The impact of lamb and ewe mortality associated with dystocia on Australian and New Zealand sheep farms: A systematic review, meta-analysis and bio-economic model.

Dystocia contributes to lamb and ewe mortality in the periparturient period but impacts for extensive sheep production systems remain poorly understood. Here we show that lamb and ewe mortality associated with dystocia has important impacts on sheep production in Australia and New Zealand, and quantify financial impacts for the Australian sheep industry. A systematic review of the literature identified 11 publications published since 1990 that reported sheep mortality due to dystocia in Australia or New Zealand. Assumptions for ewe breeding flock structure and reproductive performance were based on Australian sheep industry data. The proportion of lamb mortality attributable to dystocia (including stillbirths and perinatal deaths with evidence of hypoxic injury) pooled across all studies (pooled proportional mortality ratio) was 47 % (95 % Confidence Interval (CI): 38, 55). Pooled proportional mortality ratio for Australian studies was 53 % (95 %CI: 47, 60), and for New Zealand studies was 35 % (95 %CI: 19, 51). Pooled proportional mortality ratio was similar for lambs born to Merino and non-Merino ewes, although more data are needed to determine effects of ewe breed independent of other factors. Pooled proportional mortality ratio was higher for single lambs (59 %; 95 % CI: 55, 63) than twin (47 %; 41, 54) or triplet (49 %; 46, 52) lambs. However, the number of dystocia-associated mortalities is higher for twin-born lambs than for singles because total mortality is higher for twin-born lambs. It is estimated that approximately 7.7 million lamb deaths and 297,500 ewe deaths per year are attributable to dystocia in Australia for the national flock of 38 million breeding ewes. The whole-farm bio-economic Model of an Integrated Dryland Agricultural System (MIDAS) was used to determine the impacts of dystocia-associated ewe and lamb mortality on Australian farm profit. Dystocia is estimated to reduce Australian national farm profit by AU$780 million or $23.00 per ewe mated based on an assumed lamb sale price of AU$6.50 per kg carcass weight. These estimates do not include the costs of reduced productivity for surviving ewes and lambs, intervention, post-farmgate impacts, delayed genetic progress, or impacts on animal welfare and access into sheep meat and wool markets. Reducing dystocia through improved genetics and sheep management will improve animal welfare and farm profit.

A visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS).

BACKGROUND: Vast volumes of data, coded through hierarchical terminologies (e.g., International Classification of Diseases, Tenth Revision-Clinical Modification [ICD10-CM], Medical Subject Headings [MeSH]), are generated routinely in electronic health record systems and medical literature databases. Although graphic representations can help to augment human understanding of such data sets, a graph with hundreds or thousands of nodes challenges human comprehension. To improve comprehension, new tools are needed to extract the overviews of such data sets. We aim to develop a visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS) as an online, and publicly accessible tool. The ultimate goals are to filter, summarize the health data sets, extract insights, compare and highlight the differences between various health data sets by using VIADS. The results generated from VIADS can be utilized as data-driven evidence to facilitate clinicians, clinical researchers, and health care administrators to make more informed clinical, research, and administrative decisions. We utilized the following tools and the development environments to develop VIADS: Django, Python, JavaScript, Vis.js, Graph.js, JQuery, Plotly, Chart.js, Unittest, R, and MySQL. RESULTS: VIADS was developed successfully and the beta version is accessible publicly. In this paper, we introduce the architecture design, development, and functionalities of VIADS. VIADS includes six modules: user account management module, data sets validation module, data analytic module, data visualization module, terminology module, dashboard. Currently, VIADS supports health data sets coded by ICD-9, ICD-10, and MeSH. We also present the visualization improvement provided by VIADS in regard to interactive features (e.g., zoom in and out, customization of graph layout, expanded information of nodes, 3D plots) and efficient screen space usage. CONCLUSIONS: VIADS meets the design objectives and can be used to filter, summarize, compare, highlight and visualize large health data sets that coded by hierarchical terminologies, such as ICD-9, ICD-10 and MeSH. Our further usability and utility studies will provide more details about how the end users are using VIADS to facilitate their clinical, research or health administrative decision making.

TIA: algorithms for development of identity-linked SNP islands for analysis by massively parallel DNA sequencing.

BACKGROUND: Single nucleotide polymorphisms (SNPs) located within the human genome have been shown to have utility as markers of identity in the differentiation of DNA from individual contributors. Massively parallel DNA sequencing (MPS) technologies and human genome SNP databases allow for the design of suites of identity-linked target regions, amenable to sequencing in a multiplexed and massively parallel manner. Therefore, tools are needed for leveraging the genotypic information found within SNP databases for the discovery of genomic targets that can be evaluated on MPS platforms. RESULTS: The SNP island target identification algorithm (TIA) was developed as a user-tunable system to leverage SNP information within databases. Using data within the 1000 Genomes Project SNP database, human genome regions were identified that contain globally ubiquitous identity-linked SNPs and that were responsive to targeted resequencing on MPS platforms. Algorithmic filters were used to exclude target regions that did not conform to user-tunable SNP island target characteristics. To validate the accuracy of TIA for discovering these identity-linked SNP islands within the human genome, SNP island target regions were amplified from 70 contributor genomic DNA samples using the polymerase chain reaction. Multiplexed amplicons were sequenced using the Illumina MiSeq platform, and the resulting sequences were analyzed for SNP variations. 166 putative identity-linked SNPs were targeted in the identified genomic regions. Of the 309 SNPs that provided discerning power across individual SNP profiles, 74 previously undefined SNPs were identified during evaluation of targets from individual genomes. Overall, DNA samples of 70 individuals were uniquely identified using a subset of the suite of identity-linked SNP islands. CONCLUSIONS: TIA offers a tunable genome search tool for the discovery of targeted genomic regions that are scalable in the population frequency and numbers of SNPs contained within the SNP island regions. It also allows the definition of sequence length and sequence variability of the target region as well as the less variable flanking regions for tailoring to MPS platforms. As shown in this study, TIA can be used to discover identity-linked SNP islands within the human genome, useful for differentiating individuals by targeted resequencing on MPS technologies.

Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists.

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

Whole Farm Net Greenhouse Gas Abatement from Establishing Kikuyu-Based Perennial Pastures in South-Western Australia.

On-farm activities that reduce GHG emissions or sequester carbon from the atmosphere to compensate for anthropogenic emissions are currently being evaluated by the Australian Government as carbon offset opportunities. The aim of this study was to examine the implications of establishing and grazing Kikuyu pastures, integrated as part of a mixed Merino sheep and cropping system, as a carbon offset mechanism. For the assessment of changes in net greenhouse gas emissions, results from a combination of whole farm economic and livestock models were used (MIDAS and GrassGro). Net GHG emissions were determined by deducting increased emissions from introducing this practice change (increased methane and nitrous oxide emissions due to higher stocking rates) from the soil carbon sequestered from growing the Kikuyu pasture. Our results indicate that livestock systems using perennial pastures may have substantially lower net GHG emissions, and reduced GHG intensity of production, compared with annual plant-based production systems. Soil carbon accumulation by converting 45% of arable land within a farm enterprise to Kikuyu-based pasture was determined to be 0.80 t CO2-e farm ha(-1) yr(-1) and increased GHG emissions (leakage) was 0.19 t CO2-e farm ha(-1) yr(-1). The net benefit of this practice change was 0.61 t CO2-e farm ha(-1) yr(-1) while the rate of soil carbon accumulation remains constant. The use of perennial pastures improved the efficiency of animal production almost eight fold when expressed as carbon dioxide equivalent emissions per unit of animal product. The strategy of using perennial pasture to improve production levels and store additional carbon in the soil demonstrates how livestock should be considered in farming systems as both sources and sinks for GHG abatement.

A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis.

A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.

Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase.

SAR studies led to the identification of 4-(3-benzoylamino-6-methyl-anilino)quinazolines as potent and selective inhibitors of p38 MAP kinase. Further optimisation led to the identification of a series of 4-(3-benzoylamino-6-methyl-anilino)pyrimidines as potent inhibitors of the p38 MAP kinase signalling pathway in vitro and in vivo.

Solid-state NMR studies of pharmaceutical solids in polymer matrices.

Biodegradable drug-delivery systems can be formulated to release drug for hours to years and have been used for the controlled release of medications in animals and humans. An important consideration in developing a drug-delivery matrix is knowledge of the long-term stability of the form of the drug and matrix after formulation and any changes that might occur to the drug throughout the delivery process. Solid-state NMR spectroscopy is an effective technique for studying the state of both the drug and the matrix. Two systems that have been studied using solid-state NMR spectroscopy are presented. The first system studied involved bupivacaine, a local anesthetic compound, which was incorporated into microspheres composed of tristearin and encapsulated using a solid protein matrix. Solid-state 13C NMR spectroscopy was used to investigate the solid forms of bupivacaine in their bulk form or as incorporated into the tristearin/protein matrix. Bupivacaine free base and bupivacaine-HCl have very different solid-state NMR spectra, indicating that the molecules of these compounds pack in different crystal forms. In the tristearin matrix, the drug form could be determined at levels as low as 1:100 (w/w), and the form of bupivacaine was identified upon loading into the tristearin/protein matrix. In the second case, the possibility of using solid-state 13C NMR spectroscopy to characterize biomolecules lyophilized within polymer matrices is evaluated by studying uniformly 13C-labeled asparagine (Asn) in 1:250 (w/w) formulations with poly(vinyl pyrrolidone) (PVP) and poly(vinyl alcohol) (PVA). This work shows the capability of solid-state NMR spectroscopy to study interactions between the amino acid and the polymer matrix for synthetic peptides and peptidomimetics containing selective 13C labeling at the Asn residue.

Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity.

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.