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Leena George,1 Adam Wright,1 Vijay Mistry,1 Amanda Sutcliffe,1 Latifa Chachi,1 Koirobi Haldar,1 Mohammadali Yavari Ramsheh,1 Matthew Richardson,1 René van der Merwe,2 Ubaldo Martin,3 Paul Newbold,3 Christopher E Brightling11Department of Respiratory Sciences, Institute for Lung Health, National Institute for Health Research Biomedical Research Centre, University of Leicester, Leicester, UK; 2Clinical Respiratory Management, MedImmune Ltd., Cambridge, UK; 3Global Medical Affairs, AstraZeneca, Gaithersburg, MD, USAAbstract: We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and Streptococcus pneumoniae were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens S. pneumoniae or Haemophilus influenzae. Thus, benralizumab may have an indirect effect upon airway bacterial load.Keywords: COPD, benralizumab, IL-5, bacterial load, S. pneumoniae, H. influenzae

René van der Merwe,1 Nestor A Molfino2,31Respiratory Clinical Development, MedImmune Ltd, Cambridge, UK; 2Respiratory Clinical Development, MedImmune, LLC, Gaithersburg, MD, USA, 3KaloBios Pharmaceuticals, South San Francisco, CA, USAAbstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Current therapies confer partial benefits either by incompletely improving airflow limitation or by reducing acute exacerbations, hence new therapies are desirable. In the absence of robust early predictors of clinical efficacy, the potential success of novel therapeutic agents in COPD will not entirely be known until the drugs enter relatively large and costly clinical trials. New predictive models in humans, and new study designs are being sought to allow for confirmation of pharmacodynamic and potentially clinically meaningful effects in early development. This review focuses on human challenge models with lipopolysaccharide endotoxin, ozone, and rhinovirus, in the early clinical development phases of novel therapeutic agents for the treatment and reduction of exacerbations in COPD.Keywords: chronic obstructive pulmonary disease, challenge models, therapy assessment

Background: Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. Methods: Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. Results: Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30 % to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. Conclusions: Our study demonstrated true levels of genetic diversity within an M. tuberculosis population and showed that genetic diversity may be re-defined when a selective pressure, such as drug exposure, is imposed on M. tuberculosis populations during the course of infection. This suggests that the genome of M. tuberculosis is more dynamic than previously thought, suggesting preparedness to respond to a changing environment. [ABSTRACT FROM AUTHOR]

Agricultural engineering applies existing knowledge to provide for humanity's greatest need: food for survival. This article presents an opportunity to augment existing agricultural engineering practices with industrial engineering techniques, with the aim of encouraging financial control during the expansion of assets on farms. Facility planning techniques are combined with a well-known enterprise engineering technique, the transformation roadmap, to develop a Farm Site Development Method (FSDM). The purpose of the FSDM is to provide method guidance in developing a facilities master plan to evolve farm facilities in a phased approach towards a future/saturation state. The article also presents an evaluation of the FSDM, via a practical demonstration at Waterfall Farm. [ABSTRACT FROM AUTHOR]