Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial.

INTRODUCTION The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. METHODS Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. RESULTS Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. CONCLUSION The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02818998

New applications for the Boris Spectral Deferred Correction algorithm for plasma simulations

The paper investigates two new use cases for the Boris Spectral Deferred Corrections (Boris-SDC) time integrator for plasma simulations. First, we show that using Boris-SDC as a particle pusher in an electrostatic particle-in-cell (PIC) code can, at least in the linear regime, improve simulation accuracy compared with the standard second order Boris method. In some instances, the higher order of Boris-SDC even allows a much larger time step, leading to modest computational gains. Second, we propose a modification of Boris-SDC for the relativistic regime. Based on an implementation of Boris-SDC in the RUNKO PIC code, we demonstrate for a relativistic Penning trap that Boris-SDC retains its high order of convergence for velocities ranging from 0.5c to >0.99c

Vision-related quality of life in patients with diabetic macular edema treated with intravitreal aflibercept: The AQUA Study

Purpose: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). Design: AQUA was a multicenter, open-label, single-arm, phase 4 study. Participants: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. Methods: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. Main outcome measures: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. Results: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. Conclusions: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11034-w

Selective intra-carotid blood cooling in acute ischemic stroke : a safety and feasibility study in an ovine stroke model

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model. Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes. Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups. Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy