Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

Background: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2). We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. Methods The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. Fev$_1$ percent of predicted and Fev$_1$/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. Results: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator Fev$_1$ percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator Fev$_1$ percent of predicted and pre-bronchodilator Fev$_1$/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. Conclusions: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact

Internal and external cooling methods and their effect on body temperature, thermal perception and dexterity

© 2018 The Authors. Published by PLOS. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1371/journal.pone.0191416© 2018 Maley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity. Methods Ten male participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14C (CV14), evaporative cooling vest (CVEV), arm immersion in 10C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout. Results Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P0.05). Conclusion The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.This project is financially supported by the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

Bulk and element specific magnetism of the medium and high entropy Cantor-Wu alloys

Magnetic Compton scattering, x-ray magnetic circular dichroism spectroscopy and bulk magnetometry measurements are performed on a set of medium (NiFeCo and NiFeCoCr) and high (NiFeCoCrPd and NiFeCoCrMn) entropy Cantor-Wu alloys. The bulk spin momentum densities determined by magnetic Compton scattering are remarkably isotropic, and this is a consequence of the smearing of the electronic structure by disorder scattering of the electron quasiparticles. Non-zero x-ray magnetic circular dichroism signals are observed for every element in every alloy indicating differences in the populations of the majority and minority spin states implying finite magnetic moments. When Cr is included in the solid solution, the Cr spin moment is unambiguously antiparallel to the total magnetic moment, while a vanishingly small magnetic moment is observed for Mn, despite calculations indicating a large moment. Some significant discrepancies are observed between the experimental bulk and surface magnetic moments. Despite the lack of quantitative agreement, the element specific surface magnetic moments seem to be qualitatively reasonable

Does patient satisfaction of general practice change over a decade?

Background The Patient Participation Program (PPP) was a patient satisfaction survey endorsed by the Royal Australian College of General Practitioners and designed to assist general practitioners in continuous quality improvement (CQI). The survey was been undertaken by 3500 practices and over a million patients between 1994 and 2003. This study aimed to use pooled patient questionnaire data to investigate changes in satisfaction with primary care over time. Methods The results of 10 years of the PPP surveys were analyzed with respect to 10 variables including the year of completion, patient age, gender, practice size, attendance at other doctors, and whether the practice had previously undertaken the survey. Comparisons were made using Logistic Generalized Estimating Equations (LGEE). Results There was a very high level of satisfaction with general practice in Australia (99% of respondents). An independent indicator of satisfaction was created by pooling the results of 12 questions. This new indicator had a greater variance than the single overall satisfaction question. Participants were shown to have higher levels of satisfaction if they were male, older, did not attend other practitioners or the practice was small in size. A minimal improvement in satisfaction was detected in this pooled indicator for the second or third survey undertaken by a practice. There was however no statistically significant change in pooled satisfaction with the year of survey. Conclusion The very high level of satisfaction made it difficult to demonstrate change. It is likely that this and the presentation of results made it difficult for GPs to use the survey to improve their practices. A more useful survey would be more sensitive to detect negative patient opinions and provide integrated feedback to GPs. At present, there are concerns about the usefulness of the PPP in continuous quality improvement in general practice.James Allan, Peter Schattner, Nigel Stocks and Emmae Ramsa

Does patient satisfaction of general practice change over a decade?

Background The Patient Participation Program (PPP) was a patient satisfaction survey endorsed by the Royal Australian College of General Practitioners and designed to assist general practitioners in continuous quality improvement (CQI). The survey was been undertaken by 3500 practices and over a million patients between 1994 and 2003. This study aimed to use pooled patient questionnaire data to investigate changes in satisfaction with primary care over time. Methods The results of 10 years of the PPP surveys were analyzed with respect to 10 variables including the year of completion, patient age, gender, practice size, attendance at other doctors, and whether the practice had previously undertaken the survey. Comparisons were made using Logistic Generalized Estimating Equations (LGEE). Results There was a very high level of satisfaction with general practice in Australia (99% of respondents). An independent indicator of satisfaction was created by pooling the results of 12 questions. This new indicator had a greater variance than the single overall satisfaction question. Participants were shown to have higher levels of satisfaction if they were male, older, did not attend other practitioners or the practice was small in size. A minimal improvement in satisfaction was detected in this pooled indicator for the second or third survey undertaken by a practice. There was however no statistically significant change in pooled satisfaction with the year of survey. Conclusion The very high level of satisfaction made it difficult to demonstrate change. It is likely that this and the presentation of results made it difficult for GPs to use the survey to improve their practices. A more useful survey would be more sensitive to detect negative patient opinions and provide integrated feedback to GPs. At present, there are concerns about the usefulness of the PPP in continuous quality improvement in general practice.James Allan, Peter Schattner, Nigel Stocks and Emmae Ramsa

Rock fracture grouting with microbially induced carbonate precipitation

Microbially induced carbonate precipitation has been proposed for soil stabilization, soil strengthening and permeability reduction as an alternative to traditional cement and chemical grouts. In this paper we evaluate the grouting of fine aperture rock fractures with calcium carbonate, precipitated through urea hydrolysis, by the bacteria Sporosarcina pasteurii. Calcium carbonate was precipitated within a small-scale and a near field-scale (3.1 m2) artificial fracture consisting of a rough rock lower surfaces and clear polycarbonate upper surfaces. The spatial distribution of the calcium carbonate precipitation was imaged using time-lapse photography and the influence on flow pathways revealed from tracer transport imaging. In the large-scale experiment, hydraulic aperture was reduced from 276 μm to 22 μm, corresponding to a transmissivity reduction of 1.71x10-5 m2/s to 8.75x10-9 m2/s, over a period of 12 days under constantly flowing conditions. With a modified injection strategy a similar three orders of magnitude reduction in transmissivity was achieved over a period of three days. Calcium carbonate precipitated over the entire artificial fracture with strong adhesion to both upper and lower surfaces and precipitation was controlled to prevent clogging of the injection well by manipulating the injection fluid velocity. These experiments demonstrate that microbially induced carbonate precipitation can successfully be used to grout a fracture under constantly flowing conditions and may be a viable alternative to cement based grouts when a high level of hydraulic sealing is required and chemical grouts when a more durable grout is required

Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria