Anti-vascular endothelial growth factor for diabetic macular oedema: A network meta-analysis

BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. OBJECTIVES: The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods. SEARCH METHODS: We searched various electronic databases on 26 April 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study. MAIN RESULTS: Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference. AUTHORS' CONCLUSIONS: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death

Corporate social and environmental responsibility in India - assessing the UN global compact's role

"This report presents the results of a research project carried out as part of the postgraduate training course of the German Development Institute (GDI), Bonn, in close cooperation with the Centre for Social Markets, India, and with the support of Ashok V. Desai, Consultant Editor of the Telegraph, India. The report is based on studies of the literature and on empirical data collected in India’s main industrial districts of Delhi, Mumbai, Pune, Bangalore and Chennai from February to April 2006. The GDI research team would like to thank Sachin Joshi of the Centre for Social Markets and Ashok V. Desai for their strong scientific and technical support, without which this study would not have been possible. The research team would also like to express their thanks to the top officials of almost 40 Indian and foreign companies and 32 other stakeholders who spoke of their experience and responded to our questionnaire on CSR in India and the role of the UN Global Compact in particular. Last but not least, the authors are very grateful to experts from other Indian, international and German institutions who were kind enough to share their knowledge with us and so contributed to the writing of the report. However, the GDI team alone is responsible for the results presented here." (excerpt)Der vorliegende Beitrag untersucht die UN Global Compact-Initiative (UNGC), die im Jahr 2000 von dem damaligen UN-Generalsekretär Kofi Annan aus der Taufe gehoben wurde, unter besonderer Berücksichtigung der sozialen und ökologischen Aktivitäten in Indien. Der Global Compact, ein weltweiter Pakt, der zwischen Unternehmen und der UNO geschlossen wird, basiert auf zehn Prinzipien, die der Einhaltung bestimmter sozialer und ökologischer Mindeststandards dienen. Dies sind beispielsweise die wesentlichen Konventionen zur Einhaltung der Menschenrechte, Vereinigungsfreiheit, keine Zwangsarbeit, keine Kinderarbeit, Nicht-Diskriminierung, wesentliche Prinzipien, wie sie in den Rio-Konventionen zum Umweltschutz verfasst worden sind, sowie das Prinzip gegen alle Formen von Korruption. (ICD2

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases

Vision impairment and differential access to eye health services in Aotearoa New Zealand: protocol for a scoping review

INTRODUCTION: In Aotearoa New Zealand, Māori and Pacific people experience worse health outcomes compared with other New Zealanders. No population-based eye health survey has been conducted, and eye health services do not generate routine monitoring reports, so the extent of eye health inequality is unknown. This information is required to plan equitable eye health services. Here we outline the protocol for a scoping review to report the nature and extent of the evidence reporting vision impairment, and the use of eye health services by ethnicity in New Zealand. METHODS AND ANALYSIS: An information specialist will conduct searches on MEDLINE and Embase, with no limit on publication dates or language. We will search the grey literature via websites of relevant government and service provider agencies. Reference lists of included articles will be screened. Observational studies will be included if they report the prevalence of vision impairment, or any of the main causes (cataract, uncorrected refractive error, macular degeneration, glaucoma or diabetic retinopathy) or report the use of eye health services in New Zealand among people of any age. Two authors will independently review titles, abstracts and full-text articles, and complete data extraction. Overall findings will be summarised using descriptive statistics and thematic analysis, with an emphasis on disaggregation by ethnicity where this information is available. ETHICS AND DISSEMINATION: Ethical approval has not been sought as our review will only include published and publicly accessible data. We will publish the review in an open access peer-reviewed journal. We anticipate the findings will be useful to organisations and providers in New Zealand responsible to plan and deliver eye care services, as well as stakeholders in other countries with differential access to eye care. REGISTRATION DETAILS: The protocol has been registered with Open Science Framework (https://osf.io/yw7xb)

A systematic review of clinical practice guidelines for childhood glaucoma.

OBJECTIVE: To conduct a systematic review to identify and critically appraise clinical practice guidelines on the assessment, diagnosis and management of childhood glaucoma. METHODS AND ANALYSIS: A systematic literature search of databases and professional websites for clinical practice guidelines published on eye conditions between 2010 and April 2020 in English was conducted. Identified guidelines were screened for relevance to childhood glaucoma and exclusion criteria applied. Guidelines that passed the screening and quality appraisal with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool and, if they achieved a mean score of ≥45 and ≥3 on subsets of 9 and 5 AGREE II items, respectively, were selected for inclusion and data extracted using a standardised form. RESULTS: Following screening and critical appraisal, three guidelines were included for data extraction. None of the three guidelines was specifically developed for childhood glaucoma. A consistent recommendation was that children should undergo some form of eye screening examination or a comprehensive eye assessment to detect paediatric eye disease. Children at high risk of childhood glaucoma should undergo additional screening. One clinical practice guideline recommended interventions for childhood glaucoma consisting of tube surgery and topical beta-blockers or carbonic anhydrase inhibitors. Recommended interventions for childhood glaucoma were based on low-quality to moderate-quality evidence or expert opinion. CONCLUSION: Based on our selection criteria, we did not identify any high-quality clinical practice guidelines specifically targeted at childhood glaucoma. This is compounded by the lack of high-quality evidence on childhood glaucoma

The Community Ecology of Herbivore Regulation in an Agroecosystem: Lessons from Complex Systems

AbstractWhether an ecological community is controlled from above or below remains a popular framework that continues generating interesting research questions and takes on especially important meaning in agroecosystems. We describe the regulation from above of three coffee herbivores, a leaf herbivore (the green coffee scale, Coccus viridis), a seed predator (the coffee berry borer, Hypothenemus hampei), and a plant pathogen (the coffee rust disease, caused by Hemelia vastatrix) by various natural enemies, emphasizing the remarkable complexity involved. We emphasize the intersection of this classical question of ecology with the burgeoning field of complex systems, including references to chaos, critical transitions, hysteresis, basin or boundary collision, and spatial self-organization, all aimed at the applied question of pest control in the coffee agroecosystem

The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis

Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signalling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway-specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production

Associations between vision impairment and driving and the effectiveness of vision-related interventions : protocol for a systematic review and meta-analysis

Introduction Driving is one of the main modes of transport with safe driving requiring a combination of visual, cognitive and physical skills. With population ageing, the number of people living with vision impairment is set to increase in the decades ahead. Vision impairment may negatively impact an individual's ability to safely drive. The association between vision impairment and motor vehicle crash involvement or driving participation has yet to be systematically investigated. Further, the evidence for the effectiveness of vision-related interventions aimed at decreasing crashes and driving errors has not been synthesised. Methods and analysis A search will be conducted for relevant studies on Medline (Ovid), EMBASE and Global Health from their inception to March 2020 without date or geographical restrictions. Two investigators will independently screen abstracts and full texts using Covidence software with conflicts resolved by a third investigator. Data extraction will be conducted on all included studies, and their quality assessed to determine the risk of bias using the Joanna Briggs Institute Critical Appraisal Tools. Outcome measures include crash risk, driving cessation and surrogate measures of driving safety (eg, driving errors and performance). The results of this review will be reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline. Meta-analysis will be undertaken for outcomes with sufficient data and reported following the Meta-analyses of Observational Studies in Epidemiology guideline. Where statistical pooling is not feasible or appropriate, narrative summaries will be presented following the Synthesis Without Meta-analysis in systematic reviews guideline. Ethics and dissemination This review will only report on published data thus no ethics approval is required. Results will be included in the Lancet Global Health Commission on Global Eye Health, published in a peer-reviewed journal and presented at relevant conferences. PROSPERO registration number CRD42020172153