Nonaminoglycoside compounds induce readthrough of nonsense mutations

Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for HTS. The assay is luciferase independent. We screened ∼34,000 compounds and identified 12 low-molecular-mass nonaminoglycosides with potential PTC-readthrough activity. From these, two leading compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated readthrough activity in mdx mouse myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein

The burden of illness in initiating intermittent catheterization: an analysis of German health care claims data

Background: Intermittent catheterization (IC) is a common medical technique to drain urine from the bladder when this is no longer possible by natural means. The objective of this study was to evaluate the standard of care and the burden of illness in German individuals who perform intermittent catheterization and obtain recommendations for improvement of care. Methods: A descriptive study with a retrospective, longitudinal cohort design was conducted using the InGef research database from the German statutory health insurance claims data system. The study consisted of individuals with initial IC use in 2013-2015. Results: Within 3 years 1100 individuals with initial IC were identified in the database (similar to 19,000 in the German population). The most common IC indications were urologic diseases, spinal cord injury, Multiple Sclerosis and Spina Bifida. Urinary tract infections (UTI) were the most frequent complication occurring 1 year before index (61%) and in follow-up (year 1 60%; year 2 50%). Resource use in pre-index including hospitalizations (65%), length of stay (12.8 +/- 20.0 days), physician visits (general practitioner: 15.2 +/- 29.1), prescriptions of antibiotics (71%) and healthcare costs (euro17,950) were high. Comorbidities, complications, and healthcare resource use were highest 1 year before index, decreasing from first to second year after index. Conclusions: The data demonstrated that prior to initial catheterization, IC users experienced UTIs and high healthcare utilization. While this demonstrates a potential high burden of illness prior to initial IC, UTIs also decreased over time, suggesting that IC use may have a positive influence. The findings also showed that after the first year of initial catheterization the cost decreased. Further studies are needed to better understand the extent of the burden for IC users compared to non-IC users

A Patient-Centric Tool to Facilitate Goal Attainment Scaling in Neurogenic Bladder and Bowel Dysfunction: Path to Individualization

Contains fulltext : 231588.pdf (Publisher’s version ) (Open Access

Postauthorization safety surveillance study of antihaemophilic factor (recombinant) reconstituted in 2 mL sterile water for injection in children with haemophilia A

International audienceIntroduction - Antihaemophilic factor (recombinant) (rAHF; ADVATE ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. Aim - To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. Methods - This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. Results - Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. Conclusion - In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL