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1.  Quantifying and monitoring overdiagnosis in cancer screening: a systematic review of methods 
Objective To determine the optimal method for quantifying and monitoring overdiagnosis in cancer screening over time.
Design Systematic review of primary research studies of any design that quantified overdiagnosis from screening for nine types of cancer. We used explicit criteria to critically appraise individual studies and assess strength of the body of evidence for each study design (double blinded review), and assessed the potential for each study design to accurately quantify and monitor overdiagnosis over time.
Data sources PubMed and Embase up to 28 February 2014; hand searching of systematic reviews.
Eligibility criteria for selecting studies English language studies of any design that quantified overdiagnosis for any of nine common cancers (prostate, breast, lung, colorectal, melanoma, bladder, renal, thyroid, and uterine); excluded case series, case reports, and reviews that only reported results of other studies.
Results 52 studies met the inclusion criteria. We grouped studies into four methodological categories: (1) follow-up of a well designed randomized controlled trial (n=3), which has low risk of bias but may not be generalizable and is not suitable for monitoring; (2) pathological or imaging studies (n=8), drawing conclusions about overdiagnosis by examining biological characteristics of cancers, a simple design limited by the uncertain assumption that the measured characteristics are highly correlated with disease progression; (3) modeling studies (n=21), which can be done in a shorter time frame but require complex mathematical equations simulating the natural course of screen detected cancer, the fundamental unknown question; and (4) ecological and cohort studies (n=20), which are suitable for monitoring over time but are limited by a lack of agreed standards, by variable data quality, by inadequate follow-up time, and by the potential for population level confounders. Some ecological and cohort studies, however, have addressed these potential weaknesses in reasonable ways.
Conclusions Well conducted ecological and cohort studies in multiple settings are the most appropriate approach for quantifying and monitoring overdiagnosis in cancer screening programs. To support this work, we need internationally agreed standards for ecological and cohort studies and a multinational team of unbiased researchers to perform ongoing analysis.
doi:10.1136/bmj.g7773
PMCID: PMC4332263  PMID: 25569206
2.  Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study 
Objective To determine whether use of oral contraceptives is associated with all cause and cause specific mortality.
Design Prospective cohort study.
Setting Nurses’ Health Study, data collected between 1976 and 2012.
Population 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982.
Main outcome measures Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives.
Results In our population of 121 577 women with information on oral contraceptive use, 63 626 were never users (52%) and 57 951 were ever users (48%). After 3.6 million person years, we recorded 31 286 deaths. No association was observed between ever use of oral contraceptives and all cause mortality. However, violent or accidental deaths were more common among ever users (hazard ratio 1.20, 95% confidence interval 1.04 to 1.37). Longer duration of use was more strongly associated with certain causes of death, including premature mortality due to breast cancer (test for trend P<0.0001) and decreased mortality rates of ovarian cancer (P=0.002). Longer time since last use was also associated with certain outcomes, including a positive association with violent or accidental deaths (P=0.005).
Conclusions All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives. These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses.
doi:10.1136/bmj.g6356
PMCID: PMC4216099  PMID: 25361731
3.  Government health insurance for people below poverty line in India: quasi-experimental evaluation of insurance and health outcomes 
Objectives To evaluate the effects of a government insurance program covering tertiary care for people below the poverty line in Karnataka, India, on out-of-pocket expenditures, hospital use, and mortality.
Design Geographic regression discontinuity study.
Setting 572 villages in Karnataka, India.
Participants 31 476 households (22 796 below poverty line and 8680 above poverty line) in 300 villages where the scheme was implemented and 28 633 households (21 767 below poverty line and 6866 above poverty line) in 272 neighboring matched villages ineligible for the scheme.
Intervention A government insurance program (Vajpayee Arogyashree scheme) that provided free tertiary care to households below the poverty line in about half of villages in Karnataka from February 2010 to August 2012.
Main outcome measure Out-of-pocket expenditures, hospital use, and mortality.
