Advanced Manufacturing, Formulation and Microencapsulation of Therapeutic Phages.

Manufacturing and formulation of stable, high purity, and high dose bacteriophage drug products (DPs) suitable for clinical usage would benefit from improved process monitoring and control of critical process parameters that affect product quality attributes. Chemistry, Manufacturing, and Controls (CMC) for both upstream (USP) and downstream processes (DSP) need mapping of critical process parameters (CPP) and linking these to critical quality attributes (CQA) to ensure quality and consistency of phage drug substance (DS) and DPs development. Single-use technologies are increasingly becoming the go-to manufacturing option with benefits both for phage bioprocess development at the engineering run research stage and for final manufacture of the phage DS. Future phage DPs under clinical development will benefit from implementation of process analytical technologies (PAT) for better process monitoring and control. These are increasingly being used to improve process robustness (to reduce batch-to-batch variability) and productivity (yielding high phage titers). Precise delivery of stable phage DPs that are suitably formulated as liquids, gels, solid-oral dosage forms, and so forth, could significantly enhance efficacy of phage therapy outcomes. Pre-clinical development of phage DPs must include at an early stage of development, considerations for their formulation including their characterization of physiochemical properties (size, charge, etc.), buffer pH and osmolality, compatibility with regulatory approved excipients, storage stability (packaging, temperature, humidity, etc.), ease of application, patient compliance, ease of manufacturability using scalable manufacturing unit operations, cost, and regulatory requirements.

Spatial and chromatic properties of numerosity estimation in isolation and context.

Numerosity estimation around the subitizing range is facilitated by a shape-template matching process and shape-coding mechanisms are selective to visual features such as colour and luminance contrast polarity. Objects in natural scenes are often embedded within other objects or textured surfaces. Numerosity estimation is improved when objects are grouped into small clusters of the same colour, a phenomenon termed groupitizing, which is thought to leverage on the subitizing system. Here we investigate whether numerosity mechanisms around the subitizing range are selective to colour, luminance contrast polarity and orientation, and how spatial organisation of context and target elements modulates target numerosity estimation. Stimuli consisted of a small number (3-to-6) of target elements presented either in isolation or embedded within context elements. To examine selectivity to colour, luminance polarity and orientation, we compared target-only conditions in which all elements were either the same or different along one of these feature dimensions. We found comparable performance in the same and different feature conditions, revealing that subitizing mechanism do not depend on 'on-off' luminance-polarity, colour or orientation channel interactions. We also measured the effect of varying spatial organisation of (i) context, by arranging the elements either in a grid, mirror-symmetric, translation-symmetric or random; (ii) target, by placing the elements either mirror-symmetric, on the vertices of simple shapes or random. Our results indicate higher accuracy and lower RTs in the grid compared to all other context types, with mirror symmetric, translation and random arrangements having comparable effects on target numerosity. We also found improved performance with shape-target followed by symmetric and random target arrangements in the absence and presence of context. These findings indicate that numerosity mechanisms around the subitizing range are not selective to colour, luminance polarity and orientation, and that symmetric, translation and random contexts organisations inhibit target-numerosity encoding stronger than regular/grid context.