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1.  Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies 
Objective To quantify the link between lower, subclinically symptomatic, levels of psychological distress and cause-specific mortality in a large scale, population based study.
Design Individual participant meta-analysis of 10 large prospective cohort studies from the Health Survey for England. Baseline psychological distress measured by the 12 item General Health Questionnaire score, and mortality from death certification.
Participants 68 222 people from general population samples of adults aged 35 years and over, free of cardiovascular disease and cancer, and living in private households in England at study baseline.
Main outcome measures Death from all causes (n=8365), cardiovascular disease including cerebrovascular disease (n=3382), all cancers (n=2552), and deaths from external causes (n=386). Mean follow-up was 8.2 years (standard deviation 3.5).
Results We found a dose-response association between psychological distress across the full range of severity and an increased risk of mortality (age and sex adjusted hazard ratio for General Health Questionnaire scores of 1-3 v score 0: 1.20, 95% confidence interval 1.13 to 1.27; scores 4-6: 1.43, 1.31 to 1.56; and scores 7-12: 1.94, 1.66 to 2.26; P<0.001 for trend). This association remained after adjustment for somatic comorbidity plus behavioural and socioeconomic factors. A similar association was found for cardiovascular disease deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels.
Conclusions Psychological distress is associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress.
doi:10.1136/bmj.e4933
PMCID: PMC3409083  PMID: 22849956
2.  Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis 
Objective To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding.
Design Network meta-analysis on the primary outcome measures of amenorrhoea, heavy bleeding, and patients’ dissatisfaction with treatment.
Data sources Nineteen randomised controlled trials (involving 3287 women) were identified through electronic searches of the Cochrane Library, Medline, Embase and PsycINFO databases from inception to April 2011. The reference lists of known relevant articles were searched for further articles. Two reviewers independently selected articles without language restrictions.
Eligibility criteria for selecting studies Randomised controlled trials involving second generation endometrial destruction techniques for women with heavy menstrual bleeding unresponsive to medical treatment.
Results Of the three most commonly used techniques, network meta-analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (odds ratio 2.51, 95% confidence interval 1.53 to 4.12, P<0.001; and 1.66, 1.01 to 2.71, P=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the number of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (2.19, 1.07 to 4.50, P=0.03; and 2.91, 1.23 to 6.88, P=0.02, respectively). Compared with radio frequency ablation, free fluid ablation was associated with reduced rates of amenorrhoea (0.36, 0.19 to 0.67, P=0.004) and increased rates of dissatisfaction (4.79, 1.07 to 21.5, P=0.04). Of the less commonly used devices, endometrial laser intrauterine thermotherapy was associated with increased rates of amenorrhoea compared with all the other devices, while cryoablation led to a reduced rate compared with bipolar radio frequency and microwave.
Conclusions Bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices.
doi:10.1136/bmj.e2564
PMCID: PMC3339574  PMID: 22529302
3.  Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study 
Objective To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.
Design Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality.
Setting Nursing homes in the United States.
Participants 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5.
Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.
Results Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.
Conclusions Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.
doi:10.1136/bmj.e977
PMCID: PMC3285717  PMID: 22362541
4.  Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis  
Objectives To determine the incidence of any and referable diabetic retinopathy in people with type 2 diabetes mellitus attending an annual screening service for retinopathy and whose first screening episode indicated no evidence of retinopathy.
Design Retrospective four year analysis.
Setting Screenings at the community based Diabetic Retinopathy Screening Service for Wales, United Kingdom.
Participants 57 199 people with type 2 diabetes mellitus, who were diagnosed at age 30 years or older and who had no evidence of diabetic retinopathy at their first screening event between 2005 and 2009. 49 763 (87%) had at least one further screening event within the study period and were included in the analysis.
Main outcome measures Annual incidence and cumulative incidence after four years of any and referable diabetic retinopathy. Relations between available putative risk factors and the onset and progression of retinopathy.
Results Cumulative incidence of any and referable retinopathy at four years was 360.27 and 11.64 per 1000 people, respectively. From the first to fourth year, the annual incidence of any retinopathy fell from 124.94 to 66.59 per 1000 people, compared with referable retinopathy, which increased slightly from 2.02 to 3.54 per 1000 people. Incidence of referable retinopathy was independently associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. For participants needing insulin treatment with a duration of diabetes of 10 years or more, cumulative incidence of referable retinopathy at one and four years was 9.61 and 30.99 per 1000 people, respectively.
Conclusions Our analysis supports the extension of the screening interval for people with type 2 diabetes mellitus beyond the currently recommended 12 months, with the possible exception of those with diabetes duration of 10 years or more and on insulin treatment.
doi:10.1136/bmj.e874
PMCID: PMC3284424  PMID: 22362115
5.  Physical activity for cancer survivors: meta-analysis of randomised controlled trials 
Objective To systematically evaluate the effects of physical activity in adult patients after completion of main treatment related to cancer.
Design Meta-analysis of randomised controlled trials with data extraction and quality assessment performed independently by two researchers.
Data sources Pubmed, CINAHL, and Google Scholar from the earliest possible year to September 2011. References from meta-analyses and reviews.
Study selection Randomised controlled trials that assessed the effects of physical activity in adults who had completed their main cancer treatment, except hormonal treatment.
Results There were 34 randomised controlled trials, of which 22 (65%) focused on patients with breast cancer, and 48 outcomes in our meta-analysis. Twenty two studies assessed aerobic exercise, and four also included resistance or strength training. The median duration of physical activity was 13 weeks (range 3-60 weeks). Most control groups were considered sedentary or were assigned no exercise. Based on studies on patients with breast cancer, physical activity was associated with improvements in insulin-like growth factor-I, bench press, leg press, fatigue, depression, and quality of life. When we combined studies on different types of cancer, we found significant improvements in body mass index (BMI), body weight, peak oxygen consumption, peak power output, distance walked in six minutes, right handgrip strength, and quality of life. Sources of study heterogeneity included age, study quality, study size, and type and duration of physical activity. Publication bias did not alter our conclusions.
Conclusions Physical activity has positive effects on physiology, body composition, physical functions, psychological outcomes, and quality of life in patients after treatment for breast cancer. When patients with cancer other than breast cancer were also included, physical activity was associated with reduced BMI and body weight, increased peak oxygen consumption and peak power output, and improved quality of life.
doi:10.1136/bmj.e70
PMCID: PMC3269661  PMID: 22294757
6.  Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm 
Objective To derive and validate an algorithm to estimate the absolute risk of having ovarian cancer in women with and without symptoms.
Design Cohort study with data from 375 UK QResearch general practices for development and 189 for validation.
Participants Women aged 30-84 without a diagnosis of ovarian cancer at baseline and without appetite loss, weight loss, abdominal pain, abdominal distension, rectal bleeding, or postmenopausal bleeding recorded in previous 12 months.
Main outcome The primary outcome was incident diagnosis of ovarian cancer recorded in the next two years.
Methods Risk factors examined included age, family history of ovarian cancer, previous cancers other than ovarian, body mass index (BMI), smoking, alcohol, deprivation, loss of appetite, weight loss, abdominal pain, abdominal distension, rectal bleeding, postmenopausal bleeding, urinary frequency, diarrhoea, constipation, tiredness, and anaemia. Cox proportional hazards models were used to develop the risk equation. Measures of calibration and discrimination assessed performance in the validation cohort.
Results In the derivation cohort there were 976 incident cases of ovarian cancer from 2.03 million person years. Independent predictors were age, family history of ovarian cancer (9.8-fold higher risk), anaemia (2.3-fold higher), abdominal pain (sevenfold higher), abdominal distension (23-fold higher), rectal bleeding (twofold higher), postmenopausal bleeding (6.6-fold higher), appetite loss (5.2-fold higher), and weight loss (twofold higher). On validation, the algorithm explained 57.6% of the variation. The receiver operating characteristics curve (ROC) statistic was 0.84, and the D statistic was 2.38. The 10% of women with the highest predicted risks contained 63% of all ovarian cancers diagnosed over the next two years.
Conclusion The algorithm has good discrimination and calibration and, after independent validation in an external cohort, could potentially be used to identify those at highest risk of ovarian cancer to facilitate early referral and investigation. Further research is needed to assess how best to implement the algorithm, its cost effectiveness, and whether, on implementation, it has any impact on health outcomes.
doi:10.1136/bmj.d8009
PMCID: PMC3251328  PMID: 22217630
7.  Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study 
Objectives To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to assess early attitude to re-biopsy; to estimate healthcare resource use associated with adverse events due to biopsy; and to develop a classification scheme for reporting adverse events after prostate biopsy.
Design Prospective cohort study (Prostate Biopsy Effects: ProBE) nested within Prostate Testing for Cancer and Treatment (ProtecT) study.
Participants Between 1999 and 2008, 227 000 community dwelling men aged 50­69 years were identified at 352 practices and invited to counselling about PSA testing. 111 148 attended a nurse led clinic in the community, and 10 297 with PSA concentrations of 3-20 ng/mL were offered biopsy within ProtecT. Between February 2006 and May 2008, 1147/1753 (65%) eligible men (mean age 62.1 years, mean PSA 5.4 ng/mL) having 10 core transrectal ultrasound guided biopsy under antibiotic cover in the context of ProtecT were recruited to the ProBE study.
Outcome measures Purpose designed questionnaire administered at biopsy and 7 and 35 days after the procedure to measure frequency and effect of symptoms related to pain, infection, and bleeding; patients’ attitude to repeat biopsy assessed immediately after biopsy and 7 days later; participants’ healthcare resource use within 35 days of biopsy evaluated by questionnaire, telephone follow-up, and medical note review; each man’s adverse event profile graded according to symptoms and healthcare use.
Results Pain was reported by 429/984 (43.6%), fever by 172/985 (17.5%), haematuria by 642/976 (65.8%), haematochezia by 356/967 (36.8%), and haemoejaculate by 605/653 (92.6%) men during the 35 days after biopsy. Fewer men rated these symptoms as a major/moderate problem—71/977 (7.3%) for pain, 54/981 (5.5%) for fever, 59/958 (6.2%) for haematuria, 24/951 (2.5%) for haematochezia, and 172/646 (26.6%) for haemoejaculate. Immediately after biopsy, 124/1142 (10.9%, 95% confidence interval 9.2 to 12.8) men reported that they would consider further biopsy a major or moderate problem: seven days after biopsy, this proportion had increased to 213/1085 (19.6%, 17.4% to 22.1%). A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy (odds ratio 8.2, P<0.001) and symptoms related to infection (7.9, P<0.001) and bleeding (4.2, P<0.001); differences were evident between centres (P<0.001). 119/1147 (10.4%, 8.7% to 12.3%) men reported consultation with a healthcare professional (usually their general practitioner), most commonly for infective symptoms. Complete data for all index symptoms at all time points were available in 851 participants. Symptoms and healthcare use could be used to grade these men as follows: grade 0 (no symptoms/contact) 18 (2.1%, 1.3% to 3.3%); grade 1 (minor problem/no contact) 550 (64.6%, 61.4% to 67.8%); grade 2 (moderate/major problem or contact) 271 (31.8%, 28.8% to 35.1%); grade 3 (hospital admission) 12 (1.4%, 0.8% to 2.4%); and grade 4 (death) 0. Grade of adverse event was associated with an unfavourable attitude to repeat biopsy (Kendall’s τ-b ordinal by ordinal 0.29, P<0.001).
Conclusion This study with a high response rate of 89% at 35 days in men undergoing biopsy in the context of a randomised controlled trial has shown that although prostate biopsy is well tolerated by most men, it is associated with significant symptoms in a minority and affects attitudes to repeat biopsy and primary care resource use. These findings will inform men who seek PSA testing for detection of prostate cancer and assist their physicians during counselling about the potential risks and effect of biopsy. Variability in the adverse event profile between centres suggests that patients’ outcomes could be improved and healthcare use reduced with more effective administration of local anaesthetic and antibiotics.
Trial registration Current Controlled Trials ISRCTN20141297.
doi:10.1136/bmj.d7894
PMCID: PMC3253765  PMID: 22232535
8.  The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis 
Objective To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011.
Study selection Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes.
Results 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89).
Conclusion Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels.
doi:10.1136/bmj.e42
PMCID: PMC3253766  PMID: 22232539
9.  Vitamin A supplementation in preschool children and risk of hearing loss as adolescents and young adults in rural Nepal: randomised trial cohort follow-up study 
Objective To determine whether vitamin A supplementation administered in the preschool years can lower the risk of hearing loss in adolescence and adulthood.
Design Follow-up study of adolescents and young adults who, as preschool aged children in 1989, were enrolled into a cluster randomised, double blinded, placebo controlled trial of vitamin A supplementation.
Setting South central, rural Nepal.
Participants 2378 adolescents and young adults aged 14 to 23, representing 51% of those who finished the original trial and 71% of those living in the study area in 2006.
Interventions Every four months for 16 months preschool children were visited at home, given an oral 200 000 IU dose of vitamin A (half dose at age 1-11 months, quarter dose at <1 month) or placebo and the parents were queried about any childhood illnesses in the previous week, including purulent discharge from the ears.
Main outcome measures Prevalence of mild or worse hearing loss (≥30 dB) in the most affected ear and tympanometric measures of middle ear function (peak height, ear canal volume, and gradient).
Results During the original trial, the prevalence of middle ear infection during the preschool years did not differ between the supplement groups. By adolescence and early adulthood, a non-significant 17% reduction in hearing loss occurred among those who had periodically received vitamin A compared with placebo as preschool aged children (odds ratio 0.83, 95% confidence interval 0.62 to 1.12). Among participants with any ear discharge in early childhood, vitamin A supplementation was associated with a reduced risk of hearing loss, by 42% (0.58, 0.37 to 0.92) compared with controls, after adjusting the confidence interval for the design effect of the original trial. Abnormal tympanometric peak height of the middle ear system was less likely among participants supplemented with vitamin A in childhood.
Conclusion In undernourished settings, periodic, high dose vitamin A supplementation may reduce the risk of hearing loss associated with purulent ear infections in early childhood.
doi:10.1136/bmj.d7962
PMCID: PMC3254201  PMID: 22234907
10.  Influence of experience on performance of individual surgeons in thyroid surgery: prospective cross sectional multicentre study  
Objective To determine the association between surgeons’ experience and postoperative complications in thyroid surgery.
Design Prospective cross sectional multicentre study.
Setting High volume referral centres in five academic hospitals in France.
Participants All patients who underwent a thyroidectomy undertaken by every surgeon in these hospitals from 1 April 2008 to 31 December 2009.
Main outcome measures Presence of two permanent major complications (recurrent laryngeal nerve palsy or hypoparathyroidism), six months after thyroid surgery. We used mixed effects logistic regression to determine the association between length of experience and postoperative complications.
Results 28 surgeons completed 3574 thyroid procedures during a one year period. Overall rates of recurrent laryngeal nerve palsy and hypoparathyroidism were 2.08% (95% confidence interval 1.53% to 2.67%) and 2.69% (2.10% to 3.31%), respectively. In a multivariate analysis, 20 years or more of practice was associated with increased probability of both recurrent laryngeal nerve palsy (odds ratio 3.06 (1.07 to 8.80), P=0.04) and hypoparathyroidism (7.56 (1.79 to 31.99), P=0.01). Surgeons’ performance had a concave association with their length of experience (P=0.036) and age (P=0.035); surgeons aged 35 to 50 years had better outcomes than their younger and older colleagues.
Conclusions Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further.
doi:10.1136/bmj.d8041
PMCID: PMC3256252  PMID: 22236412
11.  Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials 
Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
Design Systematic review with meta-analyses.
Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011).
Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.
Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.
Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.
Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
doi:10.1136/bmj.d7771
PMCID: PMC3256253  PMID: 22236411
12.  Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study 
Objective To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension.
Design Nested case-control study.
Setting UK general practice database, 2000-7.
Participants All incident cases of gout (n=24 768) among adults aged 20-79 and a random sample of 50 000 matched controls.
Main outcome measure Relative risk of incident gout associated with use of antihypertensive drugs.
Results After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n=29 138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for β blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend).
Conclusions Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.
doi:10.1136/bmj.d8190
PMCID: PMC3257215  PMID: 22240117
13.  Effectiveness of agricultural interventions that aim to improve nutritional status of children: systematic review 
Objective To assess the effectiveness of agricultural interventions in improving the nutritional status of children in developing countries.
Design Systematic review.
Data sources Published and unpublished reports (after 1990) in English identified by searching 10 databases (Agris, Econlit, Eldis, IBSS, IDEAS, IFPRI, Jolis, PubMed, Web of Science, and World Bank), websites, previous systematic reviews, and reference lists and by contacting experts.
Study selection Included studies assessed effects of agricultural interventions aiming at improving the nutritional status of children (bio-fortification, home gardens, small scale fisheries and aquaculture, dairy development, and animal husbandry and poultry development). Only studies that used a valid counterfactual analysis were included. Before/after studies and participants/non-participants comparisons affected by selection bias were excluded.
Data analysis Results were analysed for four intermediate outcomes (programme participation, income, dietary diversity, and micronutrient intake) and one final outcome (prevalence of under-nutrition). Analysis was by summary tables of mean effects and by meta-analysis (for vitamin A absorption).
Results The review included 23 studies, mostly evaluating home garden interventions. The studies reviewed did not report participation rates or the characteristics of participants in programmes. The interventions had a positive effect on the production of the agricultural goods promoted, but not on households’ total income. The interventions were successful in promoting the consumption of food rich in protein and micronutrients, but the effect on the overall diet of poor people remains unclear. No evidence was found of an effect on the absorption of iron, but some evidence exists of a positive effect on absorption of vitamin A. Very little evidence was found of a positive effect on the prevalence of stunting, wasting, and underweight among children aged under 5.
Conclusions The question posed by the review cannot be answered with any level of confidence. The data available show a poor effect of these interventions on nutritional status, but methodological weaknesses of the studies cast serious doubts on the validity of these results. More rigorous and better designed studies are needed, as well as the establishment of agreed quality standards to guide researchers in this important area.
doi:10.1136/bmj.d8222
PMCID: PMC3259800  PMID: 22251864
14.  Consumption of fried foods and risk of coronary heart disease: Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study 
Objective To assess the association between consumption of fried foods and risk of coronary heart disease.
Design Prospective cohort study.
Setting Spanish cohort of the European Prospective Investigation into Cancer and Nutrition.
Participants 40 757 adults aged 29-69 and free of coronary heart disease at baseline (1992-6), followed up until 2004.
Main outcome measures Coronary heart disease events and vital status identified by record linkage with hospital discharge registers, population based registers of myocardial infarction, and mortality registers.
Results During a median follow-up of 11 years, 606 coronary heart disease events and 1135 deaths from all causes occurred. Compared with being in the first (lowest) quarter of fried food consumption, the multivariate hazard ratio of coronary heart disease in the second quarter was 1.15 (95% confidence interval 0.91 to 1.45), in the third quarter was 1.07 (0.83 to 1.38), and in the fourth quarter was 1.08 (0.82 to 1.43; P for trend 0.74). The results did not vary between those who used olive oil for frying and those who used sunflower oil. Likewise, no association was observed between fried food consumption and all cause mortality: multivariate hazard ratio for the highest versus the lowest quarter of fried food consumption was 0.93 (95% confidence interval 0.77 to 1.14; P for trend 0.98).
Conclusion In Spain, a Mediterranean country where olive or sunflower oil is used for frying, the consumption of fried foods was not associated with coronary heart disease or with all cause mortality.
doi:10.1136/bmj.e363
PMCID: PMC3265571  PMID: 22275385
15.  25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study 
Objectives To examine 25 year trends in first time hospitalisation for acute myocardial infarction in Denmark, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity.
Design Nationwide population based cohort study using medical registries.
Setting All hospitals in Denmark.
Subjects 234 331 patients with a first time hospitalisation for myocardial infarction from 1984 through 2008.
Main outcome measures Standardised incidence rate of myocardial infarction and 30 day and 31–365 day mortality by sex. Comorbidity categories were defined as normal, moderate, severe, and very severe according to the Charlson comorbidity index, and were compared by means of mortality rate ratios based on Cox regression.
Results The standardised incidence rate per 100 000 people decreased in the 25 year period by 37% for women (from 209 to 131) and by 48% for men (from 410 to 213). The 30 day, 31–365 day, and one year mortality declined from 31.4%, 15.6%, and 42.1% in 1984–8 to 14.8%, 11.1%, and 24.2% in 2004–8, respectively. After adjustment for age at time of myocardial infarction, men and women had the same one year risk of dying. The mortality reduction was independent of comorbidity category. Comparing patients with very severe versus normal comorbidity during 2004–8, the mortality rate ratio, adjusted for age and sex, was 1.96 (95% CI 1.83 to 2.11) within 30 days and 3.89 (3.58 to 4.24) within 31–365 days.
Conclusions The rate of first time hospitalisation for myocardial infarction and subsequent short term mortality both declined by nearly half between 1984 and 2008. The reduction in mortality occurred for all patients, independent of sex and comorbidity. However, comorbidity burden was a strong prognostic factor for short and long term mortality, while sex was not.
doi:10.1136/bmj.e356
PMCID: PMC3266429  PMID: 22279115
16.  Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study 
Objective To report trends in event and case fatality rates for acute myocardial infarction and examine the relative contributions of changes in these rates to changes in total mortality from acute myocardial infarction by sex, age, and geographical region between 2002 and 2010.
Design Population based study using person linked routine hospital and mortality data.
Setting England.
Participants 840 175 people of all ages who were admitted to hospital for acute myocardial infarction or died suddenly from acute myocardial infarction.
Main outcome measures Acute myocardial infarction event, 30 day case fatality, and total mortality rates.
Results From 2002 to 2010 in England, the age standardised total mortality rate fell by about half, whereas the age standardised event and case fatality rates both declined by about one third. In men, the acute myocardial infarction event, case fatality, and total mortality rates declined at an average annual rate of, respectively, 4.8% (95% confidence interval 3.0% to 6.5%), 3.6% (3.4% to 3.7%), and 8.6% (5.4% to 11.6%). In women, the corresponding figures were 4.5% (1.7% to 7.1%), 4.2% (4.0% to 4.3%), and 9.1% (4.5% to 13.6%). Overall, the relative contributions of the reductions in event and case fatality rates to the decline in acute myocardial infarction mortality rate were, respectively, 57% and 43% in men and 52% and 48% in women; however, the relative contributions differed by age, sex, and geographical region.
Conclusions Just over half of the decline in deaths from acute myocardial infarction during the 2000s in England can be attributed to a decline in event rate and just less than half to improved survival at 30 days. Both prevention of acute myocardial infarction and acute medical treatment have contributed to the decline in deaths from acute myocardial infarction over the past decade.
doi:10.1136/bmj.d8059
PMCID: PMC3266430  PMID: 22279113
17.  Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study 
Objectives To examine how much of the observed rapid decrease in mortality from coronary heart disease in Poland after the political, social, and economic transformation in the early 1990s could be explained by the use of medical and surgical treatments and how much by changes in cardiovascular risk factors.
Design A modelling study.
Setting Sources of data included controlled trials and meta-analyses, national surveys, and official statistics.
Participants Population of adults aged 25-74 in Poland in 1991-2005.
Main outcome measures Number of deaths prevented or postponed in 2005 attributable to specific treatments for coronary heart disease and changes in risk factors. A previously validated epidemiological model for coronary heart disease was used to combine and analyse data on the uptake and effectiveness of specific cardiac treatments and changes in risk factors. The observed fall in deaths from coronary heart disease from 1991 to 2005 was then partitioned among specific treatments and risk factor changes.
Results From 1991 to 2005, the death rate from coronary heart disease in Poland halved, resulting in 26 200 fewer coronary deaths in 2005 in people aged 25-74. About 37% (minimum estimate 13%, maximum estimate 77%) of this decrease was attributable to treatments, including treatments for heart failure (12%), initial treatments for acute coronary syndrome (9%), secondary prevention treatments after myocardial infarction or revascularisation (7%), chronic angina treatments (3%), and other treatments (6%). About 54% of the fall was attributed to changes in risk factors (minimum estimate 41%, maximum estimate 65%), mainly reductions in total cholesterol concentration (39%) and an increase in leisuretime physical activity (10%); however, these were partially offset by increases in body mass index (−4%) and prevalence of diabetes (−2%). Blood pressure fell in women, explaining about 29% of their decrease in mortality, but rose in men generating a negative influence (−8%). About 15% of the observed decrease in mortality was attributable to reduced smoking in men but was negligible in women.
Conclusions Over half of the recent fall in mortality from coronary heart disease in Poland can be attributed to reductions in major risk factors and about one third to evidence based medical treatments.
doi:10.1136/bmj.d8136
PMCID: PMC3266431  PMID: 22279114
18.  Understanding recent trends in incidence of invasive breast cancer in Norway: age-period-cohort analysis based on registry data on mammography screening and hormone treatment use 
Objective To quantify the separate contributions of menopausal hormone treatment and mammography screening activities on trends in incidence of invasive breast cancer between 1987 and 2008.
Design Population study using aggregated data analysed by an extended age-period-cohort model.
Setting Norway.
Population Norwegian women aged 30-90 between 1987 and 2008, including 50 102 newly diagnosed cases of invasive breast cancer.
Main outcomes measures Attributable proportions of mammography screening and hormone treatment to recent incidence of invasive breast cancer, and the remaining variation in incidence after adjustment for mammography screening and hormone treatment.
Results The incidence of invasive breast cancer in Norway increased steadily until 2002, levelled off, and then declined from 2006. All non-linear changes in incidence were explained by use of hormone treatment and mammography screening activities, with about similar contributions of each factor. In 2002, when the incidence among women aged 50-69 was highest, an estimated 23% of the cases in that age group could be attributed to mammography screening and 27% to use of hormone treatment.
Conclusions Changes in incidence trends of invasive breast cancer since the early 1990s may be fully attributed to mammography screening and hormone treatment, with about similar contributions of each factor.
doi:10.1136/bmj.e299
PMCID: PMC3268754  PMID: 22290099
19.  Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial 
Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age.
Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial.
Setting Adelaide, South Australia.
Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial.
Interventions The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks’ gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA.
Main outcome measure Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age.
Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen.
Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood.
Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
doi:10.1136/bmj.e184
PMCID: PMC3269207  PMID: 22294737
20.  Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study 
Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture.
Design Prospective cohort study.
Setting Nurses’ Health Study, which originally recruited from the 11 most populous states in the US.
Participants 79 899 postmenopausal women enrolled in the Nurses’ Health Study who provided data on the use of PPIs and other risk factors biennially since 2000 and were followed up to 1 June 2008.
Main outcome measure Incident hip fracture
Results During 565 786 person years of follow-up, we documented 893 incident hip fractures. The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)), with longer use associated with increasing risk (Ptrend<0.01). Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use. The relation between PPI use and fracture differed by smoking history (Pinteraction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture, with a multivariate hazard ratio for fracture of 1.51 (1.20 to 1.91). In contrast, among women who never smoked there was no association (multivariate hazard ratio 1.06 (0.77 to 1.46)). In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36).
Conclusion Chronic use of PPIs is associated with increased risk of hip fracture, particularly among women with a history of smoking.
doi:10.1136/bmj.e372
PMCID: PMC3269660  PMID: 22294756
21.  Influence of medical journal press releases on the quality of associated newspaper coverage: retrospective cohort study 
Objective To determine whether the quality of press releases issued by medical journals can influence the quality of associated newspaper stories.
Design Retrospective cohort study of medical journal press releases and associated news stories.
Setting We reviewed consecutive issues (going backwards from January 2009) of five major medical journals (Annals of Internal Medicine, BMJ, Journal of the National Cancer Institute, JAMA, and New England Journal of Medicine) to identify the first 100 original research articles with quantifiable outcomes and that had generated any newspaper coverage (unique stories ≥100 words long). We identified 759 associated newspaper stories using Lexis Nexis and Factiva searches, and 68 journal press releases using Eurekalert and journal website searches. Two independent research assistants assessed the quality of journal articles, press releases, and a stratified random sample of associated newspaper stories (n=343) by using a structured coding scheme for the presence of specific quality measures: basic study facts, quantification of the main result, harms, and limitations.
Main outcome Proportion of newspaper stories with specific quality measures (adjusted for whether the quality measure was present in the journal article’s abstract or editor note).
Results We recorded a median of three newspaper stories per journal article (range 1-72). Of 343 stories analysed, 71% reported on articles for which medical journals had issued press releases. 9% of stories quantified the main result with absolute risks when this information was not in the press release, 53% did so when it was in the press release (relative risk 6.0, 95% confidence interval 2.3 to 15.4), and 20% when no press release was issued (2.2, 0.83 to 6.1). 133 (39%) stories reported on research describing beneficial interventions. 24% mentioned harms (or specifically declared no harms) when harms were not mentioned in the press release, 68% when mentioned in the press release (2.8, 1.1 to 7.4), and 36% when no press release was issued (1.5, 0.49 to 4.4). 256 (75%) stories reported on research with important limitations. 16% reported any limitations when limitations were not mentioned in the press release, 48% when mentioned in the press release (3.0, 1.5 to 6.2), and 21% if no press release was issued (1.3, 0.50 to 3.6).
Conclusion High quality press releases issued by medical journals seem to make the quality of associated newspaper stories better, whereas low quality press releases might make them worse.
doi:10.1136/bmj.d8164
PMCID: PMC3267473  PMID: 22286507
22.  Effectiveness of multifaceted educational programme to reduce antibiotic dispensing in primary care: practice based randomised controlled trial 
Objective To evaluate the effectiveness and costs of a multifaceted flexible educational programme aimed at reducing antibiotic dispensing at the practice level in primary care.
Design Randomised controlled trial with general practices as the unit of randomisation and analysis. Clinicians and researchers were blinded to group allocation until after randomisation.
Setting 68 general practices with about 480 000 patients in Wales, United Kingdom.
Participants 34 practices were randomised to receive the educational programme and 34 practices to be controls. 139 clinicians from the intervention practices and 124 from control practices had agreed to participate before randomisation. Practice level data covering all the clinicians in the 68 practices were analysed.
Interventions Intervention practices followed the Stemming the Tide of Antibiotic Resistance (STAR) educational programme, which included a practice based seminar reflecting on the practices’ own dispensing and resistance data, online educational elements, and practising consulting skills in routine care. Control practices provided usual care.
Main outcome measures Total numbers of oral antibiotic items dispensed for all causes per 1000 practice patients in the year after the intervention, adjusted for the previous year’s dispensing. Secondary outcomes included reconsultations, admissions to hospital for selected causes, and costs.
Results The rate of oral antibiotic dispensing (items per 1000 registered patients) decreased by 14.1 in the intervention group but increased by 12.1 in the control group, a net difference of 26.1. After adjustment for baseline dispensing rate, this amounted to a 4.2% (95% confidence interval 0.6% to 7.7%) reduction in total oral antibiotic dispensing for the year in the intervention group relative to the control group (P=0.02). Reductions were found for all classes of antibiotics other than penicillinase-resistant penicillins but were largest and significant individually for phenoxymethylpenicillins (penicillin V) (7.3%, 0.4% to 13.7%) and macrolides (7.7%, 1.1% to 13.8%). There were no significant differences between intervention and control practices in the number of admissions to hospital or in reconsultations for a respiratory tract infection within seven days of an index consultation. The mean cost of the programme was £2923 (€3491, $4572) per practice (SD £1187). There was a 5.5% reduction in the cost of dispensed antibiotics in the intervention group compared with the control group (−0.4% to 11.4%), equivalent to a reduction of about £830 a year for an average intervention practice.
Conclusion The STAR educational programme led to reductions in all cause oral antibiotic dispensing over the subsequent year with no significant change in admissions to hospital, reconsultations, or costs.
