Effects of adding Tiotropium or Aclidinium as triple therapy using impulse oscillometry in COPD

INTRODUCTION: Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response. METHODS: Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2–3 weeks each. Measurements of IOS, spirometry, 6-min walk test, St George’s Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry. RESULTS: 13 patients were completed: mean age 69 years, FEV(1) 52 % predicted, FEV(1)/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5–R20) significantly improved with ACL. Visit-based FEV(1), and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV(1) and FEV(6) profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units. CONCLUSION: We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry

Genomic insights into neonicotinoid sensitivity in the solitary bee Osmia bicornis

This is the final version. Available from the publisher via the DOI in this record.The Osmia bicornis whole genome shotgun project has been deposited at DDBJ/ENA/GenBank under the accession MPJT00000000. The RNAseq data generated in this study has been deposited in the Sequence Read Archive (SRA) under accession SRP065762. Accession numbers of the bee P450 genes manually curated in this study are shown in S5 Table. All other relevant data are within the paper and its Supporting Information files.The impact of pesticides on the health of bee pollinators is determined in part by the capacity of bee detoxification systems to convert these compounds to less toxic forms. For example, recent work has shown that cytochrome P450s of the CYP9Q subfamily are critically important in defining the sensitivity of honey bees and bumblebees to pesticides, including neonicotinoid insecticides. However, it is currently unclear if solitary bees have functional equivalents of these enzymes with potentially serious implications in relation to their capacity to metabolise certain insecticides. To address this question, we sequenced the genome of the red mason bee, Osmia bicornis, the most abundant and economically important solitary bee species in Central Europe. We show that O. bicornis lacks the CYP9Q subfamily of P450s but, despite this, exhibits low acute toxicity to the N-cyanoamidine neonicotinoid thiacloprid. Functional studies revealed that variation in the sensitivity of O. bicornis to N-cyanoamidine and N-nitroguanidine neonicotinoids does not reside in differences in their affinity for the nicotinic acetylcholine receptor or speed of cuticular penetration. Rather, a P450 within the CYP9BU subfamily, with recent shared ancestry to the Apidae CYP9Q subfamily, metabolises thiacloprid in vitro and confers tolerance in vivo. Our data reveal conserved detoxification pathways in model solitary and eusocial bees despite key differences in the evolution of specific pesticide-metabolising enzymes in the two species groups. The discovery that P450 enzymes of solitary bees can act as metabolic defence systems against certain pesticides can be leveraged to avoid negative pesticide impacts on these important pollinators.Biotechnology and Biological Science Research Council (BBSRC)Bayer AGEuropean Research Council (ERC

Correcting the Site Frequency Spectrum for Divergence-Based Ascertainment

Comparative genomics based on sequenced referenced genomes is essential to hypothesis generation and testing within population genetics. However, selection of candidate regions for further study on the basis of elevated or depressed divergence between species leads to a divergence-based ascertainment bias in the site frequency spectrum within selected candidate loci. Here, a method to correct this problem is developed that obtains maximum-likelihood estimates of the unascertained allele frequency distribution using numerical optimization. I show how divergence-based ascertainment may mimic the effects of natural selection and offer correction formulae for performing proper estimation into the strength of selection in candidate regions in a maximum-likelihood setting

Patients' opinion on the barriers to diabetes control in areas of conflicts: The Iraqi example

<p>Abstract</p> <p>Background</p> <p>The health system in Iraq has undergone progressive decline since the embargo that followed the second gulf war in 1991. The aim of this study is to see barriers to glycemic control form the patient perspective, in a diabetic clinic in the south of Iraq.</p> <p>Methods</p> <p>A cross sectional study from the diabetes out-patient clinic in Al-Faiha general hospital in Basrah, South Iraq for the period from January to December 2007. The study includes diabetic patients whether type 1 or 2 if they have at least one year of follow up in the same clinic. Those with A1C ≥ 7% were interviewed by special questionnaire, that was filled in by the medical staff of the clinic. The subjects analyzed in this study were adults (≥ 18 years old) with previously diagnosed diabetes (n = 3522). The duration of diabetes range from 1 to 30 years.</p> <p>Results</p> <p>Mean A1C was 8.4 ± 2 percent, with 835(23.7%) patients with A1C less than 7% and 2688(76.3%) equal to or more than 7%. Of 3522 studied patients, 46.6% were men and 51.5% were women, with mean age of 53.78 ± 12.81 year and age range 18–97 years. Patient opinion for not achieving good glycemic control among 2688 patients with HbA1C ≥ 7% included the following. No drug supply from primary health care center (PHC) or drug shortage is a cause in 50.8% of cases, while drugs and or laboratory expense were the cause in 50.2%. Thirty point seven percent of patients said that they were unaware of diabetics complications and 20.9% think that diabetes is an untreatable disease. Thirty percent think that non-control of their diabetes is due to migration after the war. No electricity or erratic electricity, self-monitoring of blood glucose (SMBG) is not available, or strips were not available or could not be used, and illiteracy as a cause was seen in 15%, 10.8% and 9.9% respectively.</p> <p>Conclusion</p> <p>Our patients with diabetes mellitus declared that of the causes for poor glycemic control most of them related to the current health situation in Iraq.</p

The effect of intracoronary sodiumnitrite on the burden of ventricular arrhythmias following primary percutaneous coronary intervention for acute myocardial infarction (vol 266, pg 1, 2018)

This study was funded through the National Institute of Health Research (NIHR) (DRF-2011-04-080

A systematic review of frameworks for the interrelationships of mental health evidence and policy in low- and middle-income countries

Background: The interrelationships between research evidence and policy-making are complex. Different theoretical frameworks exist to explain general evidence–policy interactions. One largely unexplored element of these interrelationships is how evidence interrelates with, and influences, policy/political agenda-setting. This review aims to identify the elements and processes of theories, frameworks and models on interrelationships of research evidence and health policy-making, with a focus on actionability and agenda-setting in the context of mental health in low- and middle-income countries (LMICs). Methods: A systematic review of theories was conducted based on the BeHeMOTh search method, using a tested and refined search strategy. Nine electronic databases and other relevant sources were searched for peer-reviewed and grey literature. Two reviewers screened the abstracts, reviewed full-text articles, extracted data and performed quality assessments. Analysis was based on a thematic analysis. The included papers had to present an actionable theoretical framework/model on evidence and policy interrelationships, such as knowledge translation or evidence-based policy, specifically target the agenda-setting process, focus on mental health, be from LMICs and published in English. Results: From 236 publications included in the full text analysis, no studies fully complied with our inclusion criteria. Widening the focus by leaving out ‘agenda-setting’, we included ten studies, four of which had unique conceptual frameworks focusing on mental health and LMICs but not agenda-setting. The four analysed frameworks confirmed research gaps from LMICs and mental health, and a lack of focus on agenda-setting. Frameworks and models from other health and policy areas provide interesting conceptual approaches and lessons with regards to agenda-setting. Conclusion: Our systematic review identified frameworks on evidence and policy interrelations that differ in their elements and processes. No framework fulfilled all inclusion criteria. Four actionable frameworks are applicable to mental health and LMICs, but none specifically target agenda-setting. We have identified agenda-setting as a research theory gap in the context of mental health knowledge translation in LMICs. Frameworks from other health/policy areas could offer lessons on agenda-setting and new approaches for creating policy impact for mental health and to tackle the translational gap in LMICs

Environmental exposures and their genetic or environmental contribution to depression and fatigue: a twin study in Sri Lanka

Background There is very little genetically informative research identifying true environmental risks for psychiatric conditions. These may be best explored in regions with diverse environmental exposures. The current study aimed to explore similarities and differences in such risks contributing to depression and fatigue. Methods Home interviews assessed depression (lifetime-ever), fatigue and environmental exposures in 4,024 randomly selected twins from a population-based register in the Colombo district of Sri Lanka. Results Early school leaving and standard of living showed environmentally-mediated effects on depression, in men. In women, life events were associated with depression partly through genetic pathways (however, the temporal order is consistent with life events being an outcome of depression, as well as the other way around). For fatigue, there were environmentally mediated effects (through early school leaving and life events) and strong suggestions of family-environmental influences. Conclusions Compared to previous studies from higher-income countries, novel environmentally-mediated risk factors for depression and fatigue were identified in Sri Lanka. But as seen elsewhere, the association between life events and depression was partially genetically mediated in women. These results have implications for understanding environmental mechanisms around the world

Causes and importance of new particle formation in the present-day and pre-industrial atmospheres

New particle formation has been estimated to produce around half of cloud-forming particles in the present-day atmosphere, via gas-to-particle conversion. Here we assess the importance of new particle formation (NPF) for both the present-day and the pre-industrial atmospheres. We use a global aerosol model with parametrisations of NPF from previously published CLOUD chamber experiments involving sulphuric acid, ammonia, organic molecules and ions. We find that NPF produces around 67% of cloud condensation nuclei at 0.2% supersaturation (CCN0.2%) at the level of low clouds in the pre-industrial atmosphere (estimated uncertainty range 45-84%) and 54% in the present day (estimated uncertainty range 38-66%). Concerning causes, we find that the importance of biogenic volatile organic compounds (BVOCs) in NPF and CCN formation is greater than previously thought. Removing BVOCs and hence all secondary organic aerosol from our model reduces low-cloud-level CCN concentrations at 0.2% supersaturation by 26% in the present-day atmosphere and 41% in the pre-industrial. Around three-quarters of this reduction is due to the tiny fraction of the oxidation products of BVOCs that have sufficiently low volatility to be involved in NPF and early growth. Furthermore, we estimate that 40% of pre-industrial CCN0.2% are formed via ion-induced NPF, compared with 27% in the present-day, although we caution that the ion-induced fraction of NPF involving BVOCs is poorly measured at present. Our model suggests that the effect of changes in cosmic ray intensity on CCN is small and unlikely to be comparable to the effect of large variations in natural primary aerosol emissions

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Ventricular septal defect in a child with Alport syndrome: a case report

<p>Abstract</p> <p>Background</p> <p>Alport syndrome (AS) is a rare inherited disorder characterized by an inflammation of the kidneys and damage to the glomerular capillaries, ultimately leading to renal failure at an early age. To date, rare reports of cardiac involvement in AS have been described, due in the majority of cases to the higher risk of heart conduction abnormalities in these patients, at times requiring implantation of a transcutaneous pacemaker. An increased risk of hypertension is likewise commonly featured.</p> <p>Case presentation</p> <p>We report the case of a 17-year-old female affected by a very severe early form of AS. A previously unreported association of the syndrome with congenital heart disease (CHD), (in this case membranous ventricular septal defect), is also reported. A possible pathophysiological mechanism underlying the concomitant manifestation of these two disorders is suggested. Complications implicated in surgical treatment of CHD are described. Clinical and therapeutic management of AS with cardiovascular involvement are discussed, and a short literature review performed.</p> <p>Conclusions</p> <p>This first report of a cardiovascular association highlights the possible involvement of collagen mutations in the two pathologies. Even when drug-resistance appears to be responsible for the failure to control secondary hypertension in AS, clonidine may represent a safe, effective option in the normalization of high blood pressure.</p