents and Children.
Participants 5235 children aged 9-12 at start of study.
Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16.
Main outcome measures Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16.
Results In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol (<1.03 mmol/l); and 1.45 (1.22 to 1.73) for high concentration of insulin (≥16.95 IU/l). Equivalent results in boys were 1.24 (1.13 to 1.37) for systolic blood pressure; 1.30 (1.07 to 1.59) for low density lipoprotein cholesterol; 1.96 (1.51 to 2.55) for triglycerides; 1.39 (1.22 to 1.57) for high density lipoprotein cholesterol, and 1.84 (1.56 to 2.17) for insulin. BMI was associated with high fasting glucose (≥5.6 mmol/l) only in boys (1.18, 1.03 to 1.36). With these binary outcomes there was statistical evidence that associations differed between girls and boys for fasting glucose (P=0.03) and insulin (P<0.001). When risk factors were examined as continuous outcomes there was evidence for stronger associations of BMI with more adverse levels in boys than girls for fasting insulin, glucose, and triglyceride concentrations (all interaction P≤0.03). BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94), and associations of the three with cardiovascular outcomes were of similar magnitude with statistical evidence of consistency in associations (all P>0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages.
Conclusions Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.
doi:10.1136/bmj.c6224
PMCID: PMC2992109  PMID: 21109577
24.  Integrated motivational interviewing and cognitive behavioural therapy for people with psychosis and comorbid substance misuse: randomised controlled trial 
Objectives To evaluate the effectiveness of integrated motivational interviewing and cognitive behavioural therapy in addition to standard care for patients with psychosis and a comorbid substance use problem.
Design Two centre, open, rater blind randomised controlled trial.
Setting Secondary care in the United Kingdom.
Participants 327 patients with a clinical diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and a diagnosis of dependence on or misuse of drugs, alcohol, or both according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.
Intervention The intervention was integrated motivational interviewing and cognitive behavioural therapy plus standard care, which was compared with standard care alone. Phase one of therapy—“motivation building”—concerns engaging the patient, then exploring and resolving ambivalence for change in substance use. Phase two—“action”—supports and facilitates change using cognitive behavioural approaches. Up to 26 therapy sessions were delivered over one year.
Main outcome measures The primary outcome was death from any cause or admission to hospital in the 12 months after completion of therapy. Secondary outcomes were frequency and amount of substance use (assessed using the timeline followback method), readiness to change, perceived negative consequences of use, psychotic symptom ratings, number and duration of relapses, and global assessment of functioning and deliberate self harm at 12 and 24 months, with additional timeline followback assessments at 6 and 18 months. Analysis was by intention to treat and robust treatment effect estimates were produced.
Results 327 participants were randomly allocated to either the intervention (n=164) or treatment as usual (n=163). At 24 months, 326 (99.7%) were assessed on the primary outcome and 246 (75.2%) on the main secondary outcomes. Treatment had no beneficial effect on hospital admissions or death during follow-up, with 23.3% (38/163) of the therapy group and 20.2% (33/163) of controls deceased or admitted (adjusted odds ratio 1.16, 95% confidence interval 0.68 to 1.99; P=0.579). Therapy had no effect on the frequency of substance use or the perceived negative consequences of misuse, but did have a statistically significant effect on amount used per substance using day (adjusted ORs for main substance 1.50, 95% CI 1.08 to 2.09; P=0.016; and all substances 1.48, 95% CI 1.07 to 2.05; P=0.017). Treatment had a statistically significant effect on readiness to change use at 12 months (adjusted OR 2.05, 95% CI 1.26 to 3.31; P=0.004) that was not maintained at 24 months (0.78, 95% CI 0.48 to 1.28; P=0.320). There were no effects of treatment on clinical outcomes such as relapses, psychotic symptoms, functioning, and self harm.
Conclusions Integrated motivational interviewing and cognitive behavioural therapy for people with psychosis and substance misuse do not improve outcome in terms of hospitalisation, symptom outcomes, or functioning. This approach does reduce the amount of substance used for at least one year after completion of therapy.
Trial registration Current Controlled Trials: ISRCTN14404480.
doi:10.1136/bmj.c6325
PMCID: PMC2991241  PMID: 21106618
25.  Effect of retirement on major chronic conditions and fatigue: French GAZEL occupational cohort study 
Objectives To determine, using longitudinal analyses, if retirement is followed by a change in the risk of incident chronic diseases, depressive symptoms, and fatigue.
Design Prospective study with repeat measures from 7 years before to 7 years after retirement.
Setting Large French occupational cohort (the GAZEL study), 1989-2007.
Participants 11 246 men and 2858 women.
Main outcome measures Respiratory disease, diabetes, coronary heart disease and stroke, mental fatigue, and physical fatigue, measured annually by self report over the 15 year observation period; depressive symptoms measured at four time points.
Results The average number of repeat measurements per participant was 12.1. Repeated measures logistic regression with generalised estimating equations showed that the cumulative prevalence of self reported respiratory disease, diabetes, and coronary heart disease and stroke increased with age, with no break in the trend around retirement. In contrast, retirement was associated with a substantial decrease in the prevalence of both mental fatigue (odds ratio for fatigue one year after versus one year before retirement 0.19, 95% confidence interval 0.18 to 0.21) and physical fatigue (0.27, 0.26 to 0.30). A major decrease was also observed in depressive symptoms (0.60, 0.53 to 0.67). The decrease in fatigue around retirement was more pronounced among people with a chronic disease before retirement.
Conclusions Longitudinal modelling of repeat data showed that retirement did not change the risk of major chronic diseases but was associated with a substantial reduction in mental and physical fatigue and depressive symptoms, particularly among people with chronic diseases.
doi:10.1136/bmj.c6149
PMCID: PMC2990862  PMID: 21098617

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