Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies

Effect of obesity on constant workrate exercise in hyperinflated men with COPD

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD.</p> <p>Methods</p> <p>Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET.</p> <p>Results and discussion</p> <p>FEV₁% predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO₂in L·min^-1was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories.</p> <p>Conclusions</p> <p>OB and OW patients with COPD had a higher peak VO₂than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.</p

Mechanisms of Orthopnoea in Patients with Advanced COPD.

Many patients with severe chronic obstructive pulmonary disease (COPD) report unpleasant respiratory sensation at rest, further amplified by adoption of supine position (orthopnoea). The mechanisms of this acute symptomatic deterioration are poorly understood.16 patients with advanced COPD and history of orthopnoea and 16 age- and sex-matched healthy controls (CTRL) underwent pulmonary function tests and detailed sensory-mechanical measurements including inspiratory neural drive (IND, diaphragm electromyography), oesophageal and gastric pressures in sitting and supine positions.Patients had severe airflow obstruction (FEV1: 40±18%predicted) and lung hyperinflation. Regardless of the position, patients had lower inspiratory capacity (IC) and higher IND for a given tidal volume (i.e. greater neuromechanical dissociation (NMD)), higher intensity of breathing discomfort, minute ventilation (⩒E) and breathing frequency (Fb) compared with CTRL (all p<0.05). In supine position in CTRL (versus sitting erect): IC increased (by 0.48L) with a small drop in ⩒E mainly due to reduced Fb (all p<0.05). By contrast, patients' IC remained unaltered, but dynamic lung compliance decreased (p<0.05) in the supine position. Breathing discomfort, inspiratory work of breathing, inspiratory effort, IND, NMD and neuro-ventilatory uncoupling all increased in COPD in the supine position (p<0.05), but not in CTRL. Orthopnoea was associated with acute changes in IND (r=0.65, p=0.01), neuro-ventilatory uncoupling (r=0.76, p=0.001) and NMD (r=0.73, p=0.002).In COPD, onset of orthopnoea coincided with an abrupt increase in elastic loading of the inspiratory muscles in recumbency in association with increased IND and greater neuromechanical dissociation of the respiratory system

Psychological distress is related to poor health behaviours in COPD and non-COPD patients: Evidence from the CanCOLD study

Background Patients with psychiatric disorders (depression, anxiety) are more likely to have poor health behaviours, including higher smoking and lower physical activity (PA) levels. Smoking is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD), and PA is critical for COPD management. However, no studies have assessed associations between psychological distress and these behaviours among patients with vs without COPD. This is a sub-analysis of the CanCOLD study that assessed the relationships between psychological disorders (depression, anxiety) and poor health behaviours (smoking, PA). Methods 717 COPD and 797 matched non-COPD individuals from the CanCOLD study, completed the Hospital Anxiety Depression Scale (HADS) to assess anxiety and depression. Smoking behaviour was self-reported pack-years smoking. The CHAMPS PA questionnaire determined calorific expenditure as a PA measure. Regressions determined relationships between anxiety/depression and health behaviours, adjusting for age, sex, BMI, GOLD stage and COPD status. Results Across the whole sample, we observed relationships between depression (β = 1.107 ± 0.197; 95%CI = 0.691–1.462; p < .001) and anxiety (β = 0.780 ± 0.170; 95%CI = 0.446–1.114; p < .001) and pack years. Higher depression (β = −0.220 ± 0.028; 95%CI = −0.275 to −0.165; p < .001) and anxiety (β = −0.091 ± 0.025; 95%CI = −0.139 to −0.043; p < .001) scores were related to lower PA. These associations were comparable across COPD and non-COPD patients. Conclusions Results showed that higher levels of anxiety and depression were related to higher cumulative smoking and lower levels of PA in patients with and without COPD, suggesting symptoms of psychological distress is similarly associated with poorer health behaviours in COPD and non-COPD individuals. Future studies need to determine if treating symptoms of psychological distress can improve health behaviours and outcomes in this population

International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database - the quality controlled standard tool for routine identification of human and animal pathogenic fungi

Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens.This study was supported by an National Health and Medical Research Council of Australia (NH&MRC) grant [#APP1031952] to W Meyer, S Chen, V Robert, and D Ellis; CNPq [350338/2000-0] and FAPERJ [E-26/103.157/2011] grants to RM Zancope-Oliveira; CNPq [308011/2010-4] and FAPESP [2007/08575-1] Fundacao de Amparo Pesquisa do Estado de So Paulo (FAPESP) grants to AL Colombo; PEst-OE/BIA/UI4050/2014 from Fundacao para a Ciencia e Tecnologia (FCT) to C Pais; the Belgian Science Policy Office (Belspo) to BCCM/IHEM; the MEXBOL program of CONACyT-Mexico, [ref. number: 1228961 to ML Taylor and [122481] to C Toriello; the Institut Pasteur and Institut de Veil le Sanitaire to F Dromer and D Garcia-Hermoso; and the grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG) to CM de Almeida Soares and JA Parente Rocha. I Arthur would like to thank G Cherian, A Higgins and the staff of the Molecular Diagnostics Laboratory, Division of Microbiology and Infectious Diseases, Path West, QEII Medial Centre. Dromer would like to thank for the technical help of the sequencing facility and specifically that of I, Diancourt, A-S Delannoy-Vieillard, J-M Thiberge (Genotyping of Pathogens and Public Health, Institut Pasteur). RM Zancope-Oliveira would like to thank the Genomic/DNA Sequencing Platform at Fundacao Oswaldo Cruz-PDTIS/FIOCRUZ [RPT01A], Brazil for the sequencing. B Robbertse and CL Schoch acknowledge support from the Intramural Research Program of the NIH, National Library of Medicine. T Sorrell's work is funded by the NH&MRC of Australia; she is a Sydney Medical School Foundation Fellow.info:eu-repo/semantics/publishedVersio

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p&lt;1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p&lt;5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.</p

The P2X1 receptor and platelet function

Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1 receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits