Do managed clinical networks improve quality of diabetes care? : Evidence from a retrospective mixed methods evaluation

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Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun):a multicentre, single-blinded, randomised clinical trial

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods.METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete.FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA.INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden.FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.</p

Developing the specifications of an Open Angle Glaucoma screening intervention in the United Kingdom : a Delphi approach

PMID: 23216983 [PubMed - indexed for MEDLINE] PMCID: PMC3563574 Free PMC Article Acknowledgements We thank all the glaucoma specialists who took part in the Delphi process. We thank the Glaucoma screening Platform Study advisory panel including R Bativala, D Crabb, D Garway-Heath, M Griffiths, R Hitchings; S McPherson, A Tuulonen, A Viswanathan, H Waterman, R Wormald, D Wright for their guidance and contribution to the Delphi process and Luke Vale and Rodolfo Hernandez for their advice on development of the Delphi questionnaires. This paper was developed from the first phase of a project funded by the MRC (project reference G0701759) Developing the intervention & outcome components of a proposed randomized controlled trial of screening for open angle glaucoma. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health Directorates. The views expressed in this report are those of the authors and not necessarily those of the funders.Peer reviewedPublisher PD

Role of Abl Kinase and the Wave2 Signaling Complex in HIV-1 Entry at a Post-Hemifusion Step

Entry of human immunodeficiency virus type 1 (HIV-1) commences with binding of the envelope glycoprotein (Env) to the receptor CD4, and one of two coreceptors, CXCR4 or CCR5. Env-mediated signaling through coreceptor results in Gαq-mediated Rac activation and actin cytoskeleton rearrangements necessary for fusion. Guanine nucleotide exchange factors (GEFs) activate Rac and regulate its downstream protein effectors. In this study we show that Env-induced Rac activation is mediated by the Rac GEF Tiam-1, which associates with the adaptor protein IRSp53 to link Rac to the Wave2 complex. Rac and the tyrosine kinase Abl then activate the Wave2 complex and promote Arp2/3-dependent actin polymerization. Env-mediated cell-cell fusion, virus-cell fusion and HIV-1 infection are dependent on Tiam-1, Abl, IRSp53, Wave2, and Arp3 as shown by attenuation of fusion and infection in cells expressing siRNA targeted to these signaling components. HIV-1 Env-dependent cell-cell fusion, virus-cell fusion and infection were also inhibited by Abl kinase inhibitors, imatinib, nilotinib, and dasatinib. Treatment of cells with Abl kinase inhibitors did not affect cell viability or surface expression of CD4 and CCR5. Similar results with inhibitors and siRNAs were obtained when Env-dependent cell-cell fusion, virus-cell fusion or infection was measured, and when cell lines or primary cells were the target. Using membrane curving agents and fluorescence microscopy, we showed that inhibition of Abl kinase activity arrests fusion at the hemifusion (lipid mixing) step, suggesting a role for Abl-mediated actin remodeling in pore formation and expansion. These results suggest a potential utility of Abl kinase inhibitors to treat HIV-1 infected patients

A consensus-based transparency checklist

We present a consensus-based checklist to improve and document the transparency of research reports in social and behavioural research. An accompanying online application allows users to complete the form and generate a report that they can submit with their manuscript or post to a public repository

Origins Space Telescope: Baseline mission concept

The Origins Space Telescope will trace the history of our origins from the time dust and heavy elements permanently altered the cosmic landscape to present-day life. How did galaxies evolve from the earliest galactic systems to those found in the Universe today? How do habitable planets form? How common are life-bearing worlds? To answer these alluring questions, Origins will operate at mid-and far-infrared (IR) wavelengths and offer powerful spectroscopic instruments and sensitivity three orders of magnitude better than that of the Herschel Space Observatory, the largest telescope flown in space to date. We describe the baseline concept for Origins recommended to the 2020 US Decadal Survey in Astronomy and Astrophysics. The baseline design includes a 5.9-m diameter telescope cryocooled to 4.5 K and equipped with three scientific instruments. A mid-infrared instrument (Mid-Infrared Spectrometer and Camera Transit spectrometer) will measure the spectra of transiting exoplanets in the 2.8 to 20 μm wavelength range and offer unprecedented spectrophotometric precision, enabling definitive exoplanet biosignature detections. The far-IR imager polarimeter will be able to survey thousands of square degrees with broadband imaging at 50 and 250 μm. The Origins Survey Spectrometer will cover wavelengths from 25 to 588 μm, making wide-area and deep spectroscopic surveys with spectral resolving power R ∼ 300, and pointed observations at R ∼ 40,000 and 300,000 with selectable instrument modes. Origins was designed to minimize complexity. The architecture is similar to that of the Spitzer Space Telescope and requires very few deployments after launch, while the cryothermal system design leverages James Webb Space Telescope technology and experience. A combination of current-state-of-the-art cryocoolers and next-generation detector technology will enable Origins\u27 natural background-limited sensitivity

Mitochondrial Alterations in PINK1 Deficient Cells Are Influenced by Calcineurin-Dependent Dephosphorylation of Dynamin-Related Protein 1

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr