AAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A

Charcot-Marie-Tooth disease 1 A (CMT1A) results from a duplication of the PMP22 gene in Schwann cells and a deficit of myelination in peripheral nerves. Patients with CMT1A have reduced nerve conduction velocity, muscle wasting, hand and foot deformations and foot drop walking. Here, we evaluate the safety and efficacy of recombinant adeno-associated viral vector serotype 9 (AAV2/9) expressing GFP and shRNAs targeting Pmp22 mRNA in animal models of Charcot-Marie-Tooth disease 1 A. Intra-nerve delivery of AAV2/9 in the sciatic nerve allowed widespread transgene expression in resident myelinating Schwann cells in mice, rats and non-human primates. A bilateral treatment restore expression levels of PMP22 comparable to wild-type conditions, resulting in increased myelination and prevention of motor and sensory impairments over a twelve-months period in a rat model of CMT1A. We observed limited off-target transduction and immune response using the intra-nerve delivery route. A combination of previously characterized human skin biomarkers is able to discriminate between treated and untreated animals, indicating their potential use as part of outcome measures.

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010–2016

Purpose. To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions. Methods. Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data. Results. Overall, 41,836 patients received ≥1 study drug in 2010–2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up (N = 30,745), 16.0% (N = 4,890) had only one pharmacy claim, especially for ranibizumab (60.9%). Switching occurred in 8.0% of users with ≥2 pharmacy claims (N = 33,637). The algorithms had an accuracy of 83.8 (95% CI: 79.7–87.3) concerning bilateral treatment and 72.3% (95% CI: 67.5–76.8) for DME. Conclusion. Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.

Comparison Total Joint Replacement (STAR) with Arthrodesis of the Ankle

Category: Ankle Arthritis Introduction/Purpose: Total joint replacement (TJR) and arthrodesis (A) are treatment options for severe osteoarthritis of the ankle. The aim of this study was to compare outcome (clinical and pedographic) of JTR (STAR, Stryker, Airview Boulevard, MN, USA) and A of the ankle. Methods: All patients that completed follow-up of at least 24 months after TJR and A of the ankle before November 5, 2017 were included in the study. The data was extracted from a prospectively acquired database starting November 1, 2011 including all operatively treated patient at the authors´ institution. Exclusion criteria were bilateral treatment (n=14), extensive additional procedures such as arthrodesis at other joints (n=54), A for revision of TJR (n=8), TJR exchange (n=10), and not completed minimum-24-month-follow-up (n=26). Preoperatively and at follow-up, radiographs and/or weight-bearing computed tomographies were obtained. Degenerative changes were classified in four degrees. Standard dynamic pedography was performed (percentage force at hindfoot and forefoot from force of entire foot). Visual-Analogue-Scale Foot and Ankle (VAS FA) and ankle range of motion for dorsi-/plantarflexion (ROM) were registered. All parameters were compared between TJR and A and between preoperatively and follow-up. Results: From October 11, 2011 until October 31, 2015, 36 TJR and 28 A were performed. Parameters (average values if not stated otherwise) for TJR/A were preoperatively age 61/52 years; 20(56%)/14(50%) male; height 171/175 cm; weight 83/87 kg; degree degenerative changes 3.5/3.6; ROM 5.6/0/22.8°//4.8/0/22.1°; percentage force hindfoot/forefoot 45.5/38.3//48.4/34.5; VAS FA 43.8/40.3. Follow-up time on average 35.8/33.1 and range 25.4-66.4/24.1-71.3 months. VAS FA at follow-up was 68.6/61.3; percentage force hindfoot/forefoot 64.3/22.3//53.5/28.5; ROM 15.4/0/33.6°//0/0/0. Parameters did not differ between TJR and A (each p>.05) except lower age for A, higher VAS FA, hindfoot force percentage and ROM for TJR at follow-up (each p<.05). VAS FA and pedography parameters improved for TJR and A between preoperatively and follow-up, ROM increased for TJR and decreased for A (each p<.05). Conclusion: TJR and A were performed in similar patient cohorts regarding demographic parameter (except lower age for A), degree of degenerative changes, ROM, pathological pedographic pattern, and validated clinical scores (VAS FA). Both improved pathological pedographic pattern and VAS FA at minimum follow-up of 24 months. TJR additionally improved ROM and showed better pedographic pattern (and not different than physiological pattern) and VAS FA than A. TJR resulted in better clinical outcome including ROM and pedographic pattern. Survival rate of TJR was 100% up to 5.5 years. In this study, TJR outperformed A for treatment of severe ankle osteoarthritis.