Unconventional ultra scale-down techniques for active pharmaceutical ingredient filtration and size reduction

The use of scale down devices for early-stage process development enables early availability of experimental data, indicative of large-scale processes. In this work, an automated ultra scale-down (USD) filtration and a shear device which when used together allow the study of the recovery of active pharmaceutical ingredients (API) of different crystal particle size distributions at 10s of milligram-scale. For an early understanding of the process interactions based on a simple DoE design, a pressure difference of 70 kPa was observed to be significant for the filtration process when the 5 m filter pore size is used. At all other conditions investigated, the outcomes of the USD filtration were compared with established laboratory-scale filters operating at 10-fold scale based on total working mass. Good comparability was obtained for samples with narrow PSD, while samples with larger PSD had reduced predictive capability. API of narrower PSD was achieved by using a USD shear device and applied mechanical force. For the shear stressed crystals using USD shear device, crystals were found to be robust to shear stress with a small amount of fines produced, and the impact of fines on filtration was not remarkable. Mechanically size reduced crystals produced a substantial amount of fines, which resulted in a considerable reduction of the filtrate flux and approximately ten-fold rise in specific cake resistance when compared with shear stressed crystals. In general, the PSD of the crystals were found to be critical to determining the filtration conditions such as pressure difference and filter pore size. As concluded in this study, PSD is directly related to filter pore size and inversely related to the pressure difference, as would be expected. The implementation of the automated USD filtration platform enables rapid-process understanding and reduces cost and time due to a reduced amount of materials. The data obtained shows similar process trends and are primarily indicative of process performance at a larger scale

Measurement of nuclear transparency ratios for protons and neutrons

This paper presents, for the first time, measurements of neutron transparency ratios for nuclei relative to C measured using the (e,e′n) reaction, spanning measured neutron momenta of 1.4 to 2.4 GeV/c. The transparency ratios were extracted in two kinematical regions, corresponding to knockout of mean-field nucleons and to the breakup of Short-Range Correlated nucleon pairs. The extracted neutron transparency ratios are consistent with each other for the two measured kinematical regions and agree with the proton transparencies extracted from new and previous (e,e′p) measurements, including those from neutron-rich nuclei such as lead. The data also agree with and confirm the Glauber approximation that is commonly used to interpret experimental data. The nuclear-mass-dependence of the extracted transparencies scales as Aα with α=−0.289±0.007, which is consistent with nuclear-surface dominance of the reactions

ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma a

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Characteristics of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) rRNA genes of Apis mellifera (Insecta: Hymenoptera): structure, organization, and retrotransposable elements

As an accompanying manuscript to the release of the honey bee genome, we report the entire sequence of the nuclear (18S, 5.8S, 28S and 5S) and mitochondrial (12S and 16S) ribosomal RNA (rRNA)-encoding gene sequences (rDNA) and related internally and externally transcribed spacer regions of Apis mellifera (Insecta: Hymenoptera: Apocrita). Additionally, we predict secondary structures for the mature rRNA molecules based on comparative sequence analyses with other arthropod taxa and reference to recently published crystal structures of the ribosome. In general, the structures of honey bee rRNAs are in agreement with previously predicted rRNA models from other arthropods in core regions of the rRNA, with little additional expansion in non-conserved regions. Our multiple sequence alignments are made available on several public databases and provide a preliminary establishment of a global structural model of all rRNAs from the insects. Additionally, we provide conserved stretches of sequences flanking the rDNA cistrons that comprise the externally transcribed spacer regions (ETS) and part of the intergenic spacer region (IGS), including several repetitive motifs. Finally, we report the occurrence of retrotransposition in the nuclear large subunit rDNA, as R2 elements are present in the usual insertion points found in other arthropods. Interestingly, functional R1 elements usually present in the genomes of insects were not detected in the honey bee rRNA genes. The reverse transcriptase products of the R2 elements are deduced from their putative open reading frames and structurally aligned with those from another hymenopteran insect, the jewel wasp Nasonia (Pteromalidae). Stretches of conserved amino acids shared between Apis and Nasonia are illustrated and serve as potential sites for primer design, as target amplicons within these R2 elements may serve as novel phylogenetic markers for Hymenoptera. Given the impending completion of the sequencing of the Nasonia genome, we expect our report eventually to shed light on the evolution of the hymenopteran genome within higher insects, particularly regarding the relative maintenance of conserved rDNA genes, related variable spacer regions and retrotransposable elements

Information and digital literacies; a review of concepts

A detailed literature reviewing, analysing the multiple and confusing concepts around the ideas of information literacy and digital literacy at the start of the millennium. The article was well-received, and is my most highly-cited work, with over 1100 citations

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar