Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

Ophthalmology

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2/vascular endothelial growth factor (VEGF)-A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend-based regimen (T&E) with up to every-16-week (Q16W) dosing in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg Q8W, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg Q8W. The T&E up to Q16W dosing regimen was based on central subfield thickness (CST) and best-corrected visual acuity (BCVA) change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE/RHINE (N=940/951), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92/96/100 average) with faricimab Q8W (YOSEMITE/RHINE, +10.7/+10.9 letters) or T&E (+10.7/+10.1 letters) were comparable with aflibercept Q8W (+11.4/+9.4 letters). The median number of study drug injections was lower with faricimab T&E (YOSEMITE/RHINE, 10/11 injections) versus faricimab Q8W (15 injections) and aflibercept Q8W (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was further improved during year 2, with >60% of patients on Q16W dosing and ∼80% on ≥Q12W dosing at week 96. Almost 80% of patients who achieved Q16W dosing at week 52 maintained Q16W dosing without an interval reduction through week 96. Mean CST reductions were greater, and more patients achieved absence of DME (CST <325μm) and absence of intraretinal fluid with faricimab Q8W or T&E versus aflibercept Q8W through year 2. Overall, faricimab was well tolerated, with a safety profile comparable to aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to Q16W were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2/VEGF-A inhibition to promote vascular stability and provide durable efficacy for patients with DME

Odmitnuti a tolerance transplantatu rohovky

Thesis includes 2 appendixes: I. Photographs, II. List of publications of the applicantAvailable from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Methodological aspects of online forms of teaching

The paper presents results of a questionnaire survey which aim was to find out English learners´ preferences of different platforms and applications to be used for home schooling.    Concept. Key attention of the authors is paid to the issue of the transition of face-to-face forms of education to online platforms, caused by school closures due to the coronavirus pandemic in 2020. At first, they deal with the use of digital technologies in teaching in general. They analyse how digital didactic means were used prior to the pandemic situation and they present research results related to differences among the ways of the use of these means within different subjects teaching (natural science subjects, technically oriented subjects, languages, social science subjects, artwork subjects). Consequently, the authors deal with the methodological aspects of the use of online forms in foreign language teaching.    Methodology. To find answer to such questions as which educational form, school education or home schooling, is more preferred by English learners, what are the strengths and weaknesses of home schooling, which foreign language skills are being practiced via online Zoom lessons,  which foreign language skills are being practiced via worksheets, or which mobile applications are used to enlarge students` vocabulary range, a questionnaire survey was carried out. Respondents of the survey were English learners, secondary vocational school students,,aged from 16 to 20 year-olds.    Results and conclusions. Based on the analysis of the data recorded from the learners` responses to the particular questionnaire items as the most significant three weaknesses of the home schooling were identified technical problems, more homework and lack of social contacts, while as the main strengths were found out home comfort, sufficient sleeping time and less dense timetable

Author Correction: Deep learning algorithm predicts diabetic retinopathy progression in individual patients

A Correction to this paper has been published: https://doi.org/10.1038/s41746-020-00365-5

Baseline characteristics associated with early visual acuity gains after ranibizumab treatment for retinal vein occlusion

Abstract Background To identify baseline patient characteristics associated with early clinically significant visual acuity (VA) improvements within 3 months of treatment initiation in ranibizumab-treated patients with retinal vein occlusion (RVO) in the SHORE study. Methods Post hoc analysis of baseline patient characteristics in the randomized, open-label, vision examiner–masked SHORE phase 4 study that compared monthly versus pro re nata dosing of ranibizumab in patients with branch and central RVO. Patients who enrolled in SHORE fulfilled eligibility criteria per protocol (N = 202). SHORE data were retrospectively analyzed to identify baseline patient characteristics associated with early clinically significant improvements in VA, defined as improvement to a Snellen equivalent of 20/40 or better vision (≥ 69 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) or an increase in best-corrected VA (BCVA) of 15 or more ETDRS letters from baseline within 3 months of treatment initiation. Main outcome measures were BCVA gain of 15 or more ETDRS letters from baseline, Snellen equivalent of 20/40 or better vision, and baseline factors associated with early clinically significant improvement in BCVA. Results The median time for patients to achieve a BCVA of 20/40 or better was 59 days and the median time for patients to gain 15 or more ETDRS letters was 63 days. Better baseline BCVA (> 50 ETDRS letters/Snellen equivalent ≥ 20/100), greater baseline total macular volume (> 9.99 mm3), and presence of subretinal fluid at baseline were all associated with early improvement to 20/40 or better vision (ETDRS equivalent ≥ 69 letters; P < .0001, P = .02, and P = .03, respectively). Conclusions This retrospective analysis found that better BCVA, greater total macular volume, and presence of subretinal fluid at baseline were associated with more rapid vision gains. Clinicians may find these helpful when considering the likelihood of achieving early clinically significant VA improvements with ranibizumab in patients with RVO. Trial registration ClinicalTrials.gov NCT01277302

Local Treatment With Alpha-Melanocyte Stimulating Hormone Reduces Corneal Allorejection

Background Corneal grafting is by far the most common form of transplantation. Many grafts suffer from immune rejection and current therapies are associated with many side effects, requiring more effective and safe therapies. Alpha–melanocyte stimulating hormone (α–MSH) is a neuropeptide that suppresses host inflammatory defense mechanisms. The purpose of this study was to determine the role of local therapy with α-MSH on corneal allograft survival, and the mechanisms by which it may influence graft outcome. Methods Orthotopic corneal transplantation was performed, with recipients receiving subconjunctival α-MSH or sham injections twice weekly. Grafts were followed for 70 days and graft inflammation/opacification was compared between the two groups in a masked fashion. Graft infiltration and ocular gene expression of select inflammatory cytokines was evaluated at different timepoints. Additionally, allospecific delayed type hypersensitivity (DTH) was compared among the groups 3 weeks post transplantation. Results Results showed a significant increase in corneal graft survival in α-MSH-treated recipients as compared to controls. While 75% of allografts in α-MSH-treated hosts survived at 70 days, 43% survived in controls (p=0.04). Graft infiltration studies demonstrated a significant decrease in the number of mononuclear and polymorphonuclear cells in α-MSH-treated mice as compared to controls at days 7 and 14 after transplantation. Further, allospecific DTH and gene expression of interferon-γ and interleukin-2 showed a significantly reduced expression in α-MSH-treated mice as compared to controls. Conclusions In this study, we provide for the first time, in vivo evidence that treatment with local α-MSH may significantly reduce allorejection of orthotopic transplants

Spectral-Domain OCT Predictors of Visual Outcomes after Ranibizumab Treatment for Macular Edema Resulting from Retinal Vein Occlusion

PurposeTo evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE).DesignPost hoc analysis of prospective clinical trial data.ParticipantsTwo hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema.MethodsBaseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections.Main outcome measuresAssociation of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections.ResultsBefore therapy, worse baseline BCVA was associated with ERM presence (P&nbsp;= 0.0045), thicker SRF (P&nbsp;= 0.0006), larger intraretinal cysts (P&nbsp;= 0.0015), and higher percentage of DRIL (P &lt; 0.0001), percentage of ELM disruption (P &lt; 0.0001), percentage of EZ disruption (P&nbsp;= 0.0003), and percentage of IZ disruption (P&nbsp;= 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P &lt; 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P &lt; 0.0001) and worse baseline BCVA (P &lt; 0.0001).ConclusionsAlthough SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements