The process of adhering to aerosol therapy in adolescents with cystic fibrosis: patient and parent perspectives

Advances in medicine and healthcare have resulted in significant improvements for those children and adolescents living with a chronic health condition. However, the treatments prescribed will only work if they are taken. Rates of adherence to treatment in cystic fibrosis are low. This is especially true for adherence to aerosol therapy, a particular concern considering the reliance on aerosol therapy for the treatment of Pseudomonas aeruginosa. The advent of Adaptive Aerosol Delivery™ (AAD) technology has enabled accurate and objective measurement of adherence to aerosol therapy treatment. However, the factors which influence the process of adhering to aerosol therapy remain largely elusive. Therefore, the current study aims to qualitatively explore the process of adhering to aerosol therapy in a clinical sample of adolescents with CF from both a patient and parent perspective. In addition, objective data downloaded from an AAD device (the I-neb™, Respironics, Chichester, UK) will be used to cue reflections on actual events around adherence. 12 participants were interviewed (six parent-child dyads). The participating adolescents were all aged between 11 and 16 years and had a CF diagnosis. There were five mothers and one father who took part. The parent and adolescent data were analysed separately using the Grounded Theory Method. Nine core categories for the parent data and nine core categories for the adolescent data were developed into a coherent framework and represented as a theoretical formulation which described the process of adhering to aerosol therapy from both a parent and adolescent patient perspective. The theoretical formulation highlights the complexity involved and details the numerous interacting biological, psychological, social and environmental influences on adherence to aerosol therapy. These findings are discussed in relation to the existing literature and clinical implications are considered. The results of the current study complement and extend previous research on adherence in CF

Quarterly Economic Commentary, Summer 2017.

2017 has seen certain countervailing trends emerge as to the overall performance of the Irish economy. On the positive side, labour market data illustrate that the pace of employment creation and subsequent reduction in unemployment increased in the present year. In the previous Commentary, we had believed the Irish economy would experience an unemployment rate of just under 5.5 per cent by the end of 2018, we now believe this will happen earlier in that year. While most sectors of the economy are experiencing employment growth, the construction sector, along with the information and communications sector, registers the largest recent increase

Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation

Lentiviral vector mediated modification of mesenchymal stem cells & enhanced survival in an in vitro model of ischaemia

Introduction: A combination of gene and cell therapies has the potential to significantly enhance the therapeutic value of mesenchymal stem cells (MSCs). The development of efficient gene delivery methods is essential if MSCs are to be of benefit using such an approach. Achieving high levels of transgene expression for the required period of time, without adversely affecting cell viability and differentiation capacity, is crucial. In the present study, we investigate lentiviral vector-mediated genetic modification of rat bone-marrow derived MSCs and examine any functional effect of such genetic modification in an in vitro model of ischaemia. Methods: Transduction efficiency and transgene persistence of second and third generation rHIV-1 based lentiviral vectors were tested using reporter gene constructs. Use of the rHIV-pWPT-EF1-alpha-GFP-W vector was optimised in terms of dose, toxicity, cell species, and storage. The in vivo condition of ischaemia was modelled in vitro by separation into its associated constituent parts i.e. hypoxia, serum and glucose deprivation, in which the effect of therapeutic gene over-expression on MSC survival was investigated. Results: The second generation lentiviral vector rHIV-pWPT-EF1-alpha-GFP-W, was the most efficient and provided the most durable transgene expression of the vectors tested. Transduction with this vector did not adversely affect MSC morphology, viability or differentiation potential, and transgene expression levels were unaffected by cryopreservation of transduced cells. Over-expression of HSP70 resulted in enhanced MSC survival and increased resistance to apoptosis in conditions of hypoxia and ischaemia. MSC differentiation capacity was significantly reduced after oxygen deprivation, but was preserved with HSP70 over-expression. Conclusions: Collectively, these data validate the use of lentiviral vectors for efficient in vitro gene delivery to MSCs and suggest that lentiviral vector transduction can facilitate sustained therapeutic gene expression, providing an efficient tool for ex vivo MSC modification. Furthermore, lentiviral mediated over-expression of therapeutic genes in MSCs may provide protection in an ischaemic environment and enable MSCs to function in a regenerative manner, in part through maintaining the ability to differentiate. This finding may have considerable significance in improving the efficacy of MSC-based therapies

Cool Jupiters greatly outnumber their toasty siblings : Occurrence rates from the Anglo-Australian Planet Search

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society ©2019 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.Our understanding of planetary systems different to our own has grown dramatically in the past 30 yr. However, our efforts to ascertain the degree to which the Solar system is abnormal or unique have been hindered by the observational biases inherent to the methods that have yielded the greatest exoplanet hauls. On the basis of such surveys, one might consider our planetary system highly unusual - but the reality is that we are only now beginning to uncover the true picture. In this work, we use the full 18-yr archive of data from the Anglo-Australian Planet Search to examine the abundance of 'cool Jupiters' - analogues to the Solar system's giant planets, Jupiter and Saturn. We find that such planets are intrinsically far more common through the cosmos than their siblings, the hot Jupiters.We find that the occurrence rate of such 'cool Jupiters' is 6.73 +2.09 -1.13 per cent, almost an order of magnitude higher than the occurrence of hot Jupiters (at 0.84 +0.70 -0.20 per cent). We also find that the occurrence rate of giant planets is essentially constant beyond orbital distances of ~1 au. Our results reinforce the importance of legacy radial velocity surveys for the understanding of the Solar system's place in the cosmos.Peer reviewe

Association Between Residential Greenness and Cardiovascular Disease Risk

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on β-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity

Effects and mechanisms of action of sildenafil citrate in human chorionic arteries

Objectives Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. Study Design Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. Results Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. Conclusion Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO

Peptide-PEG Amphiphiles as Cytophobic Coatings for Mammalian and Bacterial Cells

SummaryAmphiphilic macromolecules containing a polystyrene-adherent peptide domain and a cell-repellent poly(ethylene glycol) domain were designed, synthesized, and evaluated as a cytophobic surface coating. Such cytophobic, or cell-repellent, coatings are of interest for varied medical and biotechnological applications. The composition of the polystyrene binding peptide domain was identified using an M13 phage display library. ELISA and atomic force spectroscopy were used to evaluate the binding affinity of the amphiphile peptide domain to polystyrene. When coated onto polystyrene, the amphiphile reduced cell adhesion of two distinct mammalian cell lines and pathogenic Staphylococcus aureus strains

Incidence, risk factors and outcomes of submacular haemorrhage with loss of vision in neovascular age-related macular degeneration in daily clinical practice: data from the FRB! registry

PURPOSE The main purpose of the study was to report the estimated incidence, cumulative rate, risk factors and outcomes of submacular haemorrhage (SMH) with loss of vision in neovascular age-related macular degeneration (nAMD) receiving intravitreal injections (IVT) of vascular endothelial growth factor (VEGF) inhibitor in routine clinical practice. METHODS Retrospective analysis of treatment-naïve eyes receiving IVTs of VEGF inhibitors (ranibizumab, aflibercept or bevacizumab) for nAMD from 1 January 2010 to 31 December 2020 that were tracked the Fight Retinal Blindness! registry. Estimated incidence, cumulative rate and hazard ratios (HR) of SMH with loss of vision during treatment were measured using the Poisson regression, Kaplan-Meier survival curves and Cox proportional hazard models. RESULTS We identified 7642 eyes (6425 patients) with a total of 135 095 IVT over a 10-year period. One hundred five eyes developed SMH with loss of vision with a rate of 1 per 1283 injections (0.08% 95% confidence interval [95% CI] [0.06; 0.09]). The estimated incidence [95% CI] was 4.6 [3.8; 5.7] SMH with loss of vision per year per 1000 treated patients during the study. The cumulative [95% CI] rate of SMH per patient did not increase significantly with each successive injection (p = 0.947). SMH cases had a mean VA drop of around 6 lines at diagnosis, which then improved moderately to a 4-line loss at 1 year. CONCLUSIONS Submacular haemorrhage (SMH) with loss of vision is an uncommon complication that can occur at any time in eyes treated for nAMD in routine clinical practice, with only limited recovery of vision 1 year later