Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD)

Objectives: The optimal method of identifying people with chronic obstructive pulmonary disease (COPD) from electronic primary care records is not known. We assessed the accuracy of different approaches using the Clinical Practice Research Datalink, a UK electronic health record database. Setting: 951 participants registered with a CPRD practice in the UK between 1 January 2004 and 31 December 2012. Individuals were selected for ≥1 of 8 algorithms to identify people with COPD. General practitioners were sent a brief questionnaire and additional evidence to support a COPD diagnosis was requested. All information received was reviewed independently by two respiratory physicians whose opinion was taken as the gold standard. Primary outcome measure: The primary measure of accuracy was the positive predictive value (PPV), the proportion of people identified by each algorithm for whom COPD was confirmed. Results: 951 questionnaires were sent and 738 (78%) returned. After quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms including a specific COPD diagnostic code performed well. Using a diagnostic code alone, the PPV was 86.5% (77.5-92.3%) while requiring a diagnosis plus spirometry plus specific medication; the PPV was slightly higher at 89.4% (80.7-94.5%) but reduced case numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2-44.4%). Conclusions: Patients with COPD can be accurately identified from UK primary care records using specific diagnostic codes. Requiring spirometry or COPD medications only marginally improved accuracy. The high accuracy applies since the introduction of an incentivised disease register for COPD as part of Quality and Outcomes Framework in 2004

Pulmonary oxygen uptake and muscle deoxygenation kinetics during recovery in trained and untrained male adolescents

Previous studies have demonstrated faster pulmonary oxygen uptake ( V ˙ O 2 ) kinetics in the trained state during the transition to and from moderate-intensity exercise in adults. Whilst a similar effect of training status has previously been observed during the on-transition in adolescents, whether this is also observed during recovery from exercise is presently unknown. The aim of the present study was therefore to examine V ˙ O 2 kinetics in trained and untrained male adolescents during recovery from moderate-intensity exercise. 15 trained (15 ± 0.8 years, V ˙ O 2max 54.9 ± 6.4 mL kg−1 min−1) and 8 untrained (15 ± 0.5 years, V ˙ O 2max 44.0 ± 4.6 mL kg−1 min−1) male adolescents performed two 6-min exercise off-transitions to 10 W from a preceding “baseline” of exercise at a workload equivalent to 80% lactate threshold; V ˙ O 2 (breath-by-breath) and muscle deoxyhaemoglobin (near-infrared spectroscopy) were measured continuously. The time constant of the fundamental phase of V ˙ O 2 off-kinetics was not different between trained and untrained (trained 27.8 ± 5.9 s vs. untrained 28.9 ± 7.6 s, P = 0.71). However, the time constant (trained 17.0 ± 7.5 s vs. untrained 32 ± 11 s, P < 0.01) and mean response time (trained 24.2 ± 9.2 s vs. untrained 34 ± 13 s, P = 0.05) of muscle deoxyhaemoglobin off-kinetics was faster in the trained subjects compared to the untrained subjects. V ˙ O 2 kinetics was unaffected by training status; the faster muscle deoxyhaemoglobin kinetics in the trained subjects thus indicates slower blood flow kinetics during recovery from exercise compared to the untrained subjects

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Comparison of conventional direct and enrichment culture methods for Erysipelothrix spp. from experimentally and naturally infected swine

The objective of the current study was to compare the diagnostic performance of a direct isolation method for Erysipelothrix spp. with a broth-based enrichment technique. Samples were obtained from three sources: 1) experimentally inoculated pigs, 2) porcine tissue samples submitted to the Iowa State University Veterinary Diagnostic Laboratory (Ames, IA), and 3) tissues from condemned carcasses at an abattoir. Culture plates from direct isolation and broth-based technique were evaluated for growth at 24 and 48 hr. Results indicated that the broth enrichment method was markedly more sensitive for the isolation of Erysipelothrix spp. To the authors' knowledge, this is the first comparison of direct culture and broth-based enrichment methods for the isolation of Erysipelothrix spp. Interestingly, in several samples, a Gram-positive bacterium with almost identical growth characteristics to Erysipelothrix spp. was detected and identified as a Vagococcus sp. through 16S ribosomal RNA gene sequencing. The results of this study indicate that the brothbased enrichment method should be used for the isolation of Erysipelothrix spp. from clinical samples with a history suggestive of erysipelas and that Vagococcus spp. is potentially an important differential diagnosis

Northern Eurasia Future Initiative (NEFI): facing the challenges and pathways of global change in the 21st century

During the past several decades, the Earth system has changed significantly, especially across Northern Eurasia. Changes in the socio-economic conditions of the larger countries in the region have also resulted in a variety of regional environmental changes that can have global consequences. The Northern Eurasia Future Initiative (NEFI) has been designed as an essential continuation of the Northern Eurasia Earth Science Partnership Initiative (NEESPI), which was launched in 2004. NEESPI sought to elucidate all aspects of ongoing environmental change, to inform societies and, thus, to better prepare societies for future developments. A key principle of NEFI is that these developments must now be secured through science-based strategies co-designed with regional decision makers to lead their societies to prosperity in the face of environmental and institutional challenges. NEESPI scientific research, data, and models have created a solid knowledge base to support the NEFI program. This paper presents the NEFI research vision consensus based on that knowledge. It provides the reader with samples of recent accomplishments in regional studies and formulates new NEFI science questions. To address these questions, nine research foci are identified and their selections are briefly justified. These foci include: warming of the Arctic; changing frequency, pattern, and intensity of extreme and inclement environmental conditions; retreat of the cryosphere; changes in terrestrial water cycles; changes in the biosphere; pressures on land-use; changes in infrastructure; societal actions in response to environmental change; and quantification of Northern Eurasia's role in the global Earth system. Powerful feedbacks between the Earth and human systems in Northern Eurasia (e.g., mega-fires, droughts, depletion of the cryosphere essential for water supply, retreat of sea ice) result from past and current human activities (e.g., large scale water withdrawals, land use and governance change) and potentially restrict or provide new opportunities for future human activities. Therefore, we propose that Integrated Assessment Models are needed as the final stage of global change assessment. The overarching goal of this NEFI modeling effort will enable evaluation of economic decisions in response to changing environmental conditions and justification of mitigation and adaptation efforts