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2.  A comparison of clinical officers with medical doctors on outcomes of caesarean section in the developing world: meta-analysis of controlled studies 
Objective To review the effectiveness and safety of clinical officers (healthcare providers trained to perform tasks usually undertaken by doctors) carrying out caesarean section in developing countries compared with doctors.
Design Systematic review with meta-analysis.
Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, BioMed Central, the Reproductive Health Library, and the Science Citation Index (inception-2010) without language restriction.
Study selection Controlled studies.
Data extraction Information was extracted from each selected article on study characteristics, quality, and outcome data. Two independent reviewers extracted data.
Results Six non-randomised controlled studies (16 018 women) evaluated the effectiveness of clinical officers carrying out caesarean section. Meta-analysis found no significant differences between the clinical officers and doctors for maternal death (odds ratio 1.46, 95% confidence interval 0.78 to 2.75; P=0.24) or for perinatal death (1.31, 0.87 to 1.95; P=0.19). The results were heterogeneous, with some studies reporting a higher incidence of both outcomes with clinical officers. Clinical officers were associated with a higher incidence of wound infection (1.58, 1.01 to 2.47; P=0.05) and wound dehiscence (1.89, 1.21 to 2.95; P=0.005). Two studies accounted for confounding factors.
Conclusion Clinical officers and doctors did not differ significantly in key outcomes for caesarean section, but the conclusions are tentative owing to the non-randomised nature of the studies. The increase in wound infection and dehiscence may highlight a particular training need for clinical officers.
PMCID: PMC3272986  PMID: 21571914
3.  Is quality of care improving in the UK? 
Yes, but we do not know why
PMCID: PMC3230115  PMID: 21292716
4.  Transitions to palliative care in acute hospitals in England: qualitative study 
Objective To explore how transitions to a palliative care approach are perceived to be managed in acute hospital settings in England.
Design Qualitative study.
Setting Secondary or primary care settings in two contrasting areas of England.
Participants 58 health professionals involved in the provision of palliative care in secondary or primary care.
Results Participants identified that a structured transition to a palliative care approach of the type advocated in UK policy guidance is seldom evident in acute hospital settings. In particular they reported that prognosis is not routinely discussed with inpatients. Achieving consensus among the clinical team about transition to palliative care was seen as fundamental to the transition being effected; however, this was thought to be insufficiently achieved in practice. Secondary care professionals reported that discussions about adopting a palliative care approach to patient management were not often held with patients; primary care professionals confirmed that patients were often discharged from hospital with “false hope” of cure because this information had not been conveyed. Key barriers to ensuring a smooth transition to palliative care included the difficulty of “standing back” in an acute hospital situation, professional hierarchies that limited the ability of junior medical and nursing staff to input into decisions on care, and poor communication.
Conclusion Significant barriers to implementing a policy of structured transitions to palliative care in acute hospitals were identified by health professionals in both primary and secondary care. These need to be addressed if current UK policy on management of palliative care in acute hospitals is to be established.
PMCID: PMC3230109  PMID: 21447572
5.  Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies 
Objective To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes.
Design Systematic review and meta-analysis of observational studies.
Data sources Searches of Medline and Embase in September 2010.
Study selection Observational studies that directly compared the risk of cardiovascular outcomes for rosiglitazone and pioglitazone among patients with type 2 diabetes mellitus were included.
Data extraction Random effects meta-analysis (inverse variance method) was used to calculate the odds ratios for cardiovascular outcomes with thiazolidinedione use. The I2 statistic was used to assess statistical heterogeneity.
Results Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810 000 thiazolidinedione users, were evaluated after a detailed review of 189 citations. Compared with pioglitazone, use of rosiglitazone was associated with a statistically significant increase in the odds of myocardial infarction (n=15 studies; odds ratio 1.16, 95% confidence interval 1.07 to 1.24; P<0.001; I2=46%), congestive heart failure (n=8; 1.22, 1.14 to 1.31; P<0.001; I2=37%), and death (n=8; 1.14, 1.09 to 1.20; P<0.001; I2=0%). Numbers needed to treat to harm (NNH), depending on the population at risk, suggest 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone.
Conclusion Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.
PMCID: PMC3230110  PMID: 21415101
6.  Honorary and ghost authorship in high impact biomedical journals: a cross sectional survey 
Objectives To assess the prevalence of honorary and ghost authors in six leading general medical journals in 2008 and compare this with the prevalence reported by authors of articles published in 1996.
Design Cross sectional survey using a web based questionnaire.
Setting International survey of journal authors.
Participants Sample of corresponding authors of 896 research articles, review articles, and editorial/opinion articles published in six general medical journals with high impact factors in 2008: Annals of Internal Medicine, JAMA, Lancet, Nature Medicine, New England Journal of Medicine, and PLoS Medicine.
Main outcome measures Self reported compliance with International Committee of Medical Journal Editors (ICMJE) criteria for authorship for all authors on the selected articles.
Results A total of 630/896 (70.3%) corresponding authors responded to the survey. The prevalence of articles with honorary authorship or ghost authorship, or both, was 21.0% (95% CI 18.0% to 24.3%), a decrease from 29.2% reported in 1996 (P=0.004). Based on 545 responses on honorary authorship, 96 articles (17.6% (95% CI 14.6% to 21.0%)) had honorary authors (range by journal 12.2% to 29.3%), a non-significant change from 1996 (19.3%; P=0.439). Based on 622 responses on ghost authorship, 49 articles (7.9% (6.0% to 10.3%)) had ghost authors (range by journal 2.1% to 11.0%), a significant decline from 1996 (11.5%; P=0.023). The prevalence of honorary authorship was 25.0% in original research reports, 15.0% in reviews, and 11.2% in editorials, whereas the prevalence of ghost authorship was 11.9% in research articles, 6.0% in reviews, and 5.3% in editorials.
Conclusions Evidence of honorary and ghost authorship in 21% of articles published in major medical journals in 2008 suggests that increased efforts by scientific journals, individual authors, and academic institutions are essential to promote responsibility, accountability, and transparency in authorship, and to maintain integrity in scientific publication.
PMCID: PMC3202014  PMID: 22028479
7.  Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9 
Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose.
Design National historical registry based cohort study.
Setting Four registries in Denmark.
Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009.
Main outcome measures Relative and absolute risks of first time venous thromboembolism.
Results Within 8 010 290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year.
Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.
PMCID: PMC3202015  PMID: 22027398
8.  Intraoperative use of tranexamic acid to reduce transfusion rate in patients undergoing radical retropubic prostatectomy: double blind, randomised, placebo controlled trial  
Objectives To determine the efficacy of intraoperative treatment with low dose tranexamic acid in reducing the rate of perioperative transfusions in patients undergoing radical retropubic prostatectomy.
Design Double blind, parallel group, randomised, placebo controlled trial.
Setting One university hospital in Milan, Italy.
Participants 200 patients older than 18 years and undergoing radical retropubic prostatectomy agreed to participate in the trial. Exclusion criteria were atrial fibrillation, coronary artery disease treated with drug eluting stent, severe chronic renal failure, congenital or acquired thrombophilia, and known or suspected allergy to tranexamic acid.
Interventions Intravenous infusion of tranexamic acid or equivalent volume of placebo (saline) according to the following protocol: loading dose of 500 mg tranexamic acid 20 minutes before surgery followed by continuous infusion of tranexamic acid at 250 mg/h during surgery.
Main outcome measures Primary outcome: number of patients receiving blood transfusions perioperatively. Secondary outcome: intraoperative blood loss. Six month follow-up to assess long term safety in terms of mortality and thromboembolic events.
Results All patients completed treatment and none was lost to follow-up. Patients transfused were 34 (34%) in the tranexamic acid group and 55 (55%) in the control group (absolute reduction in transfusion rate 21% (95% CI 7% to 34%); relative risk of receiving transfusions for patients treated with tranexamic acid 0.62 (0.45 to 0.85); number needed to treat 5 (3 to 14); P=0.004). At follow-up, no patients died and the occurrence of thromboembolic events did not differ between the two groups.
Conclusions Intraoperative treatment with low dose tranexamic acid is safe and effective in reducing the rate of perioperative blood transfusions in patients undergoing radical retropubic prostatectomy.
Trial registration identifier NCT00670345.
PMCID: PMC3198510  PMID: 22012809
9.  Magnitude, impact, and stability of primary headache subtypes: 30 year prospective Swiss cohort study 
To determine the prevalence, impact, and stability of different subtypes of headache in a 30 year prospective follow-up study of a general population sample.
Prospective cohort study.
Canton of Zurich, Switzerland.
591 people aged 19–20 from a cohort of 4547 residents of Zurich, Switzerland, interviewed seven times across 30 years of follow-up.
Main outcome measures
Prevalence of headache; stability of the predominant subtype of headache over time; and age of onset, severity, impact, family history, use of healthcare services, and drugs for headache subtypes.
The average one year prevalences of subtypes of headache were 0.9% (female:male ratio of 2.8) for migraine with aura, 10.9% (female:male ratio of 2.2) for migraine without aura, and 11.5% (female:male ratio of 1.2) for tension-type headache. Cumulative 30 year prevalences of headache subtypes were 3.0% for migraine with aura, 36.0% for migraine without aura, and 29.3% for tension-type headache. Despite the high prevalence of migraine without aura, most cases were transient and only about 20% continued to have migraine for more than half of the follow-up period. 69% of participants with migraine and 58% of those with tension-type headache manifested the same predominant subtype over time. However, the prospective stability of the predominant headache subtypes was quite low, with substantial crossover among the subtypes and no specific ordinal pattern of progression. A gradient of severity of clinical correlates and service use was present across headache subtypes; the greatest effect was for migraine with aura followed by migraine without aura, and then tension-type headache and unclassified headaches.
These findings highlight the importance of prospective follow-up of people with headache. The substantial longitudinal overlap among subtypes of headache shows the developmental heterogeneity of headache syndromes. Studies of the causes of headache that apply diagnostic nomenclature based on distinctions between discrete headache subtypes may not capture the true nature of headache in the general population.
PMCID: PMC3161722  PMID: 21868455
10.  Ageing, menopause, and ischaemic heart disease mortality in England, Wales, and the United States: modelling study of national mortality data  
Objectives To use changes in heart disease mortality rates with age to investigate the plausibility of attributing women’s lower heart disease mortality than men to the protective effects of premenopausal sex hormones.
Design Modelling study of longitudinal mortality data with models assuming (i) a linear association between mortality rates and age (absolute mortality) or (ii) a logarithmic association (proportional mortality). We fitted models to age and sex specific mortality rates in the census years 1950 to 2000 for three birth cohorts (1916-25, 1926-35, and 1936-45).
Data sources UK Office for National Statistics and the US National Center for Health Statistics.
Main outcome measure(s) Fit of models to data for England and Wales and for the US.
Results For England-Wales data, proportional increases in ischaemic heart disease mortality fitted the data better than absolute increases (improvement in deviance statistics: women, 58 logarithmic units; men, 37). We identified a deceleration in male mortality after age 45 years (decreasing from 30.3% to 5.2% per age-year, P=0.042), although the corresponding difference in women was non-significant (P=0.43, overall trend 7.9% per age-year, P<0.001). By contrast, female breast cancer mortality decelerated significantly after age 45 years (decreasing from 19.3% to 2.6% per age-year, P<0.001). We found similar results in US data.
Conclusions Proportional age related changes in ischaemic heart disease mortality, suggesting a loss of reparative reserve, fit longitudinal mortality data from England, Wales, and the United States better than absolute age related changes in mortality. Acceleration in male heart disease mortality at younger ages could explain sex differences rather than any menopausal changes in women.
PMCID: PMC3167164  PMID: 21896608
12.  Effect of manual lymph drainage in addition to guidelines and exercise therapy on arm lymphoedema related to breast cancer: randomised controlled trial 
Objective To determine the preventive effect of manual lymph drainage on the development of lymphoedema related to breast cancer.
Design Randomised single blinded controlled trial.
Setting University Hospitals Leuven, Leuven, Belgium.
Participants 160 consecutive patients with breast cancer and unilateral axillary lymph node dissection. The randomisation was stratified for body mass index (BMI) and axillary irradiation and treatment allocation was concealed. Randomisation was done independently from recruitment and treatment. Baseline characteristics were comparable between the groups.
Intervention For six months the intervention group (n=79) performed a treatment programme consisting of guidelines about the prevention of lymphoedema, exercise therapy, and manual lymph drainage. The control group (n=81) performed the same programme without manual lymph drainage.
Main outcome measures Cumulative incidence of arm lymphoedema and time to develop arm lymphoedema, defined as an increase in arm volume of 200 mL or more in the value before surgery.
Results Four patients in the intervention group and two in the control group were lost to follow-up. At 12 months after surgery, the cumulative incidence rate for arm lymphoedema was comparable between the intervention group (24%) and control group (19%) (odds ratio 1.3, 95% confidence interval 0.6 to 2.9; P=0.45). The time to develop arm lymphoedema was comparable between the two group during the first year after surgery (hazard ratio 1.3, 0.6 to 2.5; P=0.49). The sample size calculation was based on a presumed odds ratio of 0.3, which is not included in the 95% confidence interval. This odds ratio was calculated as (presumed cumulative incidence of lymphoedema in intervention group/presumed cumulative incidence of no lymphoedema in intervention group)×(presumed cumulative incidence of no lymphoedema in control group/presumed cumulative incidence of lymphoedema in control group) or (10/90)×(70/30).
Conclusion Manual lymph drainage in addition to guidelines and exercise therapy after axillary lymph node dissection for breast cancer is unlikely to have a medium to large effect in reducing the incidence of arm lymphoedema in the short term.
Trial registration Netherlands Trial Register No NTR 1055.
PMCID: PMC3164214  PMID: 21885537
13.  Socioeconomic inequalities in outcome of pregnancy and neonatal mortality associated with congenital anomalies: population based study 
Objectives To investigate socioeconomic inequalities in outcome of pregnancy and neonatal mortality associated with congenital anomalies.
Design Retrospective population based registry study.
Setting East Midlands and South Yorkshire regions of England (representing about 10% of births in England and Wales).
Participants All registered cases of nine selected congenital anomalies with poor prognostic outcome audited as part of the United Kingdom’s fetal anomaly screening programme with an end of pregnancy date between 1 January 1998 and 31 December 2007.
Main outcome measures Socioeconomic variation in the risk of selected congenital anomalies; outcome of pregnancy; incidence of live birth and neonatal mortality over time. Deprivation measured with the index of multiple deprivation 2004 at super output area level.
Results There were 1579 fetuses registered with one of the nine selected congenital anomalies. There was no evidence of variation in the overall risk of these anomalies with deprivation (rate ratio for the most deprived 10th with the least deprived 10th: 1.05, 95% confidence interval 0.89 to 1.23). The rate ratio varied with type of anomaly and maternal age (deprivation rate ratio adjusted for maternal age: 1.43 (1.17 to 1.74) for non-chromosomal anomalies; 0.85 (0.63 to 1.15) for chromosomal anomalies). Of the nine anomalies, 86% were detected in the antenatal period, and there was no evidence that this varied with deprivation (rate ratio 0.99, 0.84 to 1.17). The rate of termination after antenatal diagnosis of a congenital anomaly was lower in the most deprived areas compared with the least deprived areas (63% v 79%; rate ratio 0.80, 0.65 to 0.97). Consequently there were significant socioeconomic inequalities in the rate of live birth and neonatal mortality associated with the presence of any of these nine anomalies. Compared with the least deprived areas, the most deprived areas had a 61% higher rate of live births (1.61, 1.21 to 2.15) and a 98% higher neonatal mortality rate (1.98, 1.20 to 3.27) associated with a congenital anomaly.
Conclusions Antenatal screening for congenital anomalies has reduced neonatal mortality through termination of pregnancy. Socioeconomic variation in decisions regarding termination of pregnancy after antenatal detection, however, has resulted in wide socioeconomic inequalities in liveborn infants with a congenital anomaly and subsequent neonatal mortality.
PMCID: PMC3139368  PMID: 21771825
14.  Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study 
Objective To measure the sensitivity of modern third generation computed tomography in emergency patients being evaluated for possible subarachnoid haemorrhage, especially when carried out within six hours of headache onset.
Design Prospective cohort study.
Setting 11 tertiary care emergency departments across Canada, 2000-9.
Participants Neurologically intact adults with a new acute headache peaking in intensity within one hour of onset in whom a computed tomography was ordered by the treating physician to rule out subarachnoid haemorrhage.
Main outcome measures Subarachnoid haemorrhage was defined by any of subarachnoid blood on computed tomography, xanthochromia in cerebrospinal fluid, or any red blood cells in final tube of cerebrospinal fluid collected with positive results on cerebral angiography.
Results Of the 3132 patients enrolled (mean age 45.1, 2571 (82.1%) with worst headache ever), 240 had subarachnoid haemorrhage (7.7%). The sensitivity of computed tomography overall for subarachnoid haemorrhage was 92.9% (95% confidence interval 89.0% to 95.5%), the specificity was 100% (99.9% to 100%), the negative predictive value was 99.4% (99.1% to 99.6%), and the positive predictive value was 100% (98.3% to 100%). For the 953 patients scanned within six hours of headache onset, all 121 patients with subarachnoid haemorrhage were identified by computed tomography, yielding a sensitivity of 100% (97.0% to 100.0%), specificity of 100% (99.5% to 100%), negative predictive value of 100% (99.5% to 100%), and positive predictive value of 100% (96.9% to 100%).
Conclusion Modern third generation computed tomography is extremely sensitive in identifying subarachnoid haemorrhage when it is carried out within six hours of headache onset and interpreted by a qualified radiologist.
PMCID: PMC3138338  PMID: 21768192
15.  Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial 
Objective To determine whether a systematic approach to the treatment of pain can reduce agitation in people with moderate to severe dementia living in nursing homes.
Design Cluster randomised controlled trial.
Setting 60 clusters (single independent nursing home units) in 18 nursing homes within five municipalities of western Norway.
Participants 352 residents with moderate to severe dementia and clinically significant behavioural disturbances randomised to a stepwise protocol for the treatment of pain for eight weeks with additional follow-up four weeks after the end of treatment (33 clusters; n=175) or to usual treatment (control, 27 clusters; n=177).
Intervention Participants in the intervention group received individual daily treatment of pain for eight weeks according to the stepwise protocol, with paracetamol (acetaminophen), morphine, buprenorphine transdermal patch, or pregabaline. The control group received usual treatment and care.
Main outcome measures Primary outcome measure was agitation (scores on Cohen-Mansfield agitation inventory). Secondary outcome measures were aggression (scores on neuropsychiatric inventory-nursing home version), pain (scores on mobilisation-observation-behaviour-intensity-dementia-2), activities of daily living, and cognition (mini-mental state examination).
Results Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P<0.001): the average reduction in scores for agitation was 17% (treatment effect estimate −7.0, 95% confidence interval −3.7 to −10.3). Treatment of pain was also significantly beneficial for the overall severity of neuropsychiatric symptoms (−9.0, −5.5 to −12.6) and pain (−1.3, −0.8 to −1.7), but the groups did not differ significantly for activities of daily living or cognition.
Conclusion A systematic approach to the management of pain significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Effective management of pain can play an important part in the treatment of agitation and could reduce the number of unnecessary prescriptions for psychotropic drugs in this population.
Trial registration NCT01021696 and Norwegian Medicines Agency EudraCTnr 2008-007490-20.
PMCID: PMC3137923  PMID: 21765198
16.  Survival and risk of adverse events in older patients receiving postoperative adjuvant chemotherapy for resected stages II-IIIA lung cancer: observational cohort study 
Objective To compare the survival and risk of serious adverse events in older patients with stages II-IIIA non-small cell lung cancer treated with or without postoperative platinum based chemotherapy.
Design Observational cohort study.
Setting Cases of lung cancer in Surveillance Epidemiology and End Results registry linked to Medicare files, 1992-2005, and follow-up data to December 2007.
Participants 3324 patients aged more than 65 years with resected stages II-IIIA lung cancer.
Main outcome measures Primary outcome was overall survival and secondary outcome was the rate of serious adverse events among older patients treated with or without adjuvant chemotherapy.
Results Overall, 21% (n=684) of patients received platinum based chemotherapy. Analyses adjusted, stratified, or matched by propensity scores showed that chemotherapy was associated with improved survival (hazard ratio range 0.78-0.81). The beneficial effect of chemotherapy was also observed among patients treated with radiation therapy (0.75-0.77) or without radiation therapy (0.74-0.77); however, chemotherapy was not beneficial for patients aged 80 or more (1.32-1.46). Adjuvant chemotherapy was associated with an increased odds of serious adverse events (odds ratio 2.0, 95% confidence interval 1.5 to 2.6).
Conclusions Platinum based adjuvant chemotherapy is associated with reduced mortality and increased risk of serious adverse events in older patients with stages II-IIIA lung cancer. The magnitude of the benefit is similar to that observed in randomised controlled trials carried out among selected patients.
PMCID: PMC3136092  PMID: 21757436
17.  Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe 
Objective To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome.
Design Case-control study.
Setting Five European countries.
Participants 104 patients with Guillain-Barré syndrome and its variant Miller-Fisher syndrome matched to one or more controls. Case status was classified according to the Brighton Collaboration definition. Controls were matched to cases on age, sex, index date, and country.
Main outcome measures Relative risk estimate for Guillain-Barré syndrome after pandemic influenza vaccine.
Results Case recruitment and vaccine coverage varied considerably between countries; the most common vaccines used were adjuvanted (Pandemrix and Focetria). The unadjusted pooled risk estimate for all countries was 2.8 (95% confidence interval 1.3 to 6.0). After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome (adjusted odds ratio 1.0, 0.3 to 2.7). The 95% confidence interval shows that the absolute effect of vaccination could range from one avoided case of Guillain-Barré syndrome up to three excess cases within six weeks after vaccination in one million people.
Conclusions The risk of occurrence of Guillain-Barré syndrome is not increased after pandemic influenza vaccine, although the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people. When assessing the association between pandemic influenza vaccines and Guillain-Barré syndrome it is important to account for the effects of influenza-like illness/upper respiratory tract infection, seasonal influenza vaccination, and calendar time.
PMCID: PMC3134565  PMID: 21750072
18.  Effectiveness of vertebroplasty using individual patient data from two randomised placebo controlled trials: meta-analysis 
Objective To determine whether vertebroplasty is more effective than placebo for patients with pain of recent onset (≤6 weeks) or severe pain (score ≥8 on 0-10 numerical rating scale).
Design Meta-analysis of combined individual patient level data.
Setting Two multicentred randomised controlled trials of vertebroplasty; one based in Australia, the other in the United States.
Participants 209 participants (Australian trial n=78, US trial n=131) with at least one radiographically confirmed vertebral compression fracture. 57 (27%) participants had pain of recent onset (vertebroplasty n=25, placebo n=32) and 99 (47%) had severe pain at baseline (vertebroplasty n=50, placebo n=49).
Intervention Percutaneous vertebroplasty versus a placebo procedure.
Main outcome measure Scores for pain (0-10 scale) and function (modified, 23 item Roland-Morris disability questionnaire) at one month.
Results For participants with pain of recent onset, between group differences in mean change scores at one month for pain and disability were 0.1 (95% confidence interval −1.4 to 1.6) and 0.2 (−3.0 to 3.4), respectively. For participants with severe pain at baseline, between group differences for pain and disability scores at one month were 0.3 (−0.8 to 1.5) and 1.4 (−1.2 to 3.9), respectively. At one month those in the vertebroplasty group were more likely to be using opioids.
Conclusions Individual patient data meta-analysis from two blinded trials of vertebroplasty, powered for subgroup analyses, failed to show an advantage of vertebroplasty over placebo for participants with recent onset fracture or severe pain. These results do not support the hypothesis that selected subgroups would benefit from vertebroplasty.
PMCID: PMC3133975  PMID: 21750078
19.  Factors associated with the presence of diabetic ketoacidosis at diagnosis of diabetes in children and young adults: a systematic review 
Objective To identify the factors associated with diabetic ketoacidosis at diagnosis of type 1 diabetes in children and young adults.
Design Systematic review.
Data sources PubMed, EMBASE, Web of Science, Scopus, and Cinahl and article reference lists.
Study selection Cohort studies including unselected groups of children and young adults presenting with new onset type 1 diabetes that distinguished between those who presented in diabetic ketoacidosis and those who did not and included a measurement of either pH or bicarbonate in the definition of diabetic ketoacidosis. There were no restrictions on language of publication.
Results 46 studies involving more than 24 000 children in 31 countries were included. Together they compared 23 different factors. Factors associated with increased risk were younger age (for <2 years old v older, odds ratio 3.41 (95% confidence interval 2.54 to 4.59), for <5 years v older, odds ratio 1.59 (1.38 to 1.84)), diagnostic error (odds ratio 3.35 (2.35 to 4.79)), ethnic minority, lack of health insurance in the US (odds ratio 3.20 (2.03 to 5.04)), lower body mass index, preceding infection (odds ratio 3.14 (0.94 to 10.47)), and delayed treatment (odds ratio 1.74 (1.10 to 2.77)). Protective factors were having a first degree relative with type 1 diabetes at the time of diagnosis (odds ratio 0.33 (0.08 to 1.26)), higher parental education (odds ratios 0.4 (0.20 to 0.79) and 0.64 (0.43 to 0.94) in two studies), and higher background incidence of type 1 diabetes (correlation coefficient –0.715). The mean duration of symptoms was similar between children presenting with or without diabetic ketoacidosis (16.5 days (standard error 6.2) and 17.1 days (6.0) respectively), and up to 38.8% (285/735) of children who presented with diabetic ketoacidosis had been seen at least once by a doctor before diagnosis.
Conclusions Multiple factors affect the risk of developing diabetic ketoacidosis at the onset of type 1 diabetes in children and young adults, and there is potential time, scope, and opportunity to intervene between symptom onset and development of diabetic ketoacidosis for both parents and clinicians.
PMCID: PMC3131115  PMID: 21737470
20.  Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data 
Objective To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes.
Design Meta-analysis of randomised controlled trials.
Data sources Cochrane database for randomised controlled trials, Ovid Medline, Embase, Google Scholar, lists of papers supplied by manufacturers of continuous glucose monitors, and cited literature in retrieved articles.
Studies reviewed Randomised controlled trials of two or more months’ duration in men and non-pregnant women with type 1 diabetes that compared real time continuous glucose monitoring with self monitoring of blood glucose and where insulin delivery was the same in both arms.
Analysis Two step meta-analysis of individual patient data with the primary outcome of final glycated haemoglobin (HbA1c) percentage and area under the curve of hypoglycaemia (glucose concentration <3.9 mmol/L) during either treatment, followed by one step metaregression exploring patient level determinants of HbA1c and hypoglycaemia.
Results Six trials were identified, consisting of 449 patients randomised to continuous glucose monitoring and 443 to self monitoring of blood glucose. The overall mean difference in HbA1c for continuous glucose monitoring versus self monitoring of blood glucose was −0.30% (95% confidence interval −0.43% to −0.17%) (−3.0, −4.3 to −1.7 mmol/mol). A best fit regression model of determinants of final HbA1c showed that for every one day increase of sensor usage per week the effect of continuous glucose monitoring versus self monitoring of blood glucose increased by 0.150% (95% credibility interval −0.194% to −0.106%) (1.5, −1.9 to −1.1 mmol/mol) and every 1% (10 mmol/mol) increase in baseline HbA1c increased the effect by 0.126% (−0.257% to 0.0007%) (1.3, −2.6 to 0.0 mmol/mol). The model estimates that, for example, a patient using the sensor continuously would experience a reduction in HbA1c of about 0.9% (9 mmol/mol) when the baseline HbA1c is 10% (86 mmol/mol). The overall reduction in area under the curve of hypoglycaemia was −0.28 (−0.46 to −0.09), corresponding to a reduction in median exposure to hypoglycaemia of 23% for continuous glucose monitoring compared with self monitoring of blood glucose. In a best fit regression model, baseline area under the curve of hypoglycaemia was only weakly related to the effect of continuous glucose monitoring compared with self monitoring of blood glucose on hypoglycaemia outcome, and sensor usage was unrelated to hypoglycaemia at outcome.
Conclusions Continuous glucose monitoring was associated with a significant reduction in HbA1c percentage, which was greatest in those with the highest HbA1c at baseline and who most frequently used the sensors. Exposure to hypoglycaemia was also reduced during continuous glucose monitoring. The most cost effective or appropriate use of continuous glucose monitoring is likely to be when targeted at people with type 1 diabetes who have continued poor control during intensified insulin therapy and who frequently use continuous glucose monitoring.
PMCID: PMC3131116  PMID: 21737469
21.  Association between provision of mental illness beds and rate of involuntary admissions in the NHS in England 1988-2008: ecological study 
Objective To examine the rise in the rate of involuntary admissions for mental illness in England that has occurred as community alternatives to hospital admission have been introduced.
Design Ecological analysis.
Setting England, 1988-2008.
Data source Publicly available data on provision of beds for people with mental illness in the National Health Service from Hospital Activity Statistics and involuntary admission rates from the NHS Information Centre.
Main outcome measures Association between annual changes in provision of mental illness beds in the NHS and involuntary admission rates, using cross correlation. Partial correlation coefficients were calculated and regression analysis carried out for the time lag (interval) over which the largest association between these variables was identified.
Results The rate of involuntary admissions per annum in the NHS increased by more than 60%, whereas the provision of mental illness beds decreased by more than 60% over the same period; these changes seemed to be synchronous. The strongest association between these variables was observed when a time lag of one year was introduced, with bed reductions preceding increases in involuntary admissions (cross correlation −0.60, 95% confidence interval −1.06 to −0.15). This association increased in magnitude when analyses were restricted to civil (non-forensic) involuntary admissions and non-secure mental illness beds.
Conclusion The annual reduction in provision of mental illness beds was associated with the rate of involuntary admissions over the short to medium term, with the closure of two mental illness beds leading to one additional involuntary admission in the subsequent year. This study provides a method for predicting rates of involuntary admissions and what may happen in the future if bed closures continue.
PMCID: PMC3130113  PMID: 21729994
22.  Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study) 
Objective To assess the effect of tranexamic acid (which reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients) on intracranial haemorrhage in patients with traumatic brain injury.
Methods A nested, randomised, placebo controlled trial. All investigators were masked to treatment allocation. All analyses were by intention to treat.
Patients 270 adult trauma patients with, or at risk of, significant extracranial bleeding within 8 hours of injury, who also had traumatic brain injury.
Interventions Patients randomly allocated to tranexamic acid (loading dose 1 g over 10 minutes, then infusion of 1 g over 8 hours) or matching placebo.
Main outcome measures Intracranial haemorrhage growth (measured by computed tomography) between hospital admission and then 24–48 hours later, with adjustment for Glasgow coma score, age, time from injury to the scans, and initial haemorrhage volume.
Results Of the 133 patients allocated to tranexamic acid and 137 allocated to placebo, 123 (92%) and 126 (92%) respectively provided information on the primary outcome. All patients provided information on clinical outcomes. The mean total haemorrhage growth was 5.9 ml (SD 26.8) and 8.1 mL (SD 29.2) in the tranexamic acid and placebo groups respectively (adjusted difference –3.8 mL (95% confidence interval −11.5 to 3.9)). New focal cerebral ischaemic lesions occurred in 6 (5%) patients in the tranexamic acid group versus 12 (9%) in the placebo group (adjusted odds ratio 0.51 (95% confidence interval 0.18 to 1.44)). There were 14 (11%) deaths in the tranexamic acid group and 24 (18%) in the placebo group (adjusted odds ratio 0.47 (0.21 to 1.04)).
Conclusions This trial shows that neither moderate benefits nor moderate harmful effects of tranexamic acid in patients with traumatic brain injury can be excluded. However, the analysis provides grounds for further clinical trials evaluating the effect of tranexamic acid in this population.
Trial registration ISRCTN86750102.
PMCID: PMC3128457  PMID: 21724564
23.  Association of echocardiography before major elective non-cardiac surgery with postoperative survival and length of hospital stay: population based cohort study 
Objective To determine the association of resting echocardiography before elective intermediate to high risk non-cardiac surgery with survival and length of hospital stay.
Design Population based retrospective cohort study.
Setting Acute care hospitals in Ontario, Canada, between 1 April 1999 and 31 March 2008.
Participants Patients aged over 40 years who had elective intermediate to high risk non-cardiac surgery.
Intervention Resting echocardiography within 6 months before surgery.
Main outcome measures Postoperative survival (30 days and 1 year) and length of hospital stay; postoperative surgical site infection as an outcome for which no association with echocardiography would be expected.
Results Of the 264 823 patients in the entire cohort, 15.1% (n=40 084) had echocardiography. After use of propensity score methods to assemble a matched cohort (n=70 996) that reduced differences between patients who had or had not had echocardiography, echocardiography was associated with increases in 30 day mortality (relative risk 1.14, 95% confidence interval 1.02 to 1.27), 1 year mortality (1.07, 1.01 to 1.12), and length of hospital stay but no difference in surgical site infections (1.03, 0.98 to 1.06). The association with mortality was influenced (P=0.02) by whether patients had had stress testing or had risk factors for cardiac complications. No association existed between echocardiography and mortality among patients who had stress testing (relative risk 1.01, 0.92 to 1.11) or among patients at high risk who had not had stress testing (1.00, 0.87 to 1.13). However, echocardiography was associated with mortality in patients at low risk (relative risk 1.44, 1.14 to 1.82) and intermediate risk (1.10, 1.02 to 1.18) who had not had stress testing.
Conclusions Preoperative echocardiography was not associated with improved survival or shorter hospital stay after major non-cardiac surgery. These findings highlight the need for further research to guide better use of this common preoperative test.
PMCID: PMC3127454  PMID: 21724560
24.  Cause specific mortality, social position, and obesity among women who had never smoked: 28 year cohort study 
Objective To investigate the relations between causes of death, social position, and obesity in women who had never smoked.
Design Prospective cohort study.
Setting Renfrew and Paisley, Scotland.
Participants 8353 women and 7049 men aged 45-64 were recruited to the Renfrew and Paisley Study in 1972-6. Of these, 3613 women had never smoked and were the focus of this study. They were categorised by occupational class (I and II, III non-manual, III manual, and IV and V) and body mass index groups (normal weight, overweight, moderately obese, and severely obese).
Main outcome measures All cause and cause specific mortality during 28 years of follow-up by occupational class and body mass index, using Cox proportional hazards models adjusted for age and other confounders.
Results The women in lower occupational classes who had never smoked were on average shorter and had poorer lung function and higher systolic blood pressure than women in the higher occupational classes. Overall, 43% (n=1555) were overweight, 14% (n=515) moderately obese, and 5% (n=194) severely obese. Obesity rates were higher in lower occupational classes and much higher in all occupational classes than in current smokers in the full cohort. Half the women died, 51% (n=916) from cardiovascular disease and 27% (n=487) from cancer. Relative to occupational class I and II, all cause mortality rates were more than a third higher in occupational classes III manual (relative rate 1.35, 95% confidence interval 1.16 to 1.57) and IV and V (1.34, 1.17 to 1.55) and largely explained by differences in obesity, systolic blood pressure, and lung function. Similar upward gradients were seen for cardiovascular disease and respiratory disease but not for cancer. Mortality rates were highest in severely obese women in the lowest occupational classes.
Conclusions Women who had never smoked and were not obese had the lowest mortality rates, regardless of their social position. Where obesity is socially patterned as in this cohort, it may contribute to health inequalities and increase pressure on health and social services serving more disadvantaged populations.
PMCID: PMC3125471  PMID: 21712337
25.  Effect of financial incentives on incentivised and non-incentivised clinical activities: longitudinal analysis of data from the UK Quality and Outcomes Framework 
Objective To investigate whether the incentive scheme for UK general practitioners led them to neglect activities not included in the scheme.
Design Longitudinal analysis of achievement rates for 42 activities (23 included in incentive scheme, 19 not included) selected from 428 identified indicators of quality of care.
Setting 148 general practices in England (653 500 patients).
Main outcome measures Achievement rates projected from trends in the pre-incentive period (2000-1 to 2002-3) and actual rates in the first three years of the scheme (2004-5 to 2006-7).
Results Achievement rates improved for most indicators in the pre-incentive period. There were significant increases in the rate of improvement in the first year of the incentive scheme (2004-5) for 22 of the 23 incentivised indicators. Achievement for these indicators reached a plateau after 2004-5, but quality of care in 2006-7 remained higher than that predicted by pre-incentive trends for 14 incentivised indicators. There was no overall effect on the rate of improvement for non-incentivised indicators in the first year of the scheme, but by 2006-7 achievement rates were significantly below those predicted by pre-incentive trends.
Conclusions There were substantial improvements in quality for all indicators between 2001 and 2007. Improvements associated with financial incentives seem to have been achieved at the expense of small detrimental effects on aspects of care that were not incentivised.
PMCID: PMC3125475  PMID: 21712336

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