Activity of tedizolid against gram-positive clinical isolates causing infections in Europe and surrounding areas (2014–2015)

Activities of tedizolid and comparators were evaluated against gram-positive isolates responsible for skin and skin structure infections, pneumonia, and bloodstream infections. Non-duplicate gram-positive isolates (8011) were collected from 20 European countries/regions.

Tedizolid (0.12?mg/L) showed similar results of minimum inhibitory concentration required to inhibit the growth of 50% of organisms (MIC₅₀) regardless of pathogen/group or infection type, except for coagulase-negative staphylococci, Enterococcus faecalis, and viridans group streptococci (VGS), against which tedizolid had MIC₅₀ values of 0.06, 0.25, and 0.06?mg/L, respectively. Similar results of tedizolid MIC₅₀ and minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC₉₀) (MIC_50/90, 0.12/0.12?mg/L) were obtained against methicillin-resistant Staphylococcus aureus and methicillin-susceptible S. aureus. Tedizolid, linezolid, and daptomycin were active against enterococci. Tedizolid (MIC₉₀, 0.12–0.25?mg/L), ceftaroline (MIC₉₀, 0.12?mg/L), and vancomycin (MIC₉₀, 0.25–0.5?mg/L) had the lowest MIC₉₀ values against Streptococcus pneumoniae and VGS, whereas ceftaroline (MIC₉₀, ≤0.015?mg/L), penicillin (MIC₉₀, ≤0.06?mg/L), ceftriaxone (MIC₉₀, ≤0.06–0.12?mg/L), and tedizolid (MIC₉₀, 0.12?mg/L) were the most potent against β-haemolytic streptococci.

Tedizolid displayed potent activity against gram-positive isolates from Europe, regardless of infection type.     

A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1

ABSTRACT

Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.

Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.

Materials and Methods: Case report.

Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.

Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.     

Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized,Double-Blind,Placebo-Controlled Study

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial ({"type":"clinical-trial","attrs":{"text":"NCT02207946","term_id":"NCT02207946"}}NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p = 0.003) and Week 8 (p = 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p = 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.