Results Among households below the poverty line, the mortality rate from conditions potentially responsive to services covered by the scheme (mostly cardiac conditions and cancer) was 0.32% in households eligible for the scheme compared with 0.90% among ineligible households just south of the eligibility border (difference of 0.58 percentage points, 95% confidence interval 0.40 to 0.75; P<0.001). We found no difference in mortality rates for households above the poverty line (households above the poverty line were not eligible for the scheme), with a mortality rate from conditions covered by the scheme of 0.56% in eligible villages compared with 0.55% in ineligible villages (difference of 0.01 percentage points, −0.03 to 0.03; P=0.95). Eligible households had significantly reduced out-of-pocket health expenditures for admissions to hospitals with tertiary care facilities likely to be covered by the scheme (64% reduction, 35% to 97%; P<0.001). There was no significant increase in use of covered services, although the point estimate of a 44.2% increase approached significance (−5.1% to 90.5%; P=0.059). Both reductions in out-of-pocket expenditures and potential increases in use might have contributed to the observed reductions in mortality.
Conclusions Insuring poor households for efficacious but costly and underused health services significantly improves population health in India.
doi:10.1136/bmj.g5114
PMCID: PMC4161676  PMID: 25214509
4.  Effect of implementation of Integrated Management of Neonatal and Childhood Illness programme on treatment seeking practices for morbidities in infants: cluster randomised trial 
Objective To determine the effect of implementation of the Integrated Management of Neonatal and Childhood Illness strategy on treatment seeking practices and on neonatal and infant morbidity.
Design Cluster randomised trial.
Setting Haryana, India.
Participants 29 667 births in nine intervention clusters and 30 813 births in nine control clusters.
Main outcome measures The pre-specified outcome was the effect on treatment seeking practices. Post hoc exploratory analyses assessed morbidity, hospital admission, post-neonatal infant care, and nutritional status outcomes.
Interventions The Integrated Management of Neonatal and Childhood Illness intervention included home visits by community health workers, improved case management of sick children, and strengthening of health systems. Outcomes were ascertained through interviews with randomly selected caregivers: 6204, 3073, and 2045 in intervention clusters and 6163, 3048, and 2017 in control clusters at ages 29 days, 6 months, and 12 months, respectively.
Results In the intervention cluster, treatment was sought more often from an appropriate provider for severe neonatal illness (risk ratio 1.76, 95% confidence interval 1.38 to 2.24), for local neonatal infection (4.86, 3.80 to 6.21), and for diarrhoea at 6 months (1.96, 1.38 to 2.79) and 12 months (1.22, 1.06 to 1.42) and pneumonia at 6 months (2.09, 1.31 to 3.33) and 12 months (1.44, 1.00 to 2.08). Intervention mothers reported fewer episodes of severe neonatal illness (risk ratio 0.82, 0.67 to 0.99) and lower prevalence of diarrhoea (0.71, 0.60 to 0.83) and pneumonia (0.73, 0.52 to 1.04) in the two weeks preceding the 6 month interview and of diarrhoea (0.63, 0.49 to 0.80) and pneumonia (0.60, 0.46 to 0.78) in the two weeks preceding the 12 month interview. Infants in the intervention clusters were more likely to still be exclusively breast fed in the sixth month of life (risk ratio 3.19, 2.67 to 3.81).
Conclusion Implementation of the Integrated Management of Neonatal and Childhood Illness programme was associated with timely treatment seeking from appropriate providers and reduced morbidity, a likely explanation for the reduction in mortality observed following implementation of the programme in this study.
Trial registration Clinical trials NCT00474981; ICMR Clinical Trial Registry CTRI/2009/091/000715.
doi:10.1136/bmj.g4988
PMCID: PMC4148946  PMID: 25172514
5.  Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients 
Objective To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.
Design Meta-analysis.
Studies reviewed Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).
Results 117 411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.
Conclusions Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.
doi:10.1136/bmj.g4379
PMCID: PMC4103514  PMID: 25038074
6.  Obama widens access to government funded research 
doi:10.1136/bmj.f1339
PMCID: PMC4046902  PMID: 23449676
8.  Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study 
Objective To assess the effects of coding and coding conventions on summaries and tabulations of adverse events data on suicidality within clinical study reports.
Design Systematic electronic search for adverse events of suicidality in tables, narratives, and listings of adverse events in individual patients within clinical study reports. Where possible, for each event we extracted the original term reported by the investigator, the term as coded by the medical coding dictionary, medical coding dictionary used, and the patient’s trial identification number. Using the patient’s trial identification number, we attempted to reconcile data on the same event between the different formats for presenting data on adverse events within the clinical study report.
Setting 9 randomised placebo controlled trials of duloxetine for major depressive disorder submitted to the European Medicines Agency for marketing approval.
Data sources Clinical study reports obtained from the EMA in 2011.
Results Six trials used the medical coding dictionary COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) and three used MedDRA (Medical Dictionary for Regulatory Activities). Suicides were clearly identifiable in all formats of adverse event data in clinical study reports. Suicide attempts presented in tables included both definitive and provisional diagnoses. Suicidal ideation and preparatory behaviour were obscured in some tables owing to the lack of specificity of the medical coding dictionary, especially COSTART. Furthermore, we found one event of suicidal ideation described in narrative text that was absent from tables and adverse event listings of individual patients. The reason for this is unclear, but may be due to the coding conventions used.
Conclusion Data on adverse events in tables in clinical study reports may not accurately represent the underlying patient data because of the medical dictionaries and coding conventions used. In clinical study reports, the listings of adverse events for individual patients and narratives of adverse events can provide additional information, including original investigator reported adverse event terms, which can enable a more accurate estimate of harms.
doi:10.1136/bmj.g3555
PMCID: PMC4045315  PMID: 24899651
9.  Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications 
Objective To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms.
Design Data on primary efficacy analysis and major harms extracted from each data source and compared.
Setting Nine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder.
Data sources Clinical study reports, including protocols as appendices (total 13 729 pages), were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer’s online clinical trial registry were searched for trial results.
Results Clinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.
Conclusion Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.
doi:10.1136/bmj.g3510
PMCID: PMC4045316  PMID: 24899650
10.  Quantification of risk factors for herpes zoster: population based case-control study 
Objectives To quantify the effects of possible risk factors for herpes zoster at different ages.
Design Case-control study.
Setting UK Clinical Practice Research Datalink primary care data.
Participants 144 959 adults diagnosed with zoster between 2000 and 2011; 549 336 age, sex, and practice matched controls.
Main outcome measures Conditional logistic regression was used to generate adjusted odds ratios to estimate the strength of association of each potential risk factor with zoster and assess effect modification by age.
Results The median age of the cases and controls was 62 years. Factors associated with increased risk of zoster included rheumatoid arthritis (3111 (2.1%) v 8029 (1.5%); adjusted odds ratio 1.46, 99% confidence interval 1.38 to 1.55), inflammatory bowel disease (1851 (1.3%) v 5118 (0.9%); 1.36, 1.26 to 1.46), chronic obstructive pulmonary disease (6815 (4.7%) v 20 201 (3.7%); 1.32, 1.27 to 1.37), asthma (10 243 (7.1%) v 31 865 (5.8%); 1.21, 1.17 to 1.25), chronic kidney disease (8724 (6.0%) v 29 437 (5.4%); 1.14, 1.09 to 1.18), and depression (6830 (4.7%) v 22 052 (4.0%); 1.15, 1.10 to 1.20). Type 1, but not type 2, diabetes showed some association with zoster (adjusted odds ratio 1.27, 1.07 to 1.50). The relative effects of many assessed risk factors were larger in younger patients. Patients with severely immunosuppressive conditions were at greatest risk of zoster—for example, patients with lymphoma (adjusted odds ratio 3.90, 3.21 to 4.74) and myeloma (2.16, 1.84 to 2.53), who are not eligible for zoster vaccination.
Conclusions A range of conditions were associated with increased risk of zoster. In general, the increased risk was proportionally greater in younger age groups. Current vaccines are contraindicated in people at the greatest risk of zoster, highlighting the need for alternative risk reduction strategies in these groups.
doi:10.1136/bmj.g2911
PMCID: PMC4019782  PMID: 25134101
11.  Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys 
Objectives To quantify global consumption of key dietary fats and oils by country, age, and sex in 1990 and 2010.
Design Data were identified, obtained, and assessed among adults in 16 age- and sex-specific groups from dietary surveys worldwide on saturated, omega 6, seafood omega 3, plant omega 3, and trans fats, and dietary cholesterol. We included 266 surveys in adults (83% nationally representative) comprising 1 630 069 unique individuals, representing 113 of 187 countries and 82% of the global population. A multilevel hierarchical Bayesian model accounted for differences in national and regional levels of missing data, measurement incomparability, study representativeness, and sampling and modelling uncertainty.
Setting and population Global adult population, by age, sex, country, and time.
Results In 2010, global saturated fat consumption was 9.4%E (95%UI=9.2 to 9.5); country-specific intakes varied dramatically from 2.3 to 27.5%E; in 75 of 187 countries representing 61.8% of the world’s adult population, the mean intake was <10%E. Country-specific omega 6 consumption ranged from 1.2 to 12.5%E (global mean=5.9%E); corresponding range was 0.2 to 6.5%E (1.4%E) for trans fat; 97 to 440 mg/day (228 mg/day) for dietary cholesterol; 5 to 3,886 mg/day (163 mg/day) for seafood omega 3; and <100 to 5,542 mg/day (1,371 mg/day) for plant omega 3. Countries representing 52.4% of the global population had national mean intakes for omega 6 fat ≥5%E; corresponding proportions meeting optimal intakes were 0.6% for trans fat (≤0.5%E); 87.6% for dietary cholesterol (<300 mg/day); 18.9% for seafood omega 3 fat (≥250 mg/day); and 43.9% for plant omega 3 fat (≥1,100 mg/day). Trans fat intakes were generally higher at younger ages; and dietary cholesterol and seafood omega 3 fats generally higher at older ages. Intakes were similar by sex. Between 1990 and 2010, global saturated fat, dietary cholesterol, and trans fat intakes remained stable, while omega 6, seafood omega 3, and plant omega 3 fat intakes each increased.
Conclusions These novel global data on dietary fats and oils identify dramatic diversity across nations and inform policies and priorities for improving global health.
doi:10.1136/bmj.g2272
PMCID: PMC3987052  PMID: 24736206
12.  Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments 
Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments (“regulatory information”).
Design Systematic review of regulatory information.
Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.
Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.
Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.
Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval −0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for “pneumonia,” and no clinical study reports reported laboratory or diagnostic confirmation of “pneumonia.” The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two “pivotal” treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, −0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).
Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.
doi:10.1136/bmj.g2545
PMCID: PMC3981975  PMID: 24811411
13.  Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments 
Objectives To describe the potential benefits and harms of zanamivir.
Design Systematic review of clinical study reports of randomised placebo controlled trials and regulatory information
Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.
Eligibility criteria for selecting studies Randomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza.
Main outcome measures Time to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population.
Results We included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I2=9%), which equates to an average 14.4 hours’ reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, −0.73% to 0.70%) or radiologically confirmed pneumonia (−0.06%, −6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, −1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, −1.10% to 1.10%) or in households (1.32%, −2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086).
Conclusions Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.
doi:10.1136/bmj.g2547
PMCID: PMC3981976  PMID: 24811412
14.  Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies 
Objectives To review, summarise, and compare the evidence for effectiveness of screening sigmoidoscopy and screening colonoscopy in the prevention of colorectal cancer occurrence and deaths.
Design Systematic review and meta-analysis of randomised controlled trials and observational studies.
Data sources PubMed, Embase, and Web of Science. Two investigators independently extracted characteristics and results of identified studies and performed standardised quality ratings.
Eligibility criteria Randomised controlled trials and observational studies in English on the impact of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality in the general population at average risk.
Results For screening sigmoidoscopy, four randomised controlled trials and 10 observational studies were identified that consistently found a major reduction in distal but not proximal colorectal cancer incidence and mortality. Summary estimates of reduction in distal colorectal cancer incidence and mortality were 31% (95% confidence intervals 26% to 37%) and 46% (33% to 57%) in intention to screen analysis, 42% (29% to 53%) and 61% (27% to 79%) in per protocol analysis of randomised controlled trials, and 64% (50% to 74%) and 66% (38% to 81%) in observational studies. For screening colonoscopy, evidence was restricted to six observational studies, the results of which suggest tentatively an even stronger reduction in distal colorectal cancer incidence and mortality, along with a significant reduction in mortality from cancer of the proximal colon. Indirect comparisons of results of observational studies on screening sigmoidoscopy and colonoscopy suggest a 40% to 60% lower risk of incident colorectal cancer and death from colorectal cancer after screening colonoscopy even though this incremental risk reduction was statistically significant for deaths from cancer of the proximal colon only.
Conclusions Compelling and consistent evidence from randomised controlled trials and observational studies suggests that screening sigmoidoscopy and screening colonoscopy prevent most deaths from distal colorectal cancer. Observational studies suggest that colonoscopy compared with flexible sigmoidoscopy decreases mortality from cancer of the proximal colon. This added value should be examined in further research and weighed against the higher costs, discomfort, complication rates, capacities needed, and possible differences in compliance.
doi:10.1136/bmj.g2467
PMCID: PMC3980789  PMID: 24922745
15.  Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: population based cohort study 
Objective To determine the relative risks of prostate cancer incidence, metastasis, and mortality associated with screening by serum prostate specific antigen (PSA) levels at age 60.
