Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Examination of the influence of F6H10 fluorinated diblocks on DPPC liposomes

The interactions of unilamellar vesicles obtained by the incorporation of (1,2,3,4,5,6)-tridecafluoro-hexadecane (F6H10 diblock) to dipalmitophosphatidyl-choline (DPPC), with Gd3+, Ca(2+)supercript stop, Na+ ions were studied by electrophoretic measurements, dynamic light scattering and differential scanning calorimetry (DSC). Electrophoretic mobility measurements on unilamellar vesicles as a function of ion concentrations show that the vesicles adsorb the different ions employed. DSC has been used to determine the effect of diblock on the transition temperature (T-c) and on the change of enthalpy (Delta H-c) associated with the process

Enhancing CaP Biomimetic Growth on TiO₂ Cuboids Nanoparticles via Highly Reactive Facets

Pure decahedral anatase TiO₂ particles with high content of reactive {001} facets were obtained from titanium­(IV) tetrachloride (TiCl₄) using a microemulsions droplet system at specific conditions as chemical microreactor. The product was systematically characterized by X-ray diffraction, field-emission scanning and transmission electron microscopy (FE-SEM, TEM), N₂ adsorption–desorption isotherms, FT-IR and UV–vis spectroscopy, and photoluminescence studies. The obtained cuboids around 90 nm in size have a uniform and dense surface morphology with a BET specific surface area of 11.91 m² g^–1 and a band gap energy (3.18 eV) slightly inferior to the anatase dominated by the less-reactive {101} surface (3.20 eV). The presence of reactive facets on titania anatase favors the biomimetic growth of amorphous tricalcium phosphate after the first day of immersion in simulated human plasma. The results presented here can facilitate and improve the integration of anchored implants and enhance the biological responses to the soft tissues

Manipulation of Mg²⁺–Ca²⁺ Switch on the Development of Bone Mimetic Hydroxyapatite

Ionic substitution can affect essential physicochemical properties leading to a specific biological behavior upon implantation. Therefore, it has been proposed as a tool to increase the biological efficiency of calcium phosphate based materials. In the following study, we have evaluated the contribution of an important cation in nature, Mg²⁺, into the structure of previously studied biocompatible and biodegradable hydroxyapatite (HA) nanorods and its subsequent effect on its chemical, morphology, and bone mimetic articulation. Mg²⁺-substituted HA samples were synthesized by an aqueous wet-chemical precipitation method, followed by an hydrothermal treatment involving a Mg²⁺ precursor that partially replace Ca²⁺ ions into HA crystal lattice; Mg²⁺ concentrations were modulated to obtain a nominal composition similar to that exists in calcified tissues. Hydrothermally synthesized Mg²⁺-substituted HA nanoparticles were characterized by X-ray powder diffraction, FT-NIR and EDX spectroscopies, field emission scanning and high resolution transmission electron microscopies (FE-SEM, H-TEM). Molecular modeling combining ab initio methods and power diffraction data were also performed. Results showed that Mg²⁺-substitution promoted the formation of calcium deficient HA (cdHA) where Mg²⁺ replacement is energetically favored at Ca(1) position in a limited and specific amount directing the additional Mg²⁺ toward the surface of the crystal. The control of Mg²⁺ incorporation into HA nanorods gave rise to a tailored crystallinity degree, cell parameters, morphology, surface hydration, solubility, and degradation properties in a dose-replacement dependent manner. The obtained materials show qualities that conjugated together to drive an optimal in vitro cellular viability, spreading, and proliferation confirming their biocompatibility. In addition, an improved adhesion of osteoblast was evidenced after Mg²⁺–Ca²⁺ substitution