Anti-vascular endothelial growth factor for proliferative diabetic retinopathy.

BACKGROUND: Proliferative diabetic retinopathy (PDR) is a complication of diabetic retinopathy that can cause blindness. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. An alternative treatment such as anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR. OBJECTIVES: To assess the effectiveness and safety of anti-VEGFs for PDR. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing anti-VEGFs to another active treatment, sham treatment or no treatment for people with PDR. We also included studies that assessed the combination of anti-VEGFs with other treatments. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI). MAIN RESULTS: We included 18 RCTs with 1005 participants (1131 eyes) of whom 57% were men. The median number of participants per RCT was 40 (range 15 to 261). The studies took place in Asia (three studies), Europe (two studies), the Middle East (seven studies), North America (three studies) and South America (three studies). Eight RCTs recruited people eligible for PRP, nine RCTs enrolled people with diabetes requiring vitrectomy and one RCT recruited people undergoing cataract surgery. The median follow-up was six months (range one to 12 months). Seven studies were at high risk of bias and the remainder were unclear risk of bias in one or more domains.Very low quality evidence from one study of 61 people showed that people treated with bevacizumab and PRP were less likely to lose 3 or more lines of visual acuity at 12 months compared with people treated with PRP alone (RR 0.19, 95% CI 0.05 to 0.81). People treated with anti-VEGF had an increased chance of gaining 3 or more lines of visual acuity but the effect was imprecise and compatible with no effect or being less likely to gain vision (RR 6.78, 95% CI 0.37 to 125.95). No other study reported these two outcomes. On average, people treated with anti-VEGF (bevacizumab, pegaptanib or ranibizumab) had better visual acuity at 12 months compared with people not receiving anti-VEGF (MD -0.07 logMAR, 95% CI -0.12 to -0.02; 5 RCTs, 373 participants, low quality evidence). There was some evidence to suggest a regression of PDR with smaller leakage on fluorescein angiography but it was difficult to estimate a pooled result from the two trials reporting this outcome. People receiving anti-VEGF were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.32, 95% CI 0.16 to 0.65; 3 RCTs, 342 participants, low quality evidence). No study reported on fluorescein leakage or quality of life.All of the nine trials of anti-VEGF before or during vitrectomy investigated bevacizumab; most studies investigated bevacizumab before vitrectomy, one study investigated bevacizumab during surgery.People treated with bevacizumab and vitrectomy were less likely to lose 3 or more lines of visual acuity at 12 months compared with people given vitrectomy alone but the effect was imprecise and compatible with no effect or being more likely to lose vision (RR 0.49, 95% CI 0.08 to 3.14; 3 RCTs, 94 participants, low quality evidence). People treated with bevacizumab were more likely to gain 3 or more lines of visual acuity (RR 1.62, 95% CI 1.20 to 2.17; 3 RCTs, 94 participants, low quality evidence). On average, people treated with bevacizumab had better visual acuity at 12 months compared with people not receiving bevacizumab but there was uncertainty in the estimate (the CIs included 0; i.e. were compatible with no effect, and there was considerable inconsistency between studies; MD -0.24 logMAR, 95% CI -0.50 to 0.01; 6 RCTs, 335 participants, I(2) = 67%; low quality evidence). People receiving bevacizumab were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.30, 95% CI 0.18 to 0.52; 7 RCTs, 393 participants, low quality evidence). No study reported on quality of life.Reasons for downgrading the quality of the evidence included risk of bias in included studies, imprecision of the estimates, inconsistency of effect estimates and indirectness (few studies reported at 12 months).Adverse effects were rarely reported and there was no evidence for any increased risk with anti-VEGF but given the relatively few studies that reported these, and the low event rate, the power of the analysis to detect any differences was low. AUTHORS' CONCLUSIONS: There was very low or low quality evidence from RCTs for the efficacy and safety of anti-VEGF agents when used to treat PDR over and above current standard treatments. However, the results suggest that anti-VEGFs can reduce the risk of intraocular bleeding in people with PDR. Further carefully designed clinical trials should be able to improve this evidence

Analysis of latent tuberculosis and mycobacterium avium infection data using mixture models

BACKGROUND: Estimation of the frequency of latent tuberculosis infection (LTBI) is difficult in areas with low tuberculosis infection rates and high exposure to non-tuberculous mycobacteria (NTM), including BCG vaccination. The objective was to assess LTBI and M avium infection and to estimate their probability based on skin tests responses in an infant population from a region with the aforementioned characteristics. METHODS: A population-based tuberculin skin test (TST) and sensitin (M avium) survey was conducted on seven years old infants in Biscay, a province from The Basque Country (Spain). 2268 schoolchildren received sensitin and 5277 TST. Participation rate was 89%. Commonly used estimation methods were compared with a method based on the fit of mixture models using the Expectation Maximization algorithm. Functions estimating the probabilities of LTBI and M avium infection given the observed skin tests responses were developed for vaccinated and unvaccinated children. RESULTS: LTBI prevalences varied widely according to the estimation method. The mixture model provided prevalences higher than expected although intermediates between those obtained by currently recommended approaches. Exposure to previous BCG vaccine produces an upward shift of an average of about 3 mm on the induration size to attain the same probability of infection. CONCLUSION: Our results confirm the commonplace exposure to NTM which effect should be taken into account when performing and assessing tuberculin surveys. The use of mixture analysis under the empirical Bayes framework allows to better estimate the probability of LTBI in settings with presence of other NTM and high BCG-vaccination coverage. An estimation of the average effect of BCG vaccination on TST induration is also provided. These models maximise information coming from classical tuberculin surveys and could be used together with the newly developed blood tests to improve survey's specificity and cost-effectiveness