Design Population based cohort study.
Setting General male population of Sweden taking part in a screening trial in Gothenburg or participating in a cardiovascular study, the Malmö Preventive Project.
Participants The screened group consisted of 1756 men aged 57.5-62.5 participating in the screening arm of the Gothenburg randomized prostate cancer screening trial since 1995. The unscreened group consisted of 1162 men, born in 1921, participating in the Malmö Preventive Project, with PSA levels measured retrospectively in stored blood samples from 1981.
Intervention PSA screening versus no screening.
Main outcome measures Incidence rate ratios for the effect of screening on prostate cancer diagnosis, metastasis, and death by PSA levels at age 60.
Results The distribution of PSA levels was similar between the two cohorts. Differences in benefits by baseline PSA levels were large. Among men with baseline levels measured, 71.7% (1646/2295) had a PSA level <2 ng/mL. For men aged 60 with PSA level <2 ng/mL, there was an increase in incidence of 767 cases per 10 000 without a decrease in prostate cancer mortality. For men with PSA levels ≥2 ng/mL, the reduction in cancer mortality was large, with only 23 men needing to be screened and six diagnosed to avoid one prostate cancer death by 15 years.
Conclusions The ratio of benefits to harms of PSA screening varies noticeably with blood PSA levels at age 60. For men with a PSA level <1 ng/mL at age 60, no further screening is recommended. Continuing to screen men with PSA levels >2 ng/mL at age 60 is beneficial, with the number needed to screen and treat being extremely favourable. Screening men with a PSA level of 1-2 ng/mL is an individual decision to be based on a discussion between patient and doctor.
doi:10.1136/bmj.g2296
PMCID: PMC3968958  PMID: 24682399
16.  Role of quality measurement in inappropriate use of screening for colorectal cancer: retrospective cohort study 
Objective To examine whether the age based quality measure for screening for colorectal cancer is associated with overuse of screening in patients aged 70-75 in poor health and underuse in those aged over age 75 in good health.
Design Retrospective cohort study utilizing electronic data from the Veterans Affairs (VA) Health Care System, the largest integrated healthcare system in the United States.
Setting VA Health Care System.
Participants Veterans aged ≥50 due for repeat average risk colorectal cancer screening at a primary care visit in fiscal year 2010.
Main outcome measures Completion of colonoscopy, sigmoidoscopy, or fecal occult blood testing within 24 months of the 2010 visit.
Results 399 067 veterans met inclusion/exclusion criteria (mean age 67, 97% men). Of these, 38% had electronically documented screening within 24 months. In multivariable log binomial regression adjusted for Charlson comorbidity index, sex, and number of primary care visits, screening decreased markedly after the age of 75 (the age cut off used by the quality measure) (adjusted relative risk 0.35, 95% confidence interval 0.30 to 0.40). A veteran who was aged 75 and unhealthy (in whom life expectancy might be limited and screening more likely to result in net burden or harm) was significantly more likely to undergo screening than a veteran aged 76 and healthy (unadjusted relative risk 1.64, 1.36 to 1.97).
Conclusions Specification of a quality measure can have important implications for clinical care. Future quality measures should focus on individual risk/benefit to ensure that patients who are likely to benefit from a service receive it (regardless of age), and that those who are likely to incur harm are spared unnecessary and costly care.
doi:10.1136/bmj.g1247
PMCID: PMC3935739  PMID: 24574474
17.  Antenatal lifestyle advice for women who are overweight or obese: LIMIT randomised trial 
Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women.
Design Multicentre randomised trial. We utilised a central telephone randomisation server, with computer generated schedule, balanced variable blocks, and stratification for parity, body mass index (BMI) category, and hospital.
Setting Three public maternity hospitals across South Australia.
Participants 2212 women with a singleton pregnancy, between 10+0 and 20+0 weeks’ gestation, and BMI ≥25.
Interventions 1108 women were randomised to a comprehensive dietary and lifestyle intervention delivered by research staff; 1104 were randomised to standard care and received pregnancy care according to local guidelines, which did not include such information.
Main outcome measures Incidence of infants born large for gestational age (birth weight ≥90th centile for gestation and sex). Prespecified secondary outcomes included birth weight >4000 g, hypertension, pre-eclampsia, and gestational diabetes. Analyses used intention to treat principles.
Results 2152 women and 2142 liveborn infants were included in the analyses. The risk of the infant being large for gestational age was not significantly different in the two groups (lifestyle advice 203/1075 (19%) v standard care 224/1067 (21%); adjusted relative risk 0.90, 95% confidence interval 0.77 to 1.07; P=0.24). Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g (lifestyle advice 164/1075 (15%) v standard care 201/1067 (19%); 0.82, 0.68 to 0.99; number needed to treat (NNT) 28, 15 to 263; P=0.04). There were no differences in maternal pregnancy and birth outcomes between the two treatment groups.
Conclusions For women who were overweight or obese, the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes.
Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).
doi:10.1136/bmj.g1285
PMCID: PMC3919179  PMID: 24513442
18.  Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis 
Objective To assess the effects of different classes of antihypertensive treatments, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes.
Design Systematic review and bayesian network meta-analysis of randomised clinical trials.
Data sources Electronic literature search of PubMed, Medline, Scopus, and the Cochrane Library for studies published up to December 2011.
Study selection Randomised clinical trials of antihypertensive therapy (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), α blockers, β blockers, calcium channel blockers, diuretics, and their combinations) in patients with diabetes with a follow-up of at least 12 months, reporting all cause mortality, requirement for dialysis, or doubling of serum creatinine levels.
Data extraction Bayesian network meta-analysis combined direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects.
Results 63 trials with 36 917 participants were identified, including 2400 deaths, 766 patients who required dialysis, and 1099 patients whose serum creatinine level had doubled. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels (odds ratio 0.58, 95% credible interval 0.32 to 0.90), and only β blockers showed a significant difference in mortality (odds ratio 7.13, 95% credible interval 1.37 to 41.39). Comparisons among all treatments showed no statistical significance in the outcome of dialysis. Although the beneficial effects of ACE inhibitors compared with ARBs did not reach statistical significance, ACE inhibitors consistently showed higher probabilities of being in the superior ranking positions among all three outcomes. Although the protective effect of an ACE inhibitor plus calcium channel blocker compared with placebo was not statistically significant, the treatment ranking identified this combination therapy to have the greatest probability (73.9%) for being the best treatment on reducing mortality, followed by ACE inhibitor plus diuretic (12.5%), ACE inhibitors (2.0%), calcium channel blockers (1.2%), and ARBs (0.4%).
Conclusions Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone.
doi:10.1136/bmj.f6008
PMCID: PMC3807847  PMID: 24157497
19.  Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation 
Objective To determine whether the novel avian influenza H7N9 virus can transmit from person to person and its efficiency.
Design Epidemiological investigations conducted after a family cluster of two patients with avian H7N9 in March 2013.
Setting Wuxi, Eastern China.
Participants Two patients, their close contacts, and relevant environments. Samples from the patients and environments were collected and tested by real time reverse transcriptase-polymerase chain reaction (rRT-PCR), viral culture, and haemagglutination inhibition assay. Any contacts who became ill had samples tested for avian H7N9 by rRT-PCR. Paired serum samples were obtained from contacts for serological testing by haemagglutination inhibition assays.
Main outcomes measures Clinical data, history of exposure before the onset of illnesses, and results of laboratory testing of pathogens and further analysis of sequences and phylogenetic tree to isolated strains.
Results The index patient became ill five to six days after his last exposure to poultry. The second patient, his daughter aged 32, who provided unprotected bedside care in the hospital, had no known exposure to poultry. She developed symptoms six days after her last contact with her father. Two strains were isolated successfully from the two patients. Genome sequence and analyses of phylogenetic trees showed that both viruses were almost genetically identical. Forty three close contacts of both patients were identified. One had mild illness but had negative results for avian H7N9 by rRT-PCR. All 43 close contacts tested negative for haemagglutination inhibition antibodies specific for avian H7N9.
Conclusions The infection of the daughter probably resulted from contact with her father (the index patient) during unprotected exposure, suggesting that in this cluster the virus was able to transmit from person to person. The transmissibility was limited and non-sustainable.
doi:10.1136/bmj.f4752
PMCID: PMC3805478  PMID: 23920350
20.  Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials 
Objectives To evaluate the efficacy and safety of intravenous iron, focusing primarily on its effects on haemoglobin, requirement for transfusion, and risk of infection.
Design Systematic review and meta-analysis of randomised controlled trials investigating the safety and efficacy of intravenous iron therapy.
Data sources Randomised controlled trials from Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1966 to June 2013, with no language restrictions.
Eligibility criteria for selecting studies Eligible trials were randomised controlled trials of intravenous iron compared with either no iron or oral iron. Crossover and observational studies were excluded.
Main outcome measures Change in haemoglobin concentration and risk of allogeneic red blood cell transfusion (efficacy) and risk of infection (safety).
Results Of the 75 trials meeting the inclusion criteria, 72 studies including 10 605 patients provided quantitative outcome data for meta-analysis. Intravenous iron was associated with an increase in haemoglobin concentration (standardised mean difference 6.5 g/L, 95% confidence interval 5.1 g/L to 7.9 g/L) and a reduced risk of requirement for red blood cell transfusion (risk ratio 0.74, 95% confidence interval 0.62 to 0.88), especially when intravenous iron was used with erythroid stimulating agents (ESAs) or in patients with a lower baseline plasma ferritin concentration. There were no significant interactions between the efficacy of intravenous iron and type or dose administered. Intravenous iron was, however, associated with a significant increase in risk of infection (relative risk 1.33, 95% confidence interval 1.10 to 1.64) compared with oral or no iron supplementation. The results remained similar when only high quality trials were analysed.
Conclusions Intravenous iron therapy is effective in increasing haemoglobin concentration and reducing the risk of allogeneic red blood cell transfusion and could have broad applicability to a range of acute care settings. This potential benefit is counterbalanced by a potential increased risk of infection.
doi:10.1136/bmj.f4822
PMCID: PMC3805480  PMID: 23950195
21.  Residential exposure to aircraft noise and hospital admissions for cardiovascular diseases: multi-airport retrospective study 
Objective To investigate whether exposure to aircraft noise increases the risk of hospitalization for cardiovascular diseases in older people (≥65 years) residing near airports.
Design Multi-airport retrospective study of approximately 6 million older people residing near airports in the United States. We superimposed contours of aircraft noise levels (in decibels, dB) for 89 airports for 2009 provided by the US Federal Aviation Administration on census block resolution population data to construct two exposure metrics applicable to zip code resolution health insurance data: population weighted noise within each zip code, and 90th centile of noise among populated census blocks within each zip code.
Setting 2218 zip codes surrounding 89 airports in the contiguous states.
Participants 6 027 363 people eligible to participate in the national medical insurance (Medicare) program (aged ≥65 years) residing near airports in 2009.
Main outcome measures Percentage increase in the hospitalization admission rate for cardiovascular disease associated with a 10 dB increase in aircraft noise, for each airport and on average across airports adjusted by individual level characteristics (age, sex, race), zip code level socioeconomic status and demographics, zip code level air pollution (fine particulate matter and ozone), and roadway density.
Results Averaged across all airports and using the 90th centile noise exposure metric, a zip code with 10 dB higher noise exposure had a 3.5% higher (95% confidence interval 0.2% to 7.0%) cardiovascular hospital admission rate, after controlling for covariates.
Conclusions Despite limitations related to potential misclassification of exposure, we found a statistically significant association between exposure to aircraft noise and risk of hospitalization for cardiovascular diseases among older people living near airports.
doi:10.1136/bmj.f5561
PMCID: PMC3805481  PMID: 24103538
22.  Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years 
Objectives To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring.
Design Record linkage cohort analysis.
Setting Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems.
Population 37 709 people with birth records from 1950 to present day.
Main outcome measures Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI.
Results All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes.
Conclusions Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required.
doi:10.1136/bmj.f4539
PMCID: PMC3805484  PMID: 23943697
23.  Impact of wound edge protection devices on surgical site infection after laparotomy: multicentre randomised controlled trial (ROSSINI Trial) 
Objective To determine the clinical effectiveness of wound edge protection devices in reducing surgical site infection after abdominal surgery.
Design Multicentre observer blinded randomised controlled trial.
Participants Patients undergoing laparotomy at 21 UK hospitals.
Interventions Standard care or the use of a wound edge protection device during surgery.
Main outcome measures Surgical site infection within 30 days of surgery, assessed by blinded clinicians at seven and 30 days and by patient’s self report for the intervening period. Secondary outcomes included quality of life, duration of stay in hospital, and the effect of characteristics of the patient and operation on the efficacy of the device.
Results 760 patients were enrolled with 382 patients assigned to the device group and 378 to the control group. Six patients in the device group and five in the control group did not undergo laparotomy. Fourteen patients, seven in each group, were lost to follow-up. A total of 184 patients experienced surgical site infection within 30 days of surgery, 91/369 (24.7%) in the device group and 93/366 (25.4%) in the control group (odds ratio 0.97, 95% confidence interval 0.69 to 1.36; P=0.85). This lack of benefit was consistent across wound assessments performed by clinicians and those reported by patients and across all secondary outcomes. In the secondary analyses no subgroup could be identified in which there was evidence of clinical benefit associated with use of the device.
Conclusions Wound edge protection devices do not reduce the rate of surgical site infection in patients undergoing laparotomy, and therefore their routine use for this role cannot be recommended.
Trial registration Current Controlled Trials ISRCTN 40402832
doi:10.1136/bmj.f4305
PMCID: PMC3805488  PMID: 23903454
24.  “Hardly worth the effort”? Medical journals’ policies and their editors’ and publishers’ views on trial registration and publication bias: quantitative and qualitative study 
Objectives To determine the proportion of medical journals requiring trial registration and to understand their reasons for adopting (or not adopting) such policies and other measures designed to reduce publication bias.
Design Quantitative study of journals’ instructions to authors (in June 2012) and qualitative study of editors’ and publishers’ views on trial registration and publication bias (carried out in Autumn 2012).
Setting Random selection of 200 medical journals publishing clinical trials identified from the Cochrane CENTRAL database.
Participants Editors (n=13) and publishers (n=3) of journals with different policies on trial registration (and with recently changed policies) identified from the survey of their instructions to authors.
Results Only 55/200 journals (28%) required trial registration according to their instructions and a further three (2%) encouraged it. The editors and publishers interviewed explained their journals’ reluctance to require registration in terms of not wanting to lose out to rival journals, not wanting to reject otherwise sound articles or submissions from developing countries, and perceptions that such policies were not relevant to all journals. Some interviewees considered that registration was unnecessary for small or exploratory studies.
Conclusions Although many major medical journals state that they will only publish clinical trials that have been prospectively registered, and such policies have been associated with a dramatic increase in the number of trials being registered, most smaller journals have not adopted such policies. Editors and publishers may be reluctant to require registration because they do not understand its benefits or because they fear that adopting such a policy would put their journal at a disadvantage to competitors.
doi:10.1136/bmj.f5248
PMCID: PMC3805489  PMID: 24014339
25.  Including post-discharge mortality in calculation of hospital standardised mortality ratios: retrospective analysis of hospital episode statistics 
Objectives To assess the consequences of applying different mortality timeframes on standardised mortality ratios of individual hospitals and, secondarily, to evaluate the association between in-hospital standardised mortality ratios and early post-discharge mortality rate, length of hospital stay, and transfer rate.
Design Retrospective analysis of routinely collected hospital data to compare observed deaths in 50 diagnostic categories with deaths predicted by a case mix adjustment method.
Setting 60 Dutch hospitals.
Participants 1 228 815 patients discharged in the period 2008 to 2010.
Main outcome measures In-hospital standardised mortality ratio, 30 days post-admission standardised mortality ratio, and 30 days post-discharge standardised mortality ratio.
Results Compared with the in-hospital standardised mortality ratio, 33% of the hospitals were categorised differently with the 30 days post-admission standardised mortality ratio and 22% were categorised differently with the 30 days post-discharge standardised mortality ratio. A positive association was found between in-hospital standardised mortality ratio and length of hospital stay (Pearson correlation coefficient 0.33; P=0.01), and an inverse association was found between in-hospital standardised mortality ratio and early post-discharge mortality (Pearson correlation coefficient −0.37; P=0.004).
Conclusions Applying different mortality timeframes resulted in differences in standardised mortality ratios and differences in judgment regarding the performance of individual hospitals. Furthermore, associations between in-hospital standardised mortality rates, length of stay, and early post-discharge mortality rates were found. Combining these findings suggests that standardised mortality ratios based on in-hospital mortality are subject to so-called “discharge bias.” Hence, early post-discharge mortality should be included in the calculation of standardised mortality ratios.
doi:10.1136/bmj.f5913
PMCID: PMC3805490  PMID: 24144869

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