A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV₁ profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting β₂-agonist, in patients with chronic obstructive pulmonary disease

Background: This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 mu g) in patients with chronic obstructive pulmonary disease (COPD). Methods: Patients received olodaterol 2 mu g twice daily (BID), 5 mu g BID, 5 mu g once daily (QD) and 10 mu g QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV, area under the curve from 0 to 12 h (AUC(0-12)) and area under the curve from 12 to 24 h (AUC(12-24)) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. Results: 47 patients were treated. All olodaterol doses provided significant increases in FEV, versus baseline (p < 0.001) and FEV, time profiles were nearly identical for olodaterol 5 and 10 mu g QD. Olodaterol 5 pg QD demonstrated improved FEV, AUC(0-12) and similar AUC(12-24) versus 2 mu g BID. Olodaterol 5 mu g QD showed slightly increased FEV, AUC(0-12) but lower AUC(12-24) compared to 5 mu g BID. Bronchodilation over 24 h was similar for olodaterol 5 pg QD and BID. All doses were well tolerated. Conclusions: Olodaterol 5 pg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 mu g BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 pg QD or 5 mu g BID)

Seroprevalence and risk factors for Neospora caninum in small dairy farms in central Chile

Indexación: Scopus.Objetivos. Proveer información sobre la seroprevalencia y factores de riesgo asociados a la infección por Neospora caninum en bovinos en Chile central. Materiales y métodos. La población estudiada corresponde a pequeñas lecherías que son parte de un programa gubernamental de Asistencia Técnica (SAT), en la región de O´Higgins en Chile central. Muestras de suero fueron recolectadas desde vacas en lactancia y analizadas mediante un kit comercial ELISA. Además, se aplicó un cuestionario a los dueños de los animales para la identificación de factores de riesgo a través de regresión logística. Resultados. Se identificó una prevalencia a nivel de granja del 67%, mientras que dentro de las granjas positivas, esta fue en promedio de 55%. El historial de abortos (p= 0.037, OR=5.09), la fuente de alimentación de perros (p= 0.0429, OR=6), la fuente de agua de bebida de las vacas (p=0.034, OR=4.5) y el manejo de los abortos (p=0.017, OR=7.43) fueron identificados como factores de riesgo para la infección. Conclusiones. Se observa una alta seroprevalencia de N. caninum en pequeños productores lecheros pertenecientes al SAT en Chile central. Los resultados presentados resaltan la necesidad de mejorar las acciones de vigilancia de esta enfermedad y el desarrollo de medidas preventivas para evitar las pérdidas asociadas a esta enfermedad.Objective. To provide information about seroprevalence and risk factors of Neospora caninum infection in bovines of central Chile. Material and Methods. The study population are small dairy farms that are part of a Government Technical Support Service (SAT) in the O'Higgins region in central Chile. Sera samples were collected from milking cows and analyzed by a commercial ELISA kit. Additionally, a questionnaire was applied to farmers to identify risk factors through logistic regression. Results. The farm level prevalence was found to be 67%, and within farms seroprevalence 55%. Abortion history (p= 0.037, OR=5.09), dogs feed source (p= 0.0429, OR=6), cattle drinking water source (p=0.034, OR=4.5) and abortions management (p=0.017, OR=7.43) were found as significant risk factors for infection. Conclusion. There is a high N. caninum seroprevalence in small SAT's dairy farms in O'Higgins region. These results highlight the need of improving N. caninum surveillance, and the development of preventive measures to avoid losses related with this disease.http://revistas.unicordoba.edu.co/index.php/revistamvz/article/view/92

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S.&nbsp;aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S.&nbsp;aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S.&nbsp;aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S.&nbsp;aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S.&nbsp;aureus

Patient-doctor continuity and diagnosis of cancer:electronic medical records study in general practice

BACKGROUND: Continuity of care may affect the diagnostic process in cancer but there is little research. AIM: To estimate associations between patient–doctor continuity and time to diagnosis and referral of three common cancers. DESIGN AND SETTING: Retrospective cohort study in general practices in England. METHOD: This study used data from the General Practice Research Database for patients aged ≥40 years with a diagnosis of breast, colorectal, or lung cancer. Relevant cancer symptoms or signs were identified up to 12 months before diagnosis. Patient–doctor continuity (fraction-of-care index adjusted for number of consultations) was calculated up to 24 months before diagnosis. Time ratios (TRs) were estimated using accelerated failure time regression models. RESULTS: Patient–doctor continuity in the 24 months before diagnosis was associated with a slightly later diagnosis of colorectal (time ratio [TR] 1.01, 95% confidence interval [CI] =1.01 to 1.02) but not breast (TR = 1.00, 0.99 to 1.01) or lung cancer (TR = 1.00, 0.99 to 1.00). Secondary analyses suggested that for colorectal and lung cancer, continuity of doctor before the index consultation was associated with a later diagnosis but continuity after the index consultation was associated with an earlier diagnosis, with no such effects for breast cancer. For all three cancers, most of the delay to diagnosis occurred after referral. CONCLUSION: Any effect for patient–doctor continuity appears to be small. Future studies should compare investigations, referrals, and diagnoses in patients with and without cancer who present with possible cancer symptoms or signs; and focus on ‘difficult to diagnose’ types of cancer

Development and validation of a high density SNP genotyping array for Atlantic salmon (Salmo salar)

BackgroundDense single nucleotide polymorphism (SNP) genotyping arrays provide extensive information on polymorphic variation across the genome of species of interest. Such information can be used in studies of the genetic architecture of quantitative traits and to improve the accuracy of selection in breeding programs. In Atlantic salmon (Salmo salar), these goals are currently hampered by the lack of a high-density SNP genotyping platform. Therefore, the aim of the study was to develop and test a dense Atlantic salmon SNP array. ResultsSNP discovery was performed using extensive deep sequencing of Reduced Representation (RR-Seq), Restriction site-Associated DNA (RAD-Seq) and mRNA (RNA-Seq) libraries derived from farmed and wild Atlantic salmon samples (n = 283) resulting in the discovery of &gt; 400 K putative SNPs. An Affymetrix Axiom&reg; myDesign Custom Array was created and tested on samples of animals of wild and farmed origin (n = 96) revealing a total of 132,033 polymorphic SNPs with high call rate, good cluster separation on the array and stable Mendelian inheritance in our sample. At least 38% of these SNPs are from transcribed genomic regions and therefore more likely to include functional variants. Linkage analysis utilising the lack of male recombination in salmonids allowed the mapping of 40,214 SNPs distributed across all 29 pairs of chromosomes, highlighting the extensive genome-wide coverage of the SNPs. An identity-by-state clustering analysis revealed that the array can clearly distinguish between fish of different origins, within and between farmed and wild populations. Finally, Y-chromosome-specific probes included on the array provide an accurate molecular genetic test for sex. ConclusionsThis manuscript describes the first high-density SNP genotyping array for Atlantic salmon. This array will be publicly available and is likely to be used as a platform for high-resolution genetics research into traits of evolutionary and economic importance in salmonids and in aquaculture breeding programs via genomic selection

Impact of Donor Milk on Short- and Long-Term Growth of Very Low Birth Weight Infants

Mother’s own milk (MOM) reduces the risk of morbidities in very low birth weight (VLBW) infants. When MOM is unavailable, donor breastmilk (DM) is used, with unclear impact on short- and long-term growth. This retrospective analysis compared anthropometric data at six time points from birth to 20–24 months corrected age in VLBW infants who received MOM supplements of preterm formula (n = 160) versus fortified DM (n = 161) during neonatal intensive care unit (NICU) hospitalization. The cohort was 46% female; mean birth weight and gestational age (GA) were 998 g and 27.3 weeks. Multilevel linear growth models assessed changes in growth z-scores short-term (to NICU discharge) and long-term (post-discharge), controlling for amount of DM or formula received in first 28 days of life, NICU length of stay (LOS), birth GA, and sex. Z-scores for weight and length decreased during hospitalization but increased for all parameters including head circumference post-discharge. Short-term growth was positively associated with LOS and birth GA. A higher preterm formula proportion, but not DM proportion, was associated with slower rates of decline in short-term growth trajectories, but feeding type was unrelated to long-term growth. In conclusion, controlling for total human milk fed, DM did not affect short- or long-term growth

Electrical lithosphere beneath the Kaapvaal craton, southern Africa

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): B04105, doi:10.1029/2010JB007883.A regional-scale magnetotelluric (MT) experiment across the southern African Kaapvaal craton and surrounding terranes, called the Southern African Magnetotelluric Experiment (SAMTEX), has revealed complex structure in the lithospheric mantle. Large variations in maximum resistivity at depths to 200–250 km relate directly to age and tectonic provenance of surface structures. Within the central portions of the Kaapvaal craton are regions of resistive lithosphere about 230 km thick, in agreement with estimates from xenolith thermobarometry and seismic surface wave tomography, but thinner than inferred from seismic body wave tomography. The MT data are unable to discriminate between a completely dry or slightly “damp” (a few hundred parts per million of water) structure within the transitional region at the base of the lithosphere. However, the structure of the uppermost ∼150 km of lithosphere is consistent with enhanced, but still low, conductivities reported for hydrous olivine and orthopyroxene at levels of water reported for Kaapvaal xenoliths. The electrical lithosphere around the Kimberley and Premier diamond mines is thinner than the maximum craton thickness found between Kimberley and Johannesburg/Pretoria. The mantle beneath the Bushveld Complex is highly conducting at depths around 60 km. Possible explanations for these high conductivities include graphite or sulphide and/or iron metals associated with the Bushveld magmatic event. We suggest that one of these conductive phases (most likely melt-related sulphides) could electrically connect iron-rich garnets in a garnet-rich eclogitic composition associated with a relict subduction slab.In addition to the funding and logistical support provided by SAMTEX consortium members, this work is also supported by research grants from the National Science Foundation (EAR‐0309584 and EAR‐0455242 through the Continental Dynamics Program), the Department of Science and Technology, South Africa, and Science Foundation of Ireland (grant 05/RFP/ GEO001)

Characterisation of QTL-linked and genome-wide restriction site-associated DNA (RAD) markers in farmed Atlantic salmon

Background: Restriction site-associated DNA sequencing (RAD-Seq) is a genome complexity reduction technique that facilitates large-scale marker discovery and genotyping by sequencing. Recent applications of RAD-Seq have included linkage and QTL mapping with a particular focus on non-model species. In the current study, we have applied RAD-Seq to two Atlantic salmon families from a commercial breeding program. The offspring from these families were classified into resistant or susceptible based on survival/mortality in an Infectious Pancreatic Necrosis (IPN) challenge experiment, and putative homozygous resistant or susceptible genotype at a major IPN-resistance QTL. From each family, the genomic DNA of the two heterozygous parents and seven offspring of each IPN phenotype and genotype was digested with the SbfI enzyme and sequenced in multiplexed pools. Results: Sequence was obtained from approximately 70,000 RAD loci in both families and a filtered set of 6,712 segregating SNPs were identified. Analyses of genome-wide RAD marker segregation patterns in the two families suggested SNP discovery on all 29 Atlantic salmon chromosome pairs, and highlighted the dearth of male recombination. The use of pedigreed samples allowed us to distinguish segregating SNPs from putative paralogous sequence variants resulting from the relatively recent genome duplication of salmonid species. Of the segregating SNPs, 50 were linked to the QTL. A subset of these QTL-linked SNPs were converted to a high-throughput assay and genotyped across large commercial populations of IPNV-challenged salmon fry. Several SNPs showed highly significant linkage and association with resistance to IPN, and population linkage-disequilibrium-based SNP tests for resistance were identified. Conclusions: We used RAD-Seq to successfully identify and characterise high-density genetic markers in pedigreed aquaculture Atlantic salmon. These results underline the effectiveness of RAD-Seq as a tool for rapid and efficient generation of QTL-targeted and genome-wide marker data in a large complex genome, and its possible utility in farmed animal selection programs