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1.  Treatments for macular oedema following central retinal vein occlusion: systematic review 
BMJ Open  2014;4(2):e004120.
To review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO).
Data sources
MEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013).
Study eligibility criteria, participants and interventions
RCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions.
Study appraisal and synthesis methods
2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies.
8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40–60% gaining ≥15 letters on active drugs, compared to 12–28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias.
All studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO.
Conclusions and implications of key findings
Bevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify ‘responders’ is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.
PMCID: PMC3927713  PMID: 24513867
Systematic Review; Anti-VEGF; Central Retinal Vein Occlusion; Macular Oedema
2.  Psychosocial Impact of Alternative Management Policies for Low-Grade Cervical Abnormalities: Results from the TOMBOLA Randomised Controlled Trial 
PLoS ONE  2013;8(12):e80092.
Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination.
Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20–59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥8) and significant anxiety (≥11; “30-month percentages”). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance.
There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80–1.21) or anxiety (OR = 0.97, 95% CI 0.81–1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38–0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54–0.84). Neither anxiety nor depression differed between arms at subsequent time-points.
There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost.
Trial Registration ISRCTN 34841617
PMCID: PMC3875419  PMID: 24386076
3.  Bibliometrics of systematic reviews: analysis of citation rates and journal impact factors 
Systematic Reviews  2013;2:74.
Systematic reviews are important for informing clinical practice and health policy. The aim of this study was to examine the bibliometrics of systematic reviews and to determine the amount of variance in citations predicted by the journal impact factor (JIF) alone and combined with several other characteristics.
We conducted a bibliometric analysis of 1,261 systematic reviews published in 2008 and the citations to them in the Scopus database from 2008 to June 2012. Potential predictors of the citation impact of the reviews were examined using descriptive, univariate and multiple regression analysis.
The mean number of citations per review over four years was 26.5 (SD ±29.9) or 6.6 citations per review per year. The mean JIF of the journals in which the reviews were published was 4.3 (SD ±4.2). We found that 17% of the reviews accounted for 50% of the total citations and 1.6% of the reviews were not cited. The number of authors was correlated with the number of citations (r = 0.215, P < 0.001). Higher numbers of citations were associated with the following characteristics: first author from the United States (36.5 citations), an ICD-10 chapter heading of Neoplasms (31.8 citations), type of intervention classified as Investigation, Diagnostics or Screening (34.7 citations) and having an international collaboration (32.1 citations). The JIF alone explained more than half of the variation in citations (R2 = 0.59) in univariate analysis. Adjusting for both JIF and type of intervention increased the R2 value to 0.81. Fourteen percent of reviews published in the top quartile of JIFs (≥ 5.16) received citations in the bottom quartile (eight or fewer), whereas 9% of reviews published in the lowest JIF quartile (≤ 2.06) received citations in the top quartile (34 or more). Six percent of reviews in journals with no JIF were also in the first quartile of citations.
The JIF predicted over half of the variation in citations to the systematic reviews. However, the distribution of citations was markedly skewed. Some reviews in journals with low JIFs were well-cited and others in higher JIF journals received relatively few citations; hence the JIF did not accurately represent the number of citations to individual systematic reviews.
PMCID: PMC3847500  PMID: 24028376
Bibliometrics; Citations; Impact factor; Systematic reviews
4.  Current treatments in diabetic macular oedema: systematic review and meta-analysis 
BMJ Open  2013;3(3):e002269.
The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events
Data source
MEDLINE, EMBASE, Web of Science with Conference Proceedings and the Cochrane Library (inception to July 2012). Certain conference abstracts and drug regulatory web sites were also searched.
Study eligibility criteria, participants and interventions
Randomised controlled trials were used to assess clinical effectiveness and observational trials were used for safety. Trials which assessed triamcinolone, dexamethasone, fluocinolone, bevacizumab, ranibizumab, pegaptanib or aflibercept in patients with DMO were included.
Study appraisal and synthesis methods
Risk of bias was assessed using the Cochrane risk of bias tool. Study results are narratively described and, where appropriate, data were pooled using random effects meta-analysis.
Anti-VEGF drugs are effective compared to both laser and placebo and seem to be more effective than steroids in improving BCVA. They have been shown to be safe in the short term but require frequent injections. Studies assessing steroids (triamcinolone, dexamethasone and fluocinolone) have reported mixed results when compared with laser or placebo. Steroids have been associated with increased incidence of cataracts and intraocular pressure rise but require fewer injections, especially when steroid implants are used.
The quality of included studies varied considerably. Five of 14 meta-analyses had moderate or high statistical heterogeneity.
Conclusions and implications of key findings
The anti-VEGFs ranibizumab and bevacizumab have consistently shown good clinical effectiveness without major unwanted side effects. Steroid results have been mixed and are usually associated with cataract formation and  intraocular pressure increase. Despite the current wider spectrum of treatments for DMO, only a small proportion of patients recover good vision (≥20/40), and thus the search for new therapies needs to continue.
PMCID: PMC3612765  PMID: 23457327
5.  Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes 
BMJ Open  2012;2(5):e001007.
Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents.
To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes.
Data sources
MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers.
Inclusion criteria
Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy.
Systematic review. Quality assessment used the Cochrane risk of bias score.
Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo).
Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers.
Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.
PMCID: PMC3488745  PMID: 23087012
Diabetes & Endocrinology; Clinical Pharmacology
6.  NICE guidance: a comparative study of the introduction of the single technology appraisal process and comparison with guidance from Scottish Medicines Consortium 
BMJ Open  2012;2(1):e000671.
To compare the timelines and recommendations of the Scottish Medicines Consortium (SMC) and National Institute of Health and Clinical Excellence (NICE), in particular since the single technology assessment (STA) process was introduced in 2005.
Comparative study of drug appraisals published by NICE and SMC.
All drugs appraised by SMC and NICE, from establishment of each organisation until August 2010, were included. Data were gathered from published reports on the NICE website, SMC annual reports and European Medicines Agency website.
Primary and secondary outcome measures
Primary outcome was time from marketing authorisation until publication of first guidance. The final outcome for each drug was documented. Drug appraisals by NICE (before and after the introduction of the STA process) and SMC were compared.
NICE and SMC appraised 140 drugs, 415 were appraised by SMC alone and 102 by NICE alone. NICE recommended, with or without restriction, 90% of drugs and SMC 80%. SMC published guidance more quickly than NICE (median 7.4 compared with 21.4 months). Overall, the STA process reduced the average time to publication compared with multiple technology assessments (median 16.1 compared with 22.8 months). However, for cancer medications, the STA process took longer than multiple technology assessment (25.2 compared with 20.0 months).
Proportions of drugs recommended for NHS use by SMC and NICE are similar. SMC publishes guidance more quickly than NICE. The STA process has improved the time to publication but not for cancer drugs. The lengthier time for NICE guidance is partly due to measures to provide transparency and the widespread consultation during the NICE process.
Article summary
Article focus
Has the STA process resulted in speedier guidance for NICE?
What are the differences in recommendation and timelines between SMC and NICE?
Key messages
The STA system has resulted in speedier guidance for some drugs but not for cancer drugs.
SMC publishes speedier guidance than NICE.
SMC and NICE recommend a similar proportion of drugs.
Strength and limitations of this study
Although some differences by SMC and NICE are shown, it is not possible in this study to say which is correct.
Accuracy of outcome data taken from NICE website and SMC annual reports is unclear.
PMCID: PMC3269048  PMID: 22290398
7.  Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis 
Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs.
MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events.
Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily.
Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped.
GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.
PMCID: PMC3017518  PMID: 21143938
8.  Self monitoring of blood glucose - a survey of diabetes UK members with type 2 diabetes who use SMBG 
BMC Research Notes  2010;3:318.
Aim - to survey members of Diabetes UK who had Type 2 diabetes and who used self monitoring of blood glucose (SMBG), to elicit their views on its usefulness in the management of their diabetes, and how they used the results. A questionnaire was developed for the Diabetes UK website. The questionnaire was posted on the Diabetes UK website until over 500 people had responded. Questions asked users to specify the benefits gained from SMBG, and how these benefits were achieved. We carried out both quantitative analysis and a thematic analysis for the open ended free-text questions.
554 participants completed the survey, of whom 289 (52.2%) were male. 20% of respondents were recently diagnosed (< 6 months). Frequency of SMBG varied, with 43% of participants testing between once and four times a day and 22% testing less than once a month or for occasional periods.
80% of respondents reported high satisfaction with SMBG, and reported feeling more 'in control' of their diabetes management using it. The most frequently reported use of SMBG was to make adjustments to food intake or confirm a hyperglycaemic episode.
Women were significantly more likely to report feelings of guilt or self-chastisement associated with out of range readings (p = < .001).
SMBG was clearly of benefit to this group of confirmed users, who used the results to adjust diet, physical activity or medications. However many individuals (particularly women) reported feelings of anxiety and depression associated with its use.
PMCID: PMC2998520  PMID: 21092171
9.  Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review 
BMC Pediatrics  2010;10:50.
Many children with type 1 diabetes have poor glycaemic control. Since the Diabetes Control and Complications Trial (DCCT) showed that tighter control reduces complication rates, there has been more emphasis on intensified insulin therapy. We know that patients and families are afraid of hypoglycaemia. We hypothesised that fear of hypoglycaemia might take precedence over concern about long-term complications, and that behaviour to avoid hypoglycaemia might be at the cost of poorer control, and aimed to evaluate the effectiveness of any interventions designed to prevent that. The objective of this review was to systematically review studies concerning the extent and consequences of fear of hypoglycaemia in parents of children under 12 years of age with type 1 diabetes, and interventions to reduce it.
Data Sources: MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of EASD, ADA and Diabetes UK, Current Controlled Trials,, UK CRN, scrutiny of bibliographies of retrieved papers and contact with experts in the field.
Inclusions: Relevant studies of any design of parents of children under 12 years of age with Type 1 diabetes were included. The key outcomes were the extent and impact of fear, hypoglycaemia avoidance behaviour in parents due to parental fear of hypoglycaemia in their children, the effect on diabetes control, and the impact of interventions to reduce this fear and hypoglycaemia avoidance behaviour.
Eight articles from six studies met the inclusion criteria. All were cross sectional studies and most were of good quality. Parental fear of hypoglycaemia, anxiety and depression were reported to be common. There was a paucity of evidence on behaviour to avoid hypoglycaemia, but there were some suggestions that higher than desirable blood glucose levels might be permitted in order to avoid hypoglycaemia. No studies reporting interventions to reduce parental fear of hypoglycaemia were found.
The evidence base was limited. Parents of children with Type 1 diabetes reported considerable parental fear of hypoglycaemia, affecting both parental health and quality of life. There is some suggestion that hypoglycaemia avoidance behaviours by parents might adversely affect glycaemic control. Trials of interventions to reduce parental anxiety and hypoglycaemia avoidance behaviour are needed. We suggest that there should be a trial of structured education for parents of young children with Type 1 diabetes.
PMCID: PMC2912881  PMID: 20633252
10.  Population screening for lung cancer using computed tomography, is there evidence of clinical effectiveness? A systematic review of the literature 
Thorax  2007;62(2):131-138.
Lung cancer is the leading cause of death among all cancer types in the UK, killing approximately 34 000 people per year. By the time symptoms develop, the tumour is often at an advanced stage and the prognosis is bleak. Treatment at a less advanced stage of disease by surgical resection has been shown to substantially reduce mortality. Screening would be attractive if it could detect presymptomatic lung cancer at a stage when surgical intervention is feasible but has been the subject of scientific debate for the past three decades. The aim of this review was to examine the current evidence on the clinical effectiveness of screening for lung cancer using computed tomography. A systematic literature review searching 15 electronic databases and Internet resources from 1994 until December 2004/January 2005 was carried out. Information was summarised narratively. A total of 12 studies of computed tomography screening for lung cancer were identified including two RCTs and 10 studies of screening without comparator groups. The two RCTs were of short duration (1 year). None examined the effect of screening on mortality compared with no screening. The proportion of people with abnormal computed tomography findings varied widely between studies (5–51%). The prevalence of lung cancer detected was between 0.4% and 3.2% (number needed to screen to detect one lung cancer  = 31 to 249). Incidence rates of lung cancer were lower (0.1–1%). Among the detected tumours, a high proportion were stage I or resectable tumours, 100% in some studies. Currently, there is insufficient evidence that computed tomography screening is clinically effective in reducing mortality from lung cancer.
PMCID: PMC2111254  PMID: 17287305
11.  Reducing the rise in type 2 diabetes 
PMCID: PMC2486381  PMID: 18682017
12.  Adding Pioglitazone to Insulin Containing Regimens in Type 2 Diabetes: Systematic Review and Meta-Analysis 
PLoS ONE  2009;4(7):e6112.
Type 2 diabetes is treated in a stepwise manner, progressing from diet and physical activity to oral antidiabetic agents and insulin. The oral agent pioglitazone is licensed for use with insulin when metformin is contraindicated or not tolerated. This systematic review and meta-analysis investigates the extent to which adding pioglitazone to insulin-containing regimens produces benefits in terms of patient-relevant outcomes.
Methodology/Principal Findings
Medline, Embase, and the Cochrane Library were searched for randomised controlled trials comparing pioglitazone in combination with any insulin-containing regimen in comparison with the same insulin regimen alone in patients with type 2 diabetes. Outcomes investigated included HbA1c, hypoglycaemia, weight, and adverse events. Studies were selected, assessed and summarised according to standard systematic review methodology and in a meta-analysis. We included eight trials that examined the benefits of adding pioglitazone to an insulin regimen and studied a total of 3092 patients with type 2 diabetes. All studies included patients with previously inadequate glucose control. Trial duration was between 12 weeks and 34.5 months. The trials used pioglitazone doses of up to 45 mg/day. In our meta-analysis, the mean reduction in HbA1c was 0.58% (95% CI: −0.70, −0.46, p<0.00001). Hypoglycaemic episodes were slightly more frequent in the pioglitazone arms (relative risk 1.27; 95% CI: 0.99, 1.63, p = 0.06). Where reported, HDL-cholesterol tended to be increased with pioglitazone. Patients on pioglitazone tended to gain more weight than those who were not, with an average difference of almost 3 kg. Peripheral oedema was more frequent in the pioglitazone groups. None of the studies reported on fractures in women, and data on cardiovascular events were inconclusive, with most studies being too short or too small to assess these long-term outcomes.
When added to insulin regimens, pioglitazone confers a small advantage in terms of HbA1c in type 2 diabetes patients with previous inadequate glucose control, but at the cost of increased hypoglycaemia and weight gain. Other considerations include the risk of heart failure, fractures in women, a reduced insulin dose, and the net financial cost.
PMCID: PMC2701605  PMID: 19568428
13.  Hospital admission patterns subsequent to diagnosis of type 1 diabetes in children : a systematic review 
Patients with type 1 diabetes are known to have a higher hospital admission rate than the underlying population and may also be admitted for procedures that would normally be carried out on a day surgery basis for non-diabetics. Emergency admission rates have sometimes been used as indicators of quality of diabetes care.
In preparation for a study of hospital admissions, a systematic review was carried out on hospital admissions for children diagnosed with type 1 diabetes, whilst under the age of 15. The main thrust of this review was to ascertain where there were gaps in the literature for studies investigating post-diagnosis hospitalisations, rather than to try to draw conclusions from the disparate data sets.
A systematic search of the electronic databases PubMed, Cochrane LibrarMEDLINE and EMBASE was conducted for the period 1986 to 2006, to identify publications relating to hospital admissions subsequent to the diagnosis of type 1 diabetes under the age of 15.
Thirty-two publications met all inclusion criteria, 16 in Northern America, 11 in Europe and 5 in Australasia. Most of the studies selected were focussed on diabetic ketoacidosis (DKA) or diabetes-related hospital admissions and only four studies included data on all admissions. Admission rates with DKA as primary diagnosis varied widely between 0.01 to 0.18 per patient-year as did those for other diabetes-related co-morbidity ranging from 0.05 to 0.38 per patient year, making it difficult to interpret data from different study designs. However, people with Type 1 diabetes are three times more likely to be hospitalised than the non-diabetic populations and stay in hospital twice as long.
Few studies report on all admissions to hospital in patients diagnosed with type 1 diabetes whilst under the age of 15 years. Health care costs for type 1 patients are higher than those for the general population and information on associated patterns of hospitalisation might help to target interventions to reduce the cost of hospital admissions.
PMCID: PMC2233617  PMID: 18053255
14.  A simplified search strategy for identifying randomised controlled trials for systematic reviews of health care interventions: a comparison with more exhaustive strategies 
It is generally believed that exhaustive searches of bibliographic databases are needed for systematic reviews of health care interventions. The CENTRAL database of controlled trials (RCTs) has been built up by exhaustive searching. The CONSORT statement aims to encourage better reporting, and hence indexing, of RCTs. Our aim was to assess whether developments in the CENTRAL database, and the CONSORT statement, mean that a simplified RCT search strategy for identifying RCTs now suffices for systematic reviews of health care interventions.
RCTs used in the Cochrane reviews were identified. A brief RCT search strategy (BRSS), consisting of a search of CENTRAL, and then for variants of the word random across all fields (random$.af.) in MEDLINE and EMBASE, was devised and run. Any trials included in the meta-analyses, but missed by the BRSS, were identified. The meta-analyses were then re-run, with and without the missed RCTs, and the differences quantified. The proportion of trials with variants of the word random in the title or abstract was calculated for each year. The number of RCTs retrieved by searching with "random$.af." was compared to the highly sensitive search strategy (HSSS).
The BRSS had a sensitivity of 94%. It found all journal RCTs in 47 of the 57 reviews. The missing RCTs made some significant differences to a small proportion of the total outcomes in only five reviews, but no important differences in conclusions resulted. In the post-CONSORT years, 1997–2003, the percentage of RCTs with random in the title or abstract was 85%, a mean increase of 17% compared to the seven years pre-CONSORT (95% CI, 8.3% to 25.9%). The search using random$.af. reduced the MEDLINE retrieval by 84%, compared to the HSSS, thereby reducing the workload of checking retrievals.
A brief RCT search strategy is now sufficient to locate RCTs for systematic reviews in most cases. Exhaustive searching is no longer cost-effective, because in effect it has already been done for CENTRAL.
PMCID: PMC1183214  PMID: 16042789
15.  Systematic reviews of epidemiology in diabetes: finding the evidence 
Methodological research to support searching for those doing systematic reviews of epidemiological studies is a relatively neglected area. Our aim was to determine how many databases it is necessary to search to ensure a comprehensive coverage of the literature in diabetes epidemiology, with the aim of examining the efficiency of searching in support of systematic reviews of the epidemiology of diabetes
Three approaches were used. First, we defined a set of English language diabetes journals and examined their coverage in bibliographic databases. Second, we searched extensively for diabetes epidemiology articles (in all languages) to determine which are the most useful databases; and third, we analysed the scattering of these articles to determine the core journals in the area.
The overlap between MEDLINE and Embase for diabetes journals was 59%. A search for diabetes epidemiology articles across both MEDLINE and Embase, showed that MEDLINE alone retrieved about 94% of the total articles. Searching for diabetes epidemiology studies beyond MEDLINE and Embase retrieved no additional English language journal articles. The only diabetes epidemiology studies found by searching beyond MEDLINE and Embase were found in LILACS, and were Spanish or Portuguese language studies from Latin America; no additional English language studies were found. Only 30% of the meeting abstracts were converted to full publication after three years. One third of journal articles were published in just six journals, with Diabetes Care contributing 14.3% of the articles, followed by Diabetic Medicine (5.0%); Diabetes Research & Clinical Practice (4.1%); Diabetologia (4.0%); Diabetes & Metabolism (2.4%) and Diabetes (2.0%).
Our results show that when searching for articles on diabetes epidemiology, MEDLINE and Embase would suffice for English language papers, with LILACS giving some additional non-English articles from Latin America. Although a MEDLINE-only search will retrieve the vast majority of the relevant literature, Embase and LILACs should also be searched to ensure the search is comprehensive. Searching for meeting abstracts is recommended to alert reviewers to unpublished work. The low rate of full publication of meeting abstracts has the danger of producing bias in reviews. Our findings on scattering show that the core literature in this field is concentrated in just six journals.
PMCID: PMC545080  PMID: 15638944
17.  Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis 
BMJ : British Medical Journal  1999;319(7224):1529-1533.
To evaluate the cost utility of interferon beta-1b in secondary progressive multiple sclerosis.
Population based cost utility model (healthcare perspective). Data on use of health services were obtained from case records and routine morbidity data and utility values from a EuroQol survey. Local and published costs were used. Effectiveness was modelled using data on relative risk reductions from a randomised trial of interferon beta-1b.
Tayside region, 1993-5.
132 ambulatory people with secondary progressive multiple sclerosis.
Main outcome measures
Cost per quality adjusted life year (QALY) gained. Rate of relapse and proportion becoming wheelchair dependent over three years.
The number needed to treat for 30 months to delay time to wheelchair dependence in one person by nine months was 18 (95% confidence interval 5 to 26). For every 18 people treated for 30 months, six relapses would be prevented, gaining 0.397 discounted QALYs. The cost per QALY gained was £1 024 667 (£276 466 to £1 485 499). If treatment was restricted to patients attending neurology services, the number needed to treat was 14 (cost per QALY gained £833 514 (£161 358 to ∞)). The cost per QALY gained was not sensitive to changes in cost which took account of a societal perspective.
The cost per QALY gained from interferon beta is high because of the high drug cost and modest clinical effect. Resources could be used more efficiently elsewhere.
Key messagesSecondary progressive multiple sclerosis is a potentially disabling disorder associated with low health related quality of lifeInterferon beta-1b may reduce rate of relapseThe benefits of interferon beta-1b treatment are very low relative to its costCost utility analysis estimated a cost of over £1m per QALY gainedCost per QALY was not affected by taking into account the costs of careMoney would be better spent on other ways of improving quality of life than on interferon beta
PMCID: PMC28295  PMID: 10591710
18.  Call to needle times after acute myocardial infarction in urban and rural areas in northeast Scotland: prospective observational study 
BMJ : British Medical Journal  1998;317(7158):576-578.
Objective: To determine call to needle times and consider how best to provide timely thrombolytic treatment for patients with acute myocardial infarction.
Design: Prospective observational study.
Setting: City, suburban, and country practices referring patients to a single district general hospital in northeast Scotland.
Subjects: 1046 patients with suspected acute myocardial infarction given thrombolytic treatment.
Main outcome measures: Time from patients’ calls for medical help until receipt of opiate or thrombolytic treatment, measured against a call to needle time of 90 minutes or less, as proposed by the British Heart Foundation.
Results: General practitioners were the first medical contact in 97% (528/544) of calls by country patients and 68% (340/502) of city and suburban patients. When opiate was given by general practitioners, median call to opiate time was about 30 minutes (95% within 90 minutes) in city, suburbs, and country; call to opiate delay was about 60 minutes in city and suburban patients calling “999” for an ambulance. One third of country patients received thrombolytic treatment from their general practitioners with a median call to thrombolysis time of 45 minutes (93% within 90 minutes); this compares with 150 minutes (5% within 90 minutes) when this treatment was deferred until after hospital admission. In the city and suburbs, no thrombolytic treatment was given outside hospital, and only a minority of patients received it within 90 minutes of calling; median call to thrombolysis time was 95 (46% within 90 minutes) minutes.
Conclusions: The first medical contact after acute myocardial infarction is most commonly with a general practitioner. This contact provides the optimum opportunity to give thrombolytic treatment within the British Heart Foundation’s guideline.
Key messages A British Heart Foundation guideline recommends that patients with acute myocardial infarction should receive thrombolytic treatment within 90 minutes of calling for medical assistance In urban and rural areas in Grampian, only a minority of patients received treatment within the guideline Median call to needle times were shortest when thrombolytic treatment was given by general practitioners The first medical contact after acute myocardial infarction was most commonly with a general practitioner in both urban and rural areas First contact with a general practitioner provides a matchless opportunity to give thrombolytic treatment within the British Heart Foundation guideline
PMCID: PMC28652  PMID: 9721115
20.  The relative clinical effectiveness of ranibizumab and bevacizumab in diabetic macular oedema: an indirect comparison in a systematic review 
Objective To indirectly compare the effectiveness of ranibizumab and bevacizumab in the treatment of diabetic macular oedema.
Design Systematic review and indirect comparison.
Data sources Medline (1996–September 2011), Embase (1996–September 2011), and the Cochrane Central Register of Controlled Trials (Issue 4, 2011).
Selection criteria for studies Randomised trials evaluating ranibizumab or bevacizumab in diabetic macular oedema with a common comparator and sufficient methodological similarity to be included within an indirect comparison were eligible for inclusion.
Main outcome measures The primary outcome was the proportion of patients with an improvement in best corrected visual acuity of more than two lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Secondary outcomes included mean changes in best corrected visual acuity and in central macular thickness, and adverse events. Best corrected visual acuity was converted to logMAR units, a linear scale of visual acuity with positive values representing increasing visual loss. Indirect comparisons were done using Bayesian methods to estimate relative treatment effects of bevacizumab and ranibizumab.
Results Five randomised controlled trials with follow-up of 6–12 months and a common comparator (multiple laser treatment) were sufficiently similar to be included in the indirect comparison. Generally studies were small, resulting in wide credible intervals. The proportions of patients with an improvement in best corrected visual acuity of >2 lines were 21/77 participants (27%) for bevacizumab and 60/152 participants (39%) for ranibizumab (odds ratio 0.95 (95% credible interval 0.23 to 4.32)). The wide credible intervals cannot exclude a greater improvement, or worse outcome, for either drug. The mean change in best corrected visual acuity non-significantly favoured bevacizumab (treatment effect −0.08 logMAR units (−0.19 to 0.04)). The difference in mean change in central macular thickness was not statistically significant between ranibizumab and bevacizumab (treatment effect −6.9 μm (−88.5 to 65.4)).
Conclusions Results suggest no difference in effectiveness between bevacizumab and ranibizumab, but the wide credible intervals cannot exclude the possibility that either drug might be superior. Sufficiently powered, direct head to head trials are needed.
PMCID: PMC3418219  PMID: 22890029

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