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1.  Clinical effectiveness of manual therapy for the management of musculoskeletal and non-musculoskeletal conditions: systematic review and update of UK evidence report 
Background
This systematic review updated and extended the "UK evidence report" by Bronfort et al. (Chiropr Osteopath 18:3, 2010) with respect to conditions/interventions that received an 'inconclusive’ or 'negative’ evidence rating or were not covered in the report.
Methods
A literature search of more than 10 general medical and specialised databases was conducted in August 2011 and updated in March 2013. Systematic reviews, primary comparative studies and qualitative studies of patients with musculoskeletal or non-musculoskeletal conditions treated with manual therapy and reporting clinical outcomes were included. Study quality was assessed using standardised instruments, studies were summarised, and the results were compared against the evidence ratings of Bronfort. These were either confirmed, updated, or new categories not assessed by Bronfort were added.
Results
25,539 records were found; 178 new and additional studies were identified, of which 72 were systematic reviews, 96 were randomised controlled trials, and 10 were non-randomised primary studies. Most 'inconclusive’ or 'moderate’ evidence ratings of the UK evidence report were confirmed. Evidence ratings changed in a positive direction from inconclusive to moderate evidence ratings in only three cases (manipulation/mobilisation [with exercise] for rotator cuff disorder; spinal mobilisation for cervicogenic headache; and mobilisation for miscellaneous headache). In addition, evidence was identified on a large number of non-musculoskeletal conditions not previously considered; most of this evidence was rated as inconclusive.
Conclusions
Overall, there was limited high quality evidence for the effectiveness of manual therapy. Most reviewed evidence was of low to moderate quality and inconsistent due to substantial methodological and clinical diversity. Areas requiring further research are highlighted.
doi:10.1186/2045-709X-22-12
PMCID: PMC3997823  PMID: 24679336
Clinical effectiveness; Manual therapy; Systematic review; Musculoskeletal; Bronfort
2.  Treatments for macular oedema following central retinal vein occlusion: systematic review 
BMJ Open  2014;4(2):e004120.
Objectives
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.
Results
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.
Limitations
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.
doi:10.1136/bmjopen-2013-004120
PMCID: PMC3927713  PMID: 24513867
Systematic Review; Anti-VEGF; Central Retinal Vein Occlusion; Macular Oedema
3.  Current treatments in diabetic macular oedema: systematic review and meta-analysis 
BMJ Open  2013;3(3):e002269.
Objectives
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.
Results
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.
Limitations
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.
doi:10.1136/bmjopen-2012-002269
PMCID: PMC3612765  PMID: 23457327
Ophthalmology
4.  Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes 
BMJ Open  2012;2(5):e001007.
Background
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.
Objective
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.
Methods
Systematic review. Quality assessment used the Cochrane risk of bias score.
Results
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).
Limitations
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.
Conclusions
Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.
doi:10.1136/bmjopen-2012-001007
PMCID: PMC3488745  PMID: 23087012
Diabetes & Endocrinology; Clinical Pharmacology
5.  Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis 
Background
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.
Methods
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.
Results
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.
Conclusions
GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.
doi:10.1186/1472-6823-10-20
PMCID: PMC3017518  PMID: 21143938
6.  Adding Pioglitazone to Insulin Containing Regimens in Type 2 Diabetes: Systematic Review and Meta-Analysis 
PLoS ONE  2009;4(7):e6112.
Background
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.
Conclusions/Significance
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.
doi:10.1371/journal.pone.0006112
PMCID: PMC2701605  PMID: 19568428
7.  Interferons and Natalizumab for Multiple Sclerosis 
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which is accompanied by considerable disability and high costs. This report summarises the evidence on effectiveness and costs of beta-interferons and natalizumab in the treatment of multiple sclerosis.
The review included systematic reviews and randomised controlled trials (with an observation time of at least one year) in patients with MS which assessed outcome parameters such as progression, exacerbations and adverse effects.
An extensive literature search included databases such as MEDLINE, EMBASE, the Cochrane Library and various HTA-databases. Studies were selected according to predefined criteria, their quality was assessed according to criteria defined prospectively, and data were summarised systematically in tables. Cost-effectiveness evaluations were also included.
Two systematic reviews and 24 randomised controlled trials of beta-interferon therapy were included, as well as three trials on the effectiveness of natalizumab. A total of 22 cost-effectiveness analyses for interferons were included, whereas no economic evaluations for natalizumab were identified.
Use of interferon beta-1a or interferon beta-1b after a first demyelinating event led to a reduction of the conversion to definite MS during an observation time of two to three years. In relapsing remitting MS, interferon beta-1a reduced progression. The effects of interferon beta-1b on progression are unclear. Interferon beta-1a and interferon beta-1b reduced in some but not all studies outcomes relating to exacerbations. In direct comparison trials, interferon beta-1b (Betaferon® or Betaseron®) and interferon beta-1a (Rebif®, higher dosage of 44 µg three subcutaneous injections per week) proved superior to interferon beta-1a (Avonex®, 30 µg per week intramuscular) with respect to exacerbation outcomes. For secondary progressive MS, only one of five studies found a reduced progression with interferon beta-1a and only a part of the studies found an improvement with respect to outcomes relating to exacerbations. For primary progressive MS no advantage of therapy with beta-interferons was found with respect to patient-related outcomes. Beta-interferons showed characteristic and frequently occurring adverse effects, including reactions at the injection site and flu-like symptoms. A large proportion of patients stop interferon therapy because of adverse events. The other main reason for stopping therapy is the felt ineffectiveness of the treatment when patients experience a new exacerbation while on treatment. Many patients produce interferon-neutralising antibodies during therapy. The ultimate effect of neutralising antibodies on the efficacy of interferon treatment is unclear.
In patients with relapsing remitting (and partially with secondary progressive) MS, treatment with natalizumab led to a reduction of progression and of exacerbation rates. However, a number of cases of progressive multifocal leucoencephalopathy have been reported after natalizumab therapy. These raise serious concerns about patient safety. Reliable data on the long term effectiveness of beta-interferons or natalizumab are not yet available.
The absolute cost of interferon therapy is high and the available, international cost-effectiveness analyses indicate a high cost for achieving moderate benefits in quality of life. Further research is needed to provide specific cost-effectiveness estimates for Germany.
PMCID: PMC3011296  PMID: 21289915

Results 1-7 (7)