Trial registration ISRCT No 63355948.
doi:10.1136/bmj.d8173
PMCID: PMC3270575  PMID: 22302780
23.  Health symptoms during midlife in relation to menopausal transition: British prospective cohort study 
Objective To characterise symptoms experienced by women during the transition into natural menopause, to classify women into distinct symptom profiles or trajectories, and to relate these profiles to sociodemographic factors and health behaviours.
Design Nationally representative cohort study.
Setting England, Scotland, and Wales.
Participants 695 women followed-up since birth in 1946 and annually from age 47 to 54 who experienced natural menopause and reported on 20 common health symptoms.
Main outcome measure Longitudinal profiles for reported bothersome symptoms.
Results Of 20 individual symptoms, 18 formed into four stable symptom groups: psychological, somatic, vasomotor, and sexual discomfort. Using latent class analyses, all except the somatic group of symptoms showed a clear relation with the timing of menopause for some women. A small proportion of women (10%, n=63) had a severe psychological symptom profile that peaked at or in the year after menopause. For vasomotor symptoms, 14% of women (n=83) had the early severe profile that also peaked around early postmenopause and then declined noticeably; 11% (n=67) had the late severe profile of bothersome symptoms that increased rapidly in perimenopause and remained high for four years or more after menopause. Women were less likely to have a profile for severe vasomotor symptoms if they were from a non-manual social class (odds ratio 0.79, 95% confidence interval 0.57 to 1.01) or had degree level qualifications (0.37, 0.18 to 0.77). The 14% of women (n=85) who had the late severe profile for sexual discomfort showed a similar increase in symptoms until menopause, with symptoms persisting after menopause. Married women were more likely to have the late severe or late moderate profile than women of other marital status (2.40, 1.30 to 4.41). Four profiles each were identified for somatic symptoms (mild, moderate, severe, and very severe), although these did not vary by chronological age or age at menopause.
Conclusion Profiles for psychological, vasomotor, and sexual discomfort symptoms relative to age at menopause could help health professionals to tailor their advice for women with natural menopause.
doi:10.1136/bmj.e402
PMCID: PMC3275131  PMID: 22318435
24.  Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study 
Objectives To develop and validate a delirium prediction model for adult intensive care patients and determine its additional value compared with prediction by caregivers.
Design Observational multicentre study.
Setting Five intensive care units in the Netherlands (two university hospitals and three university affiliated teaching hospitals).
Participants 3056 intensive care patients aged 18 years or over.
Main outcome measure Development of delirium (defined as at least one positive delirium screening) during patients’ stay in intensive care.
Results The model was developed using 1613 consecutive intensive care patients in one hospital and temporally validated using 549 patients from the same hospital. For external validation, data were collected from 894 patients in four other hospitals. The prediction (PRE-DELIRIC) model contains 10 risk factors—age, APACHE-II score, admission group, coma, infection, metabolic acidosis, use of sedatives and morphine, urea concentration, and urgent admission. The model had an area under the receiver operating characteristics curve of 0.87 (95% confidence interval 0.85 to 0.89) and 0.86 after bootstrapping. Temporal validation and external validation resulted in areas under the curve of 0.89 (0.86 to 0.92) and 0.84 (0.82 to 0.87). The pooled area under the receiver operating characteristics curve (n=3056) was 0.85 (0.84 to 0.87). The area under the curve for nurses’ and physicians’ predictions (n=124) was significantly lower at 0.59 (0.49 to 0.70) for both.
Conclusion The PRE-DELIRIC model for intensive care patients consists of 10 risk factors that are readily available within 24 hours after intensive care admission and has a high predictive value. Clinical prediction by nurses and physicians performed significantly worse. The model allows for early prediction of delirium and initiation of preventive measures.
Trial registration Clinical trials NCT00604773 (development study) and NCT00961389 (validation study).
doi:10.1136/bmj.e420
PMCID: PMC3276486  PMID: 22323509
25.  Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis 
Objective To determine the efficacy and safety of enoxaparin compared with unfractionated heparin during percutaneous coronary intervention.
Design Systematic review and meta-analysis.
Data sources Medline and Cochrane database of systematic reviews, January 1996 to May 2011.
Study selection Randomised and non-randomised studies comparing enoxaparin with unfractionated heparin during percutaneous coronary intervention and reporting on both mortality (efficacy end point) and major bleeding (safety end point) outcomes.
Data extraction Sample size, characteristics, and outcomes, extracted independently and analysed.
Data synthesis 23 trials representing 30 966 patients were identified, including 10 243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11 973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13 943 patients (45.0%) received enoxaparin and 17 023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P<0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P<0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).
Conclusion Enoxaparin seems to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention and particularly in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.
doi:10.1136/bmj.e553
PMCID: PMC3271999  PMID: 22306479

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