Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones

MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy

ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction(FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies inLeiden University Medical Center (LUMC) and Cincinnati Children’s Hospital MedicalCenter (CCHMC). CCHMC included ambulant patients, while LUMC included a mixedambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidalcurve using a mixed model with random slope to predict individual trajectories. The additivevalue of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age,6-minute walking test distances were smaller and VL FFs were correspondingly higher inLUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF forthe time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA inpatients with a 10% higher VL FF at any age. Although results should be confirmed in a largercohort with prospective determination of the clinical endpoint, this added predictive value ofVL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool inclinical trials.Development and application of statistical models for medical scientific researc

An integrated view of theiInfluence of temperature, pressure, and humidity on the stability of trimorphic cysteamine hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 degrees C. Its melting temperature was found at 67.3 +/- 0.5 degrees C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature composition phase diagram is presented that has been obtained with the unary pressure temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.Postprint (author's final draft

Higher MRI muscle fat fraction at similar age is associated with earlier loss of ambulation in Duchenne muscular dystrophy